Skin Telocytes Could Fundament the Cellular Mechanisms of Wound Healing in Platelet-Rich Plasma Administration.

1. Introduction

Platelets have fundamental roles in homeostasis and thrombosis. This is evident in tissue injury caused by trauma or ischemia, like in lesions produced by myocardial infarction or stroke, when the coagulation system and immune responses activate very early, initiating the healing process. Platelets ( Figure 1 ) are fragments of thrombocytogenic megakaryocytes that are among the first cells that penetrate and accumulate within the lesioned tissue and, when activated, release a multitude of biologically active mediators into their microenvironment [ 1 ]. Apart from these traditional roles, in recent years, new and important ones have surfaced. Thrombocytes, through their growth factors (GFs), cytokines, antibiotic peptides, and extracellular matrix modulators are involved in a cascade of events starting with angiogenesis in damaged tissue, stabilizing blood vessels and restoration of connective tissue, the transformation of mesenchymal stem cells into fibroblasts, etc.

Also, more evidence suggests that platelets participate in regulating the balance between cell proliferation and cell apoptosis, the latter having a crucial role in immune tolerance with important implications in the correct regeneration of damaged tissue [ 2 , 3 , 4 , 5 ]. The recruitment, proliferation, and activation of smooth muscle cells (SMCs), mesenchymal stem cells (MSCs), and other cell types that participate in tissue regeneration are controlled by cytokines, chemokines, and growth factors released from the platelets. Pro-apoptotic mediators such as CD40 ligand (CD40L), Fas ligand (Fas L), tumor-necrosis-factor (TNF)-related apoptosis-inducing ligand (TRAIL), TNF-like weak inducer of apoptosis (TWEAK), and LIGHT (a member of the tumor necrosis factor superfamily), and antiapoptotic agents like hepatocyte growth factor (HGF), stromal-cell-derived factor-1 (SDF-1), serotonin, adenosine diphosphate, and sphingosine-1-phosphate are released from platelets, by which they modulate the balance between apoptosis and cell survival. In addition, platelet-derived microparticles (MPs) can induce apoptosis in endothelial cells (ECs) and SMCs and can provide survival signals to monocytes and stem cells [ 6 ]. All these data are relevant and may support the explanation of the complex tissue repair mechanisms that platelets are controlling. Granzyme B is also a mediator of platelet-induced apoptosis in the spleen and lungs. High-mobility group box 1 (HMGB1), a nuclear non-histonic protein, is a danger signal that is exported to the cell surface from platelets for activation and regulates apoptosis and autophagy in tumor cells (TCs), depending on its redox state. Thus, platelets are involved in the control of complex tissue repair mechanisms [ 6 ].

Moreover, in response to vascular injury, platelets become activated, secondarily releasing their granular content, amplifying the recruitment and activation of additional platelets, stabilizing clot formation, and initiating tissue repair processes. Prostaglandin E2 (PGE2), an important bioactive lipid produced by platelets and other cells during inflammatory responses, participates in the orchestration of vasodilation, which increases blood flow to the affected area, and the modulation of inflammation [ 7 ]. On the other hand, it has been shown that among endothelial cells, stimulated platelets are able to produce nitric oxide (NO), which is a limited inhibitor of platelet activation, but by reducing calcium levels, which is a major inhibitor of platelet recruitment [ 8 ]. Additionally, NO is a smooth muscle relaxant involved in vasodilatation and blood flow regulation [ 9 ],

We recently scrutinized the literature to assess the acknowledged mechanisms of tissue repair and remodeling induced by platelets administered through PRP. We considered not only the classical known mechanism orchestrated by cytokines, synthesized by growth factors, and secreted by platelets, but also a potential novel mechanism that implies the presumptive activation and recruitment of dermal telocytes (TCs)—a distinct type of interstitial cell with roles in tissue regeneration. TCs distinctiveness resides in their particular (ultra)structural features, their microRNA expression, and their proteomics and secretomics [ 10 ].

At the skin level, TCs are found in both the papillary and reticular dermis. This has been evidenced using various techniques. A transmission electron microscopy (TEM) investigation of the human dermis found TCs in constant spatial relations with vascular structures, immune cells, and/or adnexal structures [ 11 ]. However, the most particular structural feature of TCs is their unique structure combined with their particular cytokine profile [ 12 ]. TCs are still to be fully characterized and their roles within the interstitium to be fully understood, but they seem to be involved in tissue remodeling and regeneration, mainly by their pro-angiogenic potential.

2. PRP Plasma Biochemistry and Active Factors

The granular cargo of platelets is different in platelets’ granules. α-granules contain both membrane-bound proteins (usually expressed on the platelet membrane) and soluble proteins (which are secreted into the extra-platelet space) [ 13 , 14 , 15 ]. The platelets’ integral membrane proteins are mainly represented by most of the glycoproteins found in other cells. These glycoproteins are involved in platelet aggregation and adhesion, in thrombin generation, or in protein endocytosis [ 16 , 17 , 18 ].

3. The Composition of the Platelets’ α-Granules

The Golgi apparatus (specifically, the trans-Golgi network) represents the origin of α-granules. Thus, they have a secretory phenotype similar to late endosomes and lysosomes and are considered lysosome-related organelles similar to basophil granules, azurophil granules, melanosomes, Weibel–Palade granules, Odland bodies in keratinocytes, and lamellar bodies in type I pneumocytes [ 19 ]. Usually, they demonstrate similarities with these organelles, like endosomal filiation, the acid content due to the presence of various enzymes, and the protein composition of the lysosome membranes [ 20 ]. They develop from the former small granular precursors found within the cytoplasm of thrombocytogenic megakaryoblasts (MKs), which maturate α-granules and deliver them, by thrombopoiesis, to platelets for final packaging. The organelles that originate α-granules either accumulate different compounds via synthetic routes (e.g., von Willebrand Factor, β-thromboglobulin, or platelet factor 4—PF4), or acquire them by endocytosis, (e.g., albumin, fibrinogen, or immunoglobulin G) [ 21 ]. In terms of morphology, ultrastructural studies have indicated a few different types of α-granules, including tubular, spherical, and multivesicular subtypes [ 22 ]. The matured granules are released from the platelets in different pathological processes of hemostasis and wound repair, inflammation, tumor metastasis, or angiogenesis [ 23 ]. The dynamics of platelet secretion indicates their roles and functions, and their performant action in all processes they are involved in. Thus, we presume that the number, sequence, and amount of each of these factors that are released from platelets are orchestrating the steps of tissue regeneration/repair in terms cellular and molecular phenomena that feature in the healing process.

The platelets’ α-granules contain growth factors, chemokines, adhesion molecules, integral membrane proteins, coagulants, anticoagulants, and other molecules (summarized in Table 1 ).

3.1. Growth Factors

Growth factors, which are involved in regulating different cellular processes like cell proliferation, differentiation, and maturation, typically act as signaling molecules.

3.1.1. Platelet-Derived Growth Factor (PDGF), AA-AB-BB

The AA, AB, and BB are isoforms of PDGF and have been extensively studied in striated skeletal muscle cells. They have proven to have similar functions, stimulating osteoblast replication and DNA synthesis, and to have mitogenic activity (mainly observed in periosteum). However, in terms of functionality, PDGF BB is more potent than the AA and AB isoforms [ 24 ]. Thus, PDGF could promote the maintenance of and increase in the cellular pool of the osteoblastic lineage, being mitogenic for mesenchymal cells and osteoblasts, and perhaps explain the efficiency of PRP treatments in orthopedic pathology, where such treatments have proven to have noticeable benefits. Moreover, PDGF stimulates chemotaxis and mitogenesis in fibroblasts, glial cells, and smooth muscle cells [ 25 ], but also stimulates macrophage and neutrophil chemotaxis [ 26 ]. PDGF AB regulates collagenase secretion and collagen synthesis [ 27 ], through boosting the tissue regeneration/remodeling that are featured in (skin) PRP treatments. PDGF is found in platelets, in endothelial cells, macrophages, and smooth muscle cells [ 25 ].

3.1.2. Transforming Growth Factor β (TGFβ)

Transforming growth factor β (TGFβ) is a highly basic protein acting as a potent inhibitor for different cell types. TGFβ is contained by platelets’ α-granules but is also an extracellular matrix protein [ 28 ]. The TGFβ1 isoform is specific to human platelets and is found either complexed with both latent TGFβ-binding protein (LTBP) and the latency-associated peptide (LAP) or complexed only with LAP (without LTBP) [ 29 , 30 ]. TGFβ can be found in macrophages, T-lymphocytes, or keratinocytes [ 25 ]. TGFβ, through its four fasciclin1 domains, is involved in cellular proliferation, migration, adhesion, and differentiation, being implicated as a ligand for several integrins, collagen I, II, and IV, laminin, fibronectin, and glycosaminoglycan [ 31 , 32 ]. It was previously shown that the interaction between platelets and tumor cells helps promote the invasiveness and malignancy of the latter [ 33 ]. However, TGFβ inhibits the cell growth and proliferation of normal and malignant cells (including hematopoietic cells, macrophages, lymphocytes, and megakaryocytopoiesi) [ 25 , 34 ]. Moreover, TGFβ stimulates the proliferation of undifferentiated mesenchymal cells [ 35 ], regulating the endothelial-to-mesenchymal transition [ 36 ], or fibroblastic and osteoblastic mitogenesis [ 37 ] by mitogen-activated protein kinase (MAPK) pathway. Thus, TGFβ could act as a regulator of angiogenesis induced by PRP administration, maintaining an equilibrium between the old and newly formed endothelial cells. On the other hand, by the antagonistic effects on VEGF, TGFβ1 induces the rapid apoptosis of endothelial cells [ 38 ]. However, the inhibition of VEGF blocks angiogenesis and/or apoptosis induced by TGFβ1 [ 39 ]. Moreover, the TGFβ/Smad signaling pathway regulates collagen synthesis and its deposition into the interstitial structure [ 40 ].

3.1.3. Vascular Endothelial Growth Factor (VEGF)

Vascular endothelial growth factor (VEGF) is a homodimeric protein that is produced either by normal cells (e.g., platelets, leukocytes, macrophages, keratinocytes, or endothelial cells) or by tumor cells (which can synthesize great amounts of VEGF). The tumoral cells’ production of VEGF alters its plasmatic concentration levels, and thus VEGF serum levels could be predictive of cancer prognosis. However, VEGF is basically a key regulator of angiogenesis, since it stimulates neo-angiogenesis, contributing to an increased vascular permeability, as well as promoting endothelial cell viability, migration, and differentiation [ 41 , 42 , 43 ]. VEGF is normally released after the activation of thrombin by platelets. However, in many tumoral contexts, leukocytes are a more important source of VEGF, but in this case the newly formed tumoral blood vessels display many structural and functional aberrations [ 44 , 45 ]. Considering the positive expression of TCs for VEGF, it would be interesting to more deeply explore the structural outcomes regarding dermal TCs (or of stromal TCs with other locations) after administering PRP.

3.1.4. Epidermal Growth Factor (EGF)

Epidermal growth factor (EGF) is a small protein (of about 6000 Da) that is involved in cell development and differentiation [ 46 ]. EGF is synthesized by different cells (platelets, macrophages, and monocytes). Moreover, the cells of the human submaxillary glands and kidneys are the main sources of EGF (other secondary sources being epithelial cells of the duodenal Brunner glands and placenta). EGF is also present in body fluids like saliva, urine, and plasma [ 25 , 47 ]. After binding to its ligand and increasing the intracellular tyrosine kinase activity, thereby activating the signaling cascade and promoting the cell proliferation of keratinocytes, fibroblasts, endothelial cells, etc., angiogenesis also acts as a downregulator of apoptosis [ 48 ].

3.1.5. Fibroblast Growth Factor (FGF)

Fibroblast growth factor (FGF) is a signaling protein produced mainly by macrophages (but in smaller amounts it is also produced by platelets, mesenchymal cells, osteoblasts, and chondrocytes) [ 49 ]. FGF promotes endothelial cell proliferation, and along with other pro-angiogenic factors (e.g., VEGF), is involved in (neo-)angiogenesis, thus having potential biological functions in tissue repair/regeneration [ 49 , 50 ]. By connecting to the plasma membrane’s FGF receptors, it mainly activates the RAS/MAP kinase pathway, but also other intercellular signaling pathways, like the PI3K/AKT pathway and PLCγ pathway [ 51 ]. The published data on FGF indicate its involvement in modulating biological functions such as cell proliferation, survival, migration, and differentiation [ 52 ]. It is interesting the synergic effect this growth factor has (along with VEGF, EGF, and other pro-angiogenic molecules), perhaps in conjunction with the pro-angiogenic potential of other stromal cells (including TCs).

3.1.6. Connective Tissue Growth Factor (CTGF)

Connective tissue growth factor (CTGF) is a non-structural small protein (of 38,000 Da) that is dynamically expressed within the extracellular matrix and has signaling and regulatory implications. Platelets and fibroblasts contain CTGF and can release this protein after their activation. The current published data indicate an increased expression of CTGF in atherosclerotic blood vessels, and the level of expression is directly proportional to shear stress [ 50 , 53 ], but CTGF also has increased positive expressions in fibrotic disorders [ 15 ]. However, large normal blood vessels and developing blood vessels highly express CTGF mRNA, suggesting its involvement in angiogenesis and blood vessel structural maintenance processes [ 54 ]. CTGF has been shown to have roles in skeletogenesis [ 55 ], cell adhesion, proliferation, and wound repair [ 56 ]. Thus, CTGF could be involved in the structural recovery of the regressing interstitium.

3.1.7. Insulin-like Growth Factor (IGF-1)

Insulin-like growth factor (IGF-1) is a peptide hormone with roles in cell proliferation, differentiation, and migration, and is a typical constituent of platelets’ α-granules. Moreover, platelets express the IGF-1 receptor on their membrane, and it is assumed to be involved in the onset and amplification of platelets’ response to acute cardiovascular diseases [ 57 ]. IGF-1 is also secreted by the liver under the influence of growth hormone [ 58 ] and is secreted at the level of chondroblasts acting locally as a paracrine hormone [ 59 ].

3.1.8. Hepatocyte Growth Factor (HGF)

Hepatocyte growth factor (HGF) is a multifunctional cytokine involved in various biological mechanisms including cell proliferation, migration, and cell survival [ 60 ]. HGF is synthesized as a pro-HGF precursor by mesenchymal cells, and circulates within the serum, but can also be found within the connective tissue matrix, strongly bound to heparin sulfate [ 61 ]. Human platelets have a positive expression for HGFR on their membrane; thus, HGF acts as an inhibitor for platelets with some benefits in thromboses [ 62 ]. HGF is involved in endothelial/epithelial cell growth and mobility, as well as in morphogenesis and regeneration/repair skin processes through angiogenesis [ 63 , 64 ]. Its functions at least partially explain some of the regeneration/repair assets after PRP administration.

3.1.9. Keratinocyte Growth Factor/Fibroblast Growth Factor-7 (KGF/FGF-7)

Keratinocyte growth factor/fibroblast growth factor-7 (KGF/FGF-7) is a small proteic mitogen (28 kDa) produced by mesenchymal cells (e.g., fibroblasts) that acts as a protector for several types of epithelial cells (keratinocytes, enterocytes, and hepatocytes), also regulating their proliferation, migration, and differentiation [ 65 , 66 ]. KGF has also proven to exhibit reparatory capacities in lung epithelia, expressing protective and restoring capacities after radiotherapy thymic damage [ 67 ]. KGF stimulates the cells involved in angiogenesis, and by epithelial fibroblast growth factor receptor 2 (FGFR2) mediates epithelial–mesenchymal interactions [ 68 ]. However, FGFR2 is a tyrosine kinase receptor that is also required to bind with co-receptors (proteoglycans) for signal transduction [ 69 ]. KGF and other FGFs have mitogenic and motogenic properties, either in vivo or in vitro, but KGF is more potent and overexpressed in the early stages of wound healing [ 70 ]. Cytokines (IL-1 and IL-6), growth factors (PDGFβα, TGFα, and HGF) and hormones (steroid hormones, estrogen, progesterone, glucocorticoids, and androgens) regulate the expression of FGF7 in different tissues [ 68 ].

3.1.10. Angiopoietin-1 (ANG-1)

Angiopoietin-1 (ANG-1) is an angiogenic glycoprotein, along with angiopoietin-2, angiopoietin-3, and angiopoietin-4, all of which are members of the angiopoietin family [ 71 ]. ANG-1, together with VEGF, is involved in endothelium inflammation and blood vessel integrity [ 72 ]. ANG-1 has affinity for Tie-2 receptors (found on endothelial cells), by which ANG-1 influences the late stages of angiogenesis, but is also involved in the remodeling and stabilization of older blood vessels [ 73 ]. The tandem ANG-1/Tie-2 has roles in the activation and recruitment of pericytes to stabilize old blood vessels [ 74 ]. In addition to VEGF, platelet α-granules also contain ANG-1, the number of platelets in fact influencing the plasmatic concentration of both vascular active proteins [ 75 ]. ANG-1 is an important mediator of angiogenesis, maintaining endothelial cell integrity and having anti-inflammatory functions [ 76 ].

3.2. Chemokines

3.2.1. Growth-Regulated Protein Alpha (CXCL1/GRO α/KC/CINC-1)

Growth-regulated protein alpha (CXCL1/GRO α/KC/CINC-1) is a chemokine with angiogenic functions that interacts with CXCL2 and attracts neutrophils. Inter alia, the activity of CXCL1 is involved in the regulation of platelet function and is associated with tumoral angiogenesis [ 77 ]. Platelets in myeloproliferative neoplasms have an increased expression of CXCL1 associated with an elevated GRO-α production by CD56+/CD14+ monocytes, apparently with implications in disease progression [ 78 ].

3.2.2. Platelet Factor 4/Chemokine (C-X-C Motif) Ligand 4 (PF4/CXCL4)

Platelet factor 4/chemokine (C-X-C motif) ligand 4 (PF4/CXCL4), the first discovered chemokine, is a positively charged tetrameric chemokine protein belonging to a larger family of CXC chemokines [ 79 ]. PF4 produced by MKs is stored in α-granules and further transferred to platelets, which then release it after their activation [ 80 ]. However, PF4 can also be synthesized by monocytes [ 81 ]. Physiologically, PF4 promotes blood clotting, with roles in hematopoiesis, angiogenesis, hemostasis, and thrombosis. Moreover, PF4 has clear proinflammatory properties and has implications in innate/adaptive immunity [ 82 , 83 , 84 ]. However, PF4 is an important mediator of heparin-induced thrombocytopenia, a post-thrombotic side effect of a few therapies [ 79 ]. Usually, PF4 is involved in complexes with polyanion heparin and after binding to bacteria, PF4 induces specific antibodies that enhance bacterial phagocytosis [ 85 ].

3.2.3. Epithelial-Cell-Derived Neutrophil-Activating Peptide-78 (ENA-78)/C-X-C Motif Chemokine 5 (CXCL5)

Epithelial-cell-derived neutrophil-activating peptide-78 (ENA-78)/C-X-C motif chemokine 5 (CXCL5) is a potent neutrophil chemotactic molecule also found in the platelets’ α-granules. Initially, it was presumed to be exclusively synthesized by epithelial cells [ 86 ]. It binds to G-protein-coupled receptor CXCL2, leading to neutrophilic recruiting. It is also involved in angiogenesis and the development of capillary networks within lesioned tissue. Thus, it could represent a critical factor in tissue repair and regeneration or have major implications in connective tissue remodeling [ 87 ]. The involvement of CXCL5 in the pathogenesis and progression of inflammatory disorders was previously documented. This small chemotactic protein may contribute to repair and neovascularization processes and could represent a potential molecular target in regenerative medicine [ 88 ].

3.2.4. C-X-C Motif Chemokine 7 (CXCL7)/Neutrophil-Activating Peptide 2 (NAP-2)

C-X-C motif chemokine 7 (CXCL7)/neutrophil-activating peptide 2 (NAP-2) regulates neutrophil recruitment after vascular injury, by activating CXC chemokine receptor 2 (CXCR2) and binding to sulfated glycosaminoglycans (GAGs) [ 89 ]. Additionally, the interaction with GAGs dictates the affinity of CXCL7 for CXCR2, and therefore it regulates the migration of neutrophils within the thrombus, promoting tissue repair and minimizing tissue damage and disease [ 90 ].

3.2.5. C-X-C Motif Chemokine 8 (CXCL8)/Interleukin-8 (IL-8)

C-X-C motif chemokine 8 (CXCL8)/interleukin-8 (IL-8) plays definitory roles in tissue response to injury, being the most important neutrophil-attracting and activating chemokine [ 91 ]. It interacts with CXCR1, CXCR2, and GAGs, being involved in regulating the cell adhesion, chemoattraction, and activation of leukocytes [ 92 ]. On the other hand, CXCL8 may possess angiogenic properties by stimulating the proliferation of endothelial cells and/or the endothelial-to-mesenchymal transition, leading to the formation of new blood vessels, or cell migration to damaged tissue, thus favoring the entire process of tissue repair/regeneration [ 93 ].

3.2.6. Stromal-Cell-Derived Factor 1 α/C-X-C Motif Chemokine 12 (SDF-1α/CXCL12)

Stromal-cell-derived factor 1 α/C-X-C motif chemokine 12 (SDF-1α/CXCL12) is a chemokine expressed by fibroblasts, stromal cells, and endothelial cells, but also found within platelets’ α-granules. SDF-1α is a strong chemotactic cytokine for leukocytes, hematopoietic progenitor cells, that provides angiogenic support through its involvement in endothelial cell proliferation [ 25 , 94 ]. Actually, SDF-1α is a growth stimulator of pre-B lymphocytes and a chemoattractant for T-lymphocytes, monocytes, and hematopoietic stem cells [ 95 ]. Platelet-derived SDF-1α is involved in stem cell adhesion phenomena, also having implications in the differentiation of CD34+ cells into endothelial cells [ 96 , 97 ]. In cell culture, SDF-1α combined with thrombopoietin was demonstrated to favor the development of CD34+ cells [ 98 ]. Moreover, SDF-1α expression is involved in stem cell recruitment and homing after myocardial infarction, in cardiomyocytes death, and in scar remodeling [ 99 ]. Apparently, SDF-1α and PRP demonstrate synergy in bone regeneration/repair by promoting angiogenesis [ 98 ], this association having promising results for in situ regenerative/repair therapies.

3.2.7. Monocyte Chemoattractant Protein (MCP-1)/Chemokine C-C Ligand-2 (CCL2)

Monocyte chemoattractant protein (MCP-1)/Chemokine C-C ligand-2 (CCL2) is involved in chemotaxis of immune and inflammatory cells including monocytes, migration of monocytes and their transforming into macrophages [ 100 ]. In breast cancer CCL2 acts as a promoter of metastasis [ 101 ]. CCL2 also represents a proinflammatory cytokine that promotes the accumulation of inflammatory infiltrates and has immunomodulatory effects, stimulating the expression of adhesion molecules in monocytes, and stimulating the secretion of other such cytokines.

3.2.8. Macrophage Inflammatory Protein-1α (MIP-1α)/Chemokine C-C Ligand-3 (CCL3)

Macrophage inflammatory protein-1α (MIP-1α)/Chemokine C-C ligand-3 (CCL3) is involved in pathogenesis of a few inflammatory conditions such as multiple myeloma and rheumatoid arthritis. MIP-1α could also have diagnostic potential in these diseases and gained its applicative potential as biomarker [ 102 ]. CCL3 could have important roles in the progression of hematopoietic malignancies [ 103 ].

3.2.9. Chemokine C-C Ligand-5 (CCL5)/Regulated on Activation, Normal T-Cell Expressed and Secreted (RANTES)

Chemokine C-C ligand-5 (CCL5)/Regulated on Activation, Normal T-cell Expressed and Secreted (RANTES) is a proinflammatory chemokine secreted by platelets and intensely involved in immunoregulatory and inflammatory processes by recruiting immune cells to inflammation sites. CCL5 is ligating the P-selectin and thus is favoring the development of monocyte–macrophage inflammatory infiltration [ 104 ]. Usually CCL5/RANTES aggregates can be found in the presence of cell surface GAGs [ 105 ].

3.3. Adhesion Molecules

3.3.1. Fibrinogen

Immune electron microscopy and cell fracturing studies indicated the presence of fibrinogen within α-granules. However, only 3% of circulating fibrinogen is stored in platelets [ 106 ]. Platelet fibrinogen is provided by circulating plasma, but fibrinogen uptake could occur either in platelets or MKs [ 107 ]. Previous published studies documented fibrinogen uptake by platelets after plasmatic fibrinogen infusion. On the other hand, MKs can also incorporate fibrinogen into α-granules [ 22 ]. However, within the α-granule matrix, fibrinogen (together with other active factors like TNFα, TGFβ, and PF4) is uniformly distributed and frequently colocalized with VAMP8 [ 108 , 109 ].

3.3.2. Thrombospondin

Thrombospondin is a modular glycoprotein responsible for different functions of platelets and other cells. Thrombospondin is produced by MKs and is stored in α-granules, having important roles in aggregation, agglutination, the adhesion of platelets, and facilitating cell proliferation and motility [ 110 ]. At vascular injury sites, thrombospondin regulates hemostasis by the modulation of cyclic adenosine monophosphate (cAMP) [ 111 ].

3.3.3. The von Willebrand Factor (vWF)

The von Willebrand factor (vWF) circulates either in plasma (being synthesized by endothelial cells) or is deposited within the α-granules of platelets (which are synthesized by MKs). The vWF bridges platelets and acts as a pro-aggregant factor [ 112 ]. Supplementarily, the vWF carries and protects coagulation factor VIII from degradation. Moreover, the vWF is involved in acute thrombolysis in blocked blood vessels, thus mitigating the damage produced by ischemia/reperfusion injury in infarcted tissue areas [ 113 ].

3.4. Integral Membrane Proteins

3.4.1. Integrin αIIbβ3

Integrin αIIbβ3 is a signaling transmembrane glycoprotein that transmits information through platelet plasma, being highly expressed on the membrane of resting platelets [ 114 ], and in the open canalicular system and the α-granules [ 115 ]. Integrin αIIbβ3 has roles in tumor metastasis, platelet aggregation, hemostasis, and thrombosis. After activation, αIIbβ3 will ligate fibrinogen, fibrin, or the von Willebrand factor. The presence of this activated integrin represents a sign of platelet responsiveness [ 116 ].

3.4.2. Glycoprotein (GP)Ib-IX-V Complex

Glycoprotein (GP)Ib-IX-V complex is in fact the receptor for the von Willebrand factor, present on the plasma membrane of the platelets (also found in MKs). Dysfunctional or absent complexes result in macrothrombocytopenia from Bernard–Soulier syndrome, a congenital bleeding disorder [ 117 ]. This integrin regulates the adhesivity of monocytes, thrombin activity, and the polarization of macrophages [ 118 ].

3.4.3. Triggering Receptor Expressed on Myeloid Cells (TREM)-like Transcript 1 (TLT-1)

Triggering receptor expressed on myeloid cells (TREM)-like transcript 1 (TLT-1) belongs to a type I class of transmembrane proteins involved in adaptive immune responses. TLT-1 is exclusively expressed in MKs, which deliver it to the interior of platelet α-granules. Usually, it is transported onto the plasma membrane after platelet activation [ 119 ]. TLT-1 plays roles in platelet aggregation and hemostasis and uniquely acts in inflammatory bleeding [ 120 ].

3.4.4. P-Selectin

P-selectin is a platelet-specific transmembrane protein located on the membrane of α-granules and can also be found in the Weibel–Palade granules of endothelial cells [ 121 , 122 ]. After platelet activation, P-selectin is transferred to the platelet plasma membrane where it acts as a recruiter of leukocytes (in injured blood vessels), but also acts as a receptor for neutrophils and monocytes [ 123 ]. The susceptibility to form platelet tumor cell microthrombi is reduced when P-selectin is absent [ 124 ]. P-selectin also participates in platelet recruitment and aggregation by promoting the bonds between platelets and fibrin or between multiple platelets at the site of endothelial injury. It also plays a role in the recruitment of leukocytes [ 125 , 126 , 127 ].

3.5. Coagulants and Anticoagulants

3.5.1. Platelet Factor V

Platelet factor V is activated by thrombin and binds to activated platelets. It is mostly produced by liver MKs [ 128 ]. It plays dual roles in hemostasis, having both procoagulant and anticoagulant properties. The normal function of factor V contributes to the regulation of the coagulation cascade. It plays roles in platelet activation and could be a potential therapeutic target to prevent arterial thrombosis [ 129 ].

3.5.2. Factor IX (Christmas Factor)

Factor IX (Christmas factor) is a serine protease belonging to the coagulation system produced in the liver. Post-translational changes modify the factor, which is secreted into circulation [ 130 ]. It determines the rate of thrombin formation [ 131 ].

3.5.3. Factor XIII

Factor XIII is represented by a transglutaminase, which cross-links the fibrin network. It is activated by the thrombin cleavage and stabilizes the organization of the blood clot [ 132 ]. Moreover, it is involved in the further protection of the blood clot being degraded in the coagulation cascade [ 133 ]. Factor XIII has significant roles in angiogenesis and wound healing. Additionally, in bone tissue it is responsible for matrix stabilization [ 134 ].

3.5.4. Growth Arrest Specific-6 (Gas6)

Growth arrest specific-6 (Gas6) is a protein that belongs to the vitamin-K-dependent protein family, and it has a structural resemblance to the anticoagulant of protein S, but it shows no anticoagulant functions [ 135 ]. Gas6 binds to tyrosine kinase receptors (Tyro3, Axl, and Mer) which activate the intracellular PI3K and Akt pathways. Thus, losing Gas6 functionality (by reducing platelet granule secretion) affects platelet aggregates, and blocking its receptor Gas6-R–αIIbβ3 integrin reduces thrombotic events [ 136 ]. Previous published data indicated the involvement of Gas6 in the etiology of various diseases (e.g., rheumatoid arthritis, breast cancer, etc.) [ 137 ].

3.6. Antimicrobial Agents

Beyond the well-acknowledged platelet function in vascular integrity and functionality, there is also an important body of published data indicating platelets’ active molecular response to microorganisms. These molecules fall into the groups of kinocidins, represented by the antimicrobial chemokines thrombocidin-1 (TC-1) and thrombocidin-2 (TC-2), and cationic host defense peptides (CHDPs), represented by the defensins and cathelicidins that are initially synthesized as immature peptides [ 138 ]. This antimicrobial capacity was experimentally tested against bacteria and fungi, and a structural and functional similarity between granulocytes and platelets confirmed the former results. The thrombin-activated platelets secrete platelet factor 4 (PF4) and connective-tissue-activating peptide 3 (CTAP-3), which act synergically in the platelet’s antibacterial capacity [ 139 ]. On the other hand, platelets recognize microorganisms by the damage-associated molecular patterns (DAMPs) they produce. DAMPs interfere with different platelet receptors like toll-like receptors (TLRs), among them TLR2 and TLR4 being the best described C-type lectin receptors, hemostatic platelet receptors GP Ib (glycoprotein Ib), and NLRs (NOD [nucleotide-binding oligomerization domain]-like receptors) [ 140 ].

3.7. Inflammatory/Immune Agents

There is progressively increasing evidence that platelets play crucial roles in the regulation of immunity and inflammatory responses. Platelets express in α-granules immune mediators like complement precursors C3, C4, C1 inhibitor, immunoglobulin G, etc. [ 141 ]. Platelets can bind pathogens like bacteria through synthesizing IgG to opsonize E. Coli [ 142 ], or through P-selectin, which ligates S. aureus [ 143 ], etc.; a large variety of viruses, including enteroviruses, influenza A viruses, coronaviruses, human immunodeficiency virus type-1 (HIV-1), herpes simplex virus type 1, etc. [ 144 ]; and parasites, contributing to the regulation of parasitemia, by binding to Plasmodium parasites species, thereby contributing to the intracellular accumulation of PF4 [ 145 ]. Moreover, TNFα, a proinflammatory molecule, can activate tissular pro-coagulant molecules, which can hyper-activate platelets through the endothelial cell’s molecular expression of anticoagulant molecules [ 146 ]. However, it will be interesting to document the interaction between pharmaceutical agents like non-steroidal anti-inflammatory drugs (NSAIDs) and PRP administration, in terms of the potential alteration of the PRP secretome induced by NSAIDs. Presently, it is well known that NSAIDs enhance TNFα production and its roles, presumably also in injected PRP [ 25 ].

4. Composition of Platelets’ Dense δ-Granules

Dense granules are electron-dense spherical vesicles of about 200 nm and are the second most abundant platelet organelle. δ-granules contain molecules involved in both homeostasis (evidenced by the bleeding propensity, which features in a few hematologic diseases—e.g., Chediak–Higashi syndrome, which exhibits a deficit of platelets’ dense granules) and thrombosis through the inhibition of arterial thrombosis by ADP, etc. Platelets’ δ-granules are maturated within MKs and then transferred to enucleated cells. The early endosomes contribute to the formation of δ-granules [ 147 ] and they also share lysosomal features; thus, dense granules are considered lysosome-related organelles, having and acidic content and housing lysosomal enzymes (e.g., tetraspanin CD63) [ 148 ].

These dense granules are small secretory deposits within platelets that harbor small molecules necessary for effective hemostasis ( Table 2 ).

4.1. Nucleotides

4.1.1. Adenosine Triphosphate (ATP)

The secretion of ATP (together with ADP) is a prerogative for platelet aggregation. ATP promotes the interaction between platelets, contributing to thrombus formation [ 149 ]. ATP, via P2X1 receptor, can activate platelets and inhibit the ADP platelet activation pathway, increasing the influx of Ca 2+ within platelets [ 150 ].

4.1.2. Adenosine Diphosphate (ADP)

Adenosine diphosphate (ADP) is usually contained by dense δ-granules serving as the primary source of ADP, since ADP is credited as a platelet aggregation factor, having multiple roles in hemostasis and thrombosis [ 151 , 152 ]. Platelets present plasma membrane P2Y receptors (P2Y1 and P2Y12) for ADP that are responsible for partial or full platelet aggregation. Another receptor, P2X1, which is activated by ATP, is responsible for the rapid influx of Ca 2+ and produces platelet shape modification or platelet collagen activation by shear conditions [ 153 ]. During platelet activation, the granules containing ADP move towards the center of the cell and deliver ADP to the open canalicular system [ 154 ]. Other previous published data indicated ADP as an influential factor that regulates the release of VEGF from platelets’ α-granules. Moreover, it seems that ADP regulates the preferential release of other angiogenic promoters from platelets [ 155 ].

4.1.3. Cyclic Adenosine Monophosphate (cAMP)

Cyclic adenosine monophosphate (cAMP) is a small hydrophilic molecule that acts as a second messenger within cells, being involved in cellular biological processes through intracellular signaling induction. cAMP is an important inhibitor of the platelet activation pathway [ 156 ].

4.1.4. Uridine Triphosphate (UTP)

Uridine triphosphate (UTP), stored within the δ-granules of platelets, may antagonize P2Y12 receptor binding and, through cAMP, is involved in platelet aggregation. UTP could also antagonize collagen-induced platelet aggregation [ 157 ].

4.1.5. Guanosine-5′-Triphosphate (GTP)

Guanosine-5′-triphosphate (GTP), found in δ-granules, participates in platelet activation and could be involved in eliciting platelet degranulation [ 158 ]. There are similarities between the thrombin molecule and the molecule of GTP. Considering this, it was hypothesized that GTP could be involved (in permeabilized platelets) in diacylglycerol formation that, through 1,4,5-inositol triphosphate, stimulates Ca 2+ entry into platelets [ 159 ].

4.2. Bioactive Amines

4.2.1. Serotonin (5-hydroxytryptamine)

Serotonin (5-hydroxytryptamine) is a biogenic amine with a broad spectrum of functions. Platelets transport and store significant concentrations of serotonin within δ-granules. By storing serotonin, platelets regulate and maintain the low concentration of plasma serotonin [ 160 ]. Abnormal concentrations of plasma serotonin can be found in sepsis, thrombosis, and myocardial infarction [ 161 ]. Serotonin is implicated in platelet development, especially in increasing their procoagulant activity by interacting with tissue factor, with significant involvement in thrombus formation [ 162 , 163 ]. On the other hand, many previously published data cited serotonin as an efficient vasoconstriction factor, mainly acting on venules and large blood vessels, possibly due to direct action on smooth muscle, the amplification of the muscle constriction mechanism, or the stimulation of the secretion of endogenous vasoconstrictors [ 163 ].

4.2.2. Histamine

Histamine is stored in dense granules and is released, together with many other newly generated molecules, by thrombin activation. The platelet secretion of histamine could be regulated by immunological or aggreging factors and can explain some clinical findings in allergic vasculitis. However, histamine stimulates platelet aggregation through particular binding to the receptors of H 1 antagonists [ 164 ].

4.2.3. Phosphates (Polyphosphate, Pyrophosphate)

Phosphates (polyphosphate, pyrophosphate) are contained by normal human platelets, and they share biochemical and ultrastructural similarities with bacterial acidocalcisomes (documented with calcium- and proton-accumulating features) [ 165 ]. Polyphosphate is an important inductor of coagulation; thus, the possibility of neutralizing it could represent one molecular target against thrombosis (but without disrupting hemostasis) [ 166 ]. However, a potent inorganic pyrophosphate is present in δ-granules at a concentration of 1.4–3.1 nmol/10 8 platelets and is not released by thrombin stimulation [ 167 ].

4.3. Ions

Dense granules also contain a high concentration of cations, particularly Ca 2+ (but also Mg 2+ , K + , and P + [ 168 , 169 , 170 ]. Similar to in other cells, Ca 2+ is involved in the external discharge of granules. The release of granules seems to be Ca 2+ -dependent under specific circumstances (e.g., enzyme-induced sensitivity) [ 168 ]. Moreover, the aggregation of human blood platelets seems to be influenced by divalent cations (Ca 2+ , Mg 2+ ) [ 171 ].

5. The Composition of the Platelet’s Lysosomes

Besides α-granules and δ-granules, like other cells, platelets contain lysosomes [ 172 ]. They are membrane-bound organelles that contain highly glycosylated proteins (enzymes) that are involved in the degradation of different constituents (proteins, carbohydrates, and phosphate esters) while protecting the lysosomal endomembrane [ 173 ]. The contents of these lysosomes are released from platelets after their activation, helping to achieve their functions, including when they are delivered in PRP.

6. Platelet T-Granules

T-granules represent a relatively recently described system of electron-dense tubules within platelets. T-granules consist of, inter alia, TLR9, VAMP7, and VAMP8, which are involved in the regulation of platelet distribution upon their activation [ 21 ]. Mammal platelets show (either human or murine) the positive expression of toll-like receptors (TLRs). Moreover, TLRs are upregulated during proplatelet production [ 174 ]. It was previously shown that the contact of platelets with collagen IV determines the overexpression of surface TLR9 and CD62P [ 175 ]. Moreover, T-granules exclusively contain protein disulfide isomerase (PDI), which is a major contributor to thrombus formation [ 176 ].

7. The Physiological Process of Skin Repair/Regeneration

The skin is a multifaceted organ, the largest of the human body. External threats to this protective barrier are represented by harmful UV radiation, intrusive pathogens, heat, and trauma. Notably, apart from providing a protective envelope, the skin is vital in safeguarding internal organs. Being the first line of defense against the external world, the skin is persistently at risk of damage, making the wound repair process indispensable. Gaining a deeper insight into the cellular and molecular dynamics of wound repair can pave the way for interventions that expedite the healing and regeneration process. This knowledge can be particularly beneficial for severe burn victims or amputees, especially when confronted with substantial tissue damage and scar formation.

Wound repair is an evolutionary process shared across species, encompassing stages that overlap in both time and space. These stages include inflammation, coagulation, and the dual process of cellular proliferation combined with extracellular matrix (ECM) restructuring [ 177 , 178 ]. Yet, the outcome of skin wound healing varies among different species. Some primitive vertebrates, such as zebrafish and certain amphibians like axolotls and xenopus, have the remarkable ability to regenerate their skin flawlessly. For instance, the full-thickness skin removal in these species is followed by the regeneration of the entire skin, together with its secretory structures [ 179 , 180 ]. Intriguingly, within this regenerative process, even the distinctive skin pigmentation patterns can be perfectly restored. Similarly, injured zebrafish skin not only reclaims its striped pigmentation but also regenerates the underlying fat cells and scales. It eventually results in normally structured and healed skin that is nearly identical to the previously un-lesioned skin [ 181 ].

While certain vertebrates demonstrate an impressive capability for skin regeneration, adult mammals, including humans, typically do not have such regenerative prowess. In most adult mammals, wounds often culminate in scar formation, usually characterized by skin appendages. While these scars serve the basic protective function of the skin, warding off infections and preventing dehydration, their presence is not entirely featured by benignity. Owing to their pronounced deviation from the native skin in appearance, scars, especially from severe burns or injuries, can lead to significant cosmetic and psychological distress, thereby affecting an individual’s overall quality of life.

The importance of skin appendages transcends mere aesthetics, playing pivotal roles in the skin’s biology and physiology. Nevertheless, epithelial skin appendages are sources of epidermal cells, contributing to the process of wound repair. Structures like hair follicles and sebaceous glands have roles beyond aesthetics, functioning either as a sensory element due to the special interactions they have with nerve endings, or as thermoregulatory units [ 182 , 183 ]. Consequently, the emergence of scars inhibits the full restoration of the skin’s multifaceted functions.

8. Cellular and Biochemical Milieu of Skin Repair/Regeneration Scene

Wound healing is a multi-step process, and it is crucial to grasp the initial cues that spark the cellular reaction in injured tissue. The activation of transcriptional systems is progressive. Consequently, the wound initially triggers transcription-independent pathways for immediate activation. Primary among these is Ca 2+ waves, reactive oxygen species (ROS) gradients, and purinergic signals. Within the first moments following the injury, there is a surge in intracellular Ca 2+ at the wound’s periphery, which then radiates towards its center [ 184 ].

Various signaling molecules, released by the damaged cells, play a pivotal role in attracting inflammatory cells to the wound site, neutrophils being the major cellular population. The involved signaling molecules, termed damage-associated molecular patterns (DAMPs), encompass a wide range of components such as DNA, peptides, components of the extracellular matrix (ECM), ATP, and uric acid. Hydrogen peroxide (H 2 O 2 ) and lipid mediators, along with chemokines, are also released by the injured cells, further facilitating this recruitment [ 185 ]. Research involving multiple organisms has highlighted the importance of the swift generation of H 2 O 2 at the wound site. Not only does this serve as a defense against potential infections, but it also propels the regeneration of keratinocytes, draws in neutrophils, and aids in the formation of new blood vessels [ 186 ].

8.1. Neutrophils

Neutrophils are only transient within the human dermis, and they originate from bone marrow promyelocytes. In the case of injury or infection, neutrophils are swiftly mobilized to act as the first line of defense. This recruitment is prompted by signals known as “find me” cues, which include DAMPs, H 2 O 2 , lipid mediators and chemokines emitted from affected areas [ 187 ]. Neutrophils are equipped with more than 30 different surface receptors, such as G-protein-coupled receptors (GPCRs), Fc receptors, integrins, and pattern recognition receptors, enabling them to sense these injury-induced signals. About 24 h after the injury, neutrophils account for approximately 50% of all cells within the wound site [ 188 ]. Once activated, these cells can release compounds that both prolong and amplify further neutrophil migration to the site [ 187 ]. To combat infectious agents, neutrophils employ various mechanisms like toxin granule release, initiating oxidative bursts, undergoing phagocytosis, and forming neutrophil extracellular traps (NETs).

During their maturation, neutrophils form distinct granules, each packed with specific agents designed for dedicated functions. Azurophilic (primary) granules are the first formed while the neutrophil is still maturing in the bone marrow and [ 189 ] are the latest to be secreted. Their primary role is intracellular bacterial destruction, merging their action to that of phagolysosomes. These granules contain components like myeloperoxidase, azurocidin, lysozyme, bacterial permeability-increasing protein, and several serine proteases, including cathepsin G, elastase, and protease 3 [ 190 ]. Subsequently, the secondary (or specific) granules are later formed, housing human cationic antimicrobial protein (hCAP-18), lactoferrin, matrix metalloproteinase 8 (MMP-8), and collagenase-2 [ 191 ]. Gelatinase is a marker for terminal neutrophil differentiation, and gelatinase granules are specialized for MMPs with gelatinase activity [ 192 ]. The final developed granules are secretory vesicles, which pack integrins, growth factors, and cytokine receptors for swift release from the cell [ 193 ].

Proteases, constituting a significant portion of the toxic granules in neutrophils, play a dual role in their activity. These enzymes are crucial for antimicrobial actions and for the degradation of the basement membrane and the extracellular matrix (ECM). This degradation facilitates neutrophils to cross from blood vessels into the affected tissue [ 194 ]. Additionally, proteases act as activators for matrix metalloproteinases (MMPs) and simultaneously inhibit protease inhibitors, intensifying the proteolytic activity. Studies involving elastase knockout mice have revealed a diminished neutrophil capability in bacterial clearance [ 195 ], highlighting the crucial role that elastase plays in the wound healing process. Nonetheless, an overproduction of proteolytic enzymes sourced from neutrophils, especially as observed in chronic wounds, can have detrimental effects. This excessive enzyme production can lead to the cleavage of growth factors, their respective receptors, and the ECM. Such cleavage impedes vital vascular activities, disrupts blood circulation, and inflicts tissue damage [ 196 ].

When activated, neutrophils also release neutrophil extracellular traps (NETs). These are intricate structures formed from chromatin fibers that spread into the extracellular domain. Laden with histones, cytosolic proteins, and proteases, NETs serve as a primary function of attracting and neutralizing foreign pathogens, including bacteria, fungi, and viruses. This extracellular trap mechanism is an essential part of the immune response, offering a unique way to combat invading microorganisms beyond traditional phagocytosis [ 197 , 198 ].

8.2. Macrophages

Macrophages are immune cells with a particular immunophenotype, being CD45-positive/CD11b-positive/CD66b-negative. Within a normal course of wound progression, the peak of the accumulation of macrophages within an injury site was 24–48 h [ 199 ]. For example, in young and healthy mice, wounds typically closed within 14 days. The macrophage concentration within the wound peaked around day 3, then reduced by day 5, and nearly returned to base levels by day 10. This macrophage surge can be attributed to both the proliferation of local tissue-resident macrophages and the recruitment of monocytes from bone marrow [ 200 ].

The exact role of tissue-resident macrophages during wound healing remains somewhat ambiguous. It is speculated that these macrophages, present in the skin since embryonic development, proliferate during wound healing. However, definitive evidence is still pending. Most of this research focuses on monocytes that differentiate into macrophages once inside the wound [ 201 , 202 ]. These monocytes are lured to the wound in reaction to degranulation events from platelets and mast cells, elevated levels of hypoxia-inducible factors, and the presence of chemokines like stromal-derived factor 1 (SDF1/CXCL12). Wound-residing macrophages also play a role in summoning more monocytes, intensifying the macrophage-mediated inflammatory response through the secretion of powerful chemoattractant(s), such as monocyte chemoattractant protein (MCP)-1 [ 203 ].

Macrophages hold significant importance in standard wound healing and tissue rejuvenation. In vivo experiments on mice, involving subjects deliberately depleted of macrophages, revealed delayed wound closure [ 204 , 205 ]. Such macrophage-deficient wounds manifested a compensatory neutrophil influx, coupled with a decline in angiogenesis, granulation tissue formation, collagen layering, and growth factor secretion [ 206 , 207 ]. On the other hand, artificially boosting the count of monocytes or macrophages in wounds can notably hasten the healing process in both typical and diabetic mice wounds [ 208 ]. Observations from other species align with these findings. In salamanders, a complete macrophage depletion post-limb amputation prevents limb regeneration. Remarkably, restoring the endogenous macrophage population post-amputation in these previously depleted salamanders can reinstate limb regeneration capabilities [ 209 ].

Macrophage malfunction is distinctly apparent in the compromised healing processes seen in diabetic wounds. Diabetic wounds manifest a temporal delay in the expression of chemokines essential for both monocyte attraction and macrophage stimulation [ 210 ]. This lag in macrophage recruitment results in postponed efferocytosis—the process by which dead or dying cells, such as neutrophils, as well as ECM and wound debris, are cleared away. Consequently, the transition to the proliferative phase of wound healing is delayed [ 211 ]. Over time, this leads to the establishment of a persistent inflammatory state, with both macrophages and apoptotic cells continuing to be dominant even during the remodeling phase of wound healing [ 212 ]. Furthermore, the macrophages present in diabetic wounds are not as efficient as in non-diabetic wounds. Their ability to release growth factors is hindered, and they are less effective in fostering neovascularization [ 213 ]. This compromised functionality further exacerbates the challenges associated with wound healing in diabetic patients.

8.3. Mast Cells

Mast cells play a pivotal role in skin defense, during the initial stages of wound healing. They release antimicrobial peptides that act as a protective barrier against potential skin infections [ 214 , 215 , 216 ]. Integral enzymes like chymase and tryptase, synthesized by mast cells, facilitate the breakdown of the biochemical components of the ECM. Moreover, these cells produce histamines and VEGF, which increase vascular permeability and facilitate neutrophil infiltration into the wound site [ 217 , 218 ]. It has been found that mast-cell-derived histamine actively promotes the proliferation of keratinocytes, with crucial implications in the wound re-epithelialization process [ 219 ]. Additionally, mast cell tryptase and histamine have been demonstrated to amplify fibroblast proliferation and boost collagen synthesis. This heightened activity is crucial in promoting and progressing wound contraction [ 220 , 221 ].

However, there is also a downside to this increased mast cell activity. Published data indicated that elevated numbers of mast cells have been linked to scarring and skin fibrosis [ 217 ]. Their impact on scar development was evaluated using a fetal wound healing model. According to this model, while wounds inflicted on mice on embryonic day 15 healed without forming scars, those on embryonic day 18 resulted in scarring. Intriguingly, introducing mast cell lysate into the day 15 wounds prompted a transition from scar-free healing to scar generation. In contrast, depleting the mast cells on embryonic day 18 led to diminished scar formation [ 222 ]. While these experiments underline the significant involvement of mast cells in scar development, the exact mechanisms remain to be fully elucidated. Additionally, the influence of mast cells on chronic wounds has not been extensively explored [ 223 ]. Preliminary findings suggest diminished mast cell numbers and reduced degranulation during diabetic wound healing. However, more comprehensive studies are needed to delineate their role in cases of compromised wound healing [ 224 ].

8.4. Langerhans Cells

Langerhans cells, resident in the epidermis, act as cellular sentinels, monitoring for pathogens and orchestrating contact hypersensitivity reactions [ 225 ]. Originating from early myeloid progenitors (EMPs) during embryogenesis, these cells migrate into the epidermis [ 226 ]. Throughout adulthood, their presence and density within the epidermis are predominantly governed by signaling from proximate keratinocytes [ 227 ]. When these cells recognize antigens, there is a downregulation of e-cadherin expression, which otherwise anchors them to keratinocytes [ 228 ]. This modulation facilitates their transit from the epidermis, through the dermis, culminating in their eventual arrival at the draining lymph nodes. Here, they play a seminal role in kindling a T-cell-driven adaptive immune response [ 226 , 229 ].

Apart from the resident dendritic cells (DCs), there is another variant, plasmacytoid dendritic cells (pDCs), which are not typically found in skin, in physiological conditions. However, these cells are ushered into the skin post-injury or during an infection [ 230 ]. After skin injury, the wound witnesses an immediate, albeit transient influx of pDCs. These pDCs, in reaction to self-nucleic acids liberated by the injured cells, become activated. This activation leads them to produce interferon (IFN)-α/β, facilitated by TLR7 and TLR9 receptors [ 230 ]. The experimental depletion of pDCs during the wound healing process has shown significant damping of the acute inflammatory cytokine response, leading to a lag in wound re-epithelialization [ 231 ].

8.5. Dendritic Epithelial T-Cells (DETCs)

Dendritic epithelial T-cells (DETCs) play a pivotal role in the immediate response following skin injury. When the skin is wounded, the affected keratinocytes exhibit an increase expression of specific ligands, notably SKINTs and CD100. This elevation in ligand expression triggers the activation of DETCs [ 232 , 233 ]. Within the first 24–48 h post-injury, there is a discernible transformation in the morphology of DETCs from a dendritic shape to a more rounded silhouette [ 234 ]. Upon activation, these DETCs become sources of various growth factors, e.g., keratinocyte growth factors (KGFs). Among these, KGF-1, KGF-2, and insulin growth factor-1 (IGF-1) stand out for their significant influence in boosting the proliferation of keratinocytes in the wound vicinity [ 235 , 236 ]. The crucial role of DETCs in wound healing can be emphasized by observing mice models. Mice that are devoid of DETCs demonstrate a marked delay in wound closure. This lag is characterized by diminished keratinocyte proliferation, postponed macrophage infiltration, and a reduced deposition of components of the ECM, such as hyaluronan [ 237 ].

Noteworthily, the process of wound healing undergoes alterations as organisms age. In aged mice, wound healing appears to be compromised, a phenomenon attributed to dysfunctional signaling dynamics between injured keratinocytes and DETCs [ 232 ]. Such observations highlight the critical role of DETCs and their interactions with keratinocytes in ensuring an effective wound healing response.

8.6. Invariant Natural Killer Cells (iNKTs)

Invariant natural killer cells (iNKTs) represent a unique subset of lymphocytes that simultaneously express markers indicative of both αβT-cells and NK cells. These cells play a multi-valent role in immunological responses, exerting regulatory control over allergic reactions, autoimmune conditions, and safeguarding the host against various pathogens [ 238 , 239 ]. One of the significant roles of iNKTs pertains to the process of acute wound healing, during which they produce IFN-γ, a cytokine with a crucial role in the inflammatory response. Experiments utilizing mice that lack iNKT cells reveal pronounced delays in wound closure. These delays are accompanied by a reduced deposition of collagen, diminished presence of α-smooth muscle actin—a marker for myofibroblast differentiation—and compromised neo-angiogenesis, or new blood vessel formation, within the wound [ 240 ]. Furthermore, iNKT cells serve a protective function, curbing prolonged neutrophil-driven inflammatory responses that could be deleterious to the healing process [ 241 ].

Turning to another crucial component of the immune system, T-cells, anomalies in their function have been associated with the development of skin fibrosis. In the context of human hypertrophic scars—a pathological, raised scar that may result from burn injuries—there is an increased presence of T-cells [ 242 ]. This interesting observation finds resonance in murine studies. These experiments indicate the fact that scar development is intimately tied to the activation of a Th2 CD4 T-cell response. This response is based on the release of specific interleukins, namely IL-4, IL-5, and IL-13 [ 243 , 244 , 245 , 246 ]. Considering the mechanistic aspects of scar development, heightened mechanical forces exerted on healing skin have been linked to the activation of T-cell pathways in hypertrophic scars [ 247 ]. This provides an interesting interplay between mechanical forces and immunological responses in the context of wound healing and scar formation.

9. Dermal TCs: A Distinct Cell Population with a Promising Skin Regenerative Potential

Over one decade ago, a distinct type of interstitial cell was initially documented in the stroma of few different peri-digestive organs [ 248 ] and were named telocytes (TCs) due to their morphology and location within tissues. Morphologically, their most prominent trait is the presence of very long cellular prolongations featured by a particular long-lump aspect—termed telopodes (Tps). From the peri-digestive compartment, their presence was afterwards documented in many different other organs from different species, including the (human) skin [ 249 , 250 , 251 , 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 , 260 , 261 , 262 , 263 , 264 , 265 , 266 , 267 , 268 , 269 , 270 , 271 , 272 , 273 , 274 , 275 ]. Interestingly, in all these locations, TCs display the same peculiar structural and ultrastructural features, as described in other organs, only with some minor variation in terms of their immunohistochemical phenotype [ 251 , 276 , 277 , 278 , 279 , 280 ]. Since their presence always features the stroma (connective tissue) of organs, it was understandable to find TCs within skin dermal layers [ 276 , 281 ]. In this location, TCs are grossly distributed in the deeper reticular dermis, in close vicinity to hair follicles strictly boarding the glassy membrane of the hair follicle ( Figure 2 ), sweat glands ( Figure 3 ), or sebaceous glands [ 282 ]. TCs are less dense in the superficial papillary dermis. Powerful and complex scanning electron microscopy techniques gave valuable conformational details about TCs and the spatial conformation of their Tps (as they are mostly veil-like structures rather than thread-like cellular prolongations [ 282 ]. Also, these techniques proved the complex three-dimensional disposal of dermal Tps ( Figure 4 ), and their disposal in a network involving other TCs (by their Tps) and/or other types of interstitial cells, nerve cells, endothelial cells, or even immune cells [ 283 , 284 ].

However, in terms of ultrastructural phenotype, dermal TCs show a particular double-positive expression for CD34 and PDFGRα. Moreover, in comparison with the connective tissue, mostly present in interstitial cells—the fibroblasts (Fbs)—TCs possess a characteristic positive expression for epithelial-derived neutrophil-activating peptide-78 (ENA-78) and granulocyte chemotactic protein 2 (GCP-2) [ 10 ], molecules also found within the platelets’ α-granules. Contrarily, dermal Fbs have a characteristic positive expression for CD90 (procollagen type I), and supplementarily, ELISA testing has confirmed their differential expression for 37 other cytokines, which are more highly expressed than in TCs (IL 5, MCP-3, MCP-4, MIP-3, angiogenin, and thrombopoietin) than Fbs [ 11 ].

Of course, corroborating structural data and immunohistochemical data many presumptive roles were suggested for dermal and non-dermal TCs, including intercellular signaling [ 285 ], interstitial homeostasis [ 11 ], vascular homeostasis [ 284 ], (neo)angiogenesis [ 12 ], wound healing [ 286 ]. Roles of nursing cells either in epithelial stem cells or implications in skin immune physiopathology (interactions with mast cells) are suggested, considering the cytokine/immune profile of TCs. Moreover, these hypotheses consider TC networking within normal tissue and, moreover, TC-specific localization within reticular dermis, in close vicinity to skin adnexa, blood vessels, and nerve endings ( Figure 5 ). TCs’ paracrine secretion (shed vesicles) suggests roles for TCs in either controlling or modulating dermal Fbs’ activity or phenotype [ 276 ], or in organizing the dermal connective tissue environment [ 287 ]. Additionally, the positive expression of TCs for several angiogenic factors (either in skin, or in other organs [ 10 , 288 ]) strongly suggests TCs’ roles in (neo)angiogenesis, additionally documented by ultrastructural studies [ 12 , 289 , 290 ].

10. Dermal Telocytes’ Involvement in the Course of a Few Dermatologic Pathologies

The presence and distribution of TCs within the dermis is influenced either by or a few studied physiological or pathological conditions of the skin [ 282 ]. In all pathological conditions in which TCs were studied in terms of their distribution and density, these parameters were documented as being affected differently by various skin conditions and their different levels of severity [ 276 ]. Previously documented data on various dermatological disorders indicated a series of changes in dermal TCs either in terms of dermal distribution, structural changes, or participation to lesion progression/remission [ 291 ]. Thus, the abnormal accumulation of dermal collagen (a structural feature of scleroderma), particularly collagen II and the reticular fibers (collagen III) along mucoid oedema and panniculitis (that are structurally also featuring scleroderma) produces separation of TCs in their networks, disarranging this supra-cellular structure, and individualizes affected TCs, with effects on the architecture of the normal dermal tissue [ 292 , 293 ]. The TC density reduction is initially seen in the superficial dermis, but the reticular dermis follows these changes closely [ 293 ]. Within fibrotic masses or enwrapped in edematous areas in scleroderma lesion skin, TCs display degenerative ultrastructural features, having enlarged cell shapes, also with enlarged Tps and distended mitochondria with scarce cristae within a dense cytoplasm. Moreover, the cytoplasm of affected TCs also contains vacuoles and lipofuscin bodies [ 287 ]. Within scleroderma TCs, degenerative processes advance hypoxically along the disruption of the TC network, and along with the fibrotic process, simultaneously altering the extracellular matrix. However, interesting ultrastructural details showed no TCs in the vicinity of occluded blood vessels, but rather TCs of normal morphology surrounding blood vessels with an opened lumen and thickened basement membrane [ 287 ]. In scleroderma skin, numerically reduced TCs are mainly found around skin adnexa and nerve fibers [ 282 ]. Moreover, in experimental bleomycin-induced scleroderma, the dermis shows a reduced density of TCs, also with disintegration of their ultrastructure. The nuclear fragmentation is more prominent, with the condensation of chromatin in apoptotic fashion [ 292 ]. However, the documented TC changes in scleroderma and the whole cellular and molecular tissue milieu are still a debate, since there are different opinions about what came first [ 11 ]. Some opinions advocate for TC changes being secondary to a hypoxic microenvironment, and others for the accumulation of large deposits of collagens due to TCs ultrastructural changes [ 293 ].

Psoriasis, an immune inflammation of the skin, is featured by (ultra)structural changes of TCs, including ultrastructural dimorphisms of the cellular bodies with cytoplasm fragmentation and cell membrane shatters with nuclear exclusion). Moreover, Tps were documented with serial fragmentations [ 282 ]. Disruption of TCs network integrity with ultrastructural changes of TCs seemed to coexist with serial changes in the activity of antigen presenting cells—the Langerhans cells—and their presence and increased activity below the dermal-epidermal junction, within the dermis [ 10 ].

TCs presence is influenced either by neoplastic pathology, since in basal and squamous cell carcinoma they establish preferentially heterocellular junctions or contain cytoplasmic dense electron plaques [ 285 ].

11. Variable Results of PRP on Treated Skin

However, despite the growing popularity of PRP administration, the effects of PRP administration in different dermatological conditions could be highly variable, being influenced by numerous unpredictable factors. These factors could be related to patients’ unique biological characteristics, but they could also be dependent to specific protocols used in the preparation and application of PRP. Thus, several factors are contributing to the variability in outcomes, and these could fall into two major categories—patient-related factors and PRP-product-related factors [ 294 , 295 , 296 , 297 , 298 , 299 ]:

The age of the patients represents a condition for PRP therapy outcomes. It is well known that younger patients have a more robust and reliable repairing process compared to older individuals. It is acknowledged for different organs that the regenerative capacity is decreasing with age, and this can alco affect the results of the PRP treatments on the skin.

Different skin types respond differently to the PRP treatments, depending on the structure of involved skin (thin or thick).

The severity of the affected skin could affect the outcome of PRP application. There are many cases of skin lesions in which additional alternative treatments could be necessary to deliver good results in PRP treated patients.

The health status of the treated patients could interfere with the results of PRP treatments, usually the healthy individuals have better responses to the PRP treatment.

Products containing a higher concentration of platelets (containing their corresponding growth factors and cytokines) are associated with better results. However, excessively highly concentrated products might not necessarily yield better results.

Different protocols used for the preparation of PRP products deliver different concentrated platelet products. However, it is well known that the speed and duration of centrifuge spinning can influence the quality of PRP products. Thus, consequently, different methods of PRP preparation and concentration deliver different results.

The technique of administration (injection, micro-needling, etc.), single or in combination with other techniques or treatments, is also influencing the results. Moreover, the anatomical region, the depth and the pattern of injection represent some critical factors for PRP outcomes.

PRP treatments offer a promising and smart approach to skin rejuvenation, employing, leveraging, and eliciting the body’s natural resources involved in the healing processes. However, the effects of PRP on the skin are variable and frequently biased by multiple factors. As research progresses and the protocols become more standardized, the predictability and efficacy of PRP therapy are both likely to improve, making PRP treatments more reliable options for skin rejuvenation.

The previous published results offer a mixed view of PRP’s efficacy in skin rejuvenation. There are research groups showing that PRP therapies are showing promising results [ 300 , 301 ], improving the skin texture, rhytids and fine lines, the general aspect and skin luminosity of the study participants. Conversely, other studies have reported minimal to no significant improvements, indicating the variable nature of PRP therapy [ 302 , 303 ]. However, these variances in reports indicate a stringent need for standardizing the protocols and for identifying those factors that could optimize the PRP efficacy [ 304 ].

12. PRP Treatment Limitations, Contraindications, and Practical Considerations

Supplementary, PRP therapy has several limitations that can affect its efficacy and applicability. As variable outcomes are resulting from patient-specific factors (e.g., health status, severity of the dermatological condition to be treated), or PRP preparation (which into the lack of standardization leads to a great variability that can affect treatments outcome. A thorough evaluation of the patient’s skin condition(s), medical history, and individual characteristics will help determine whether PRP represents an appropriate treatment option. However, for the patients who are considering PRP therapy for skin rejuvenation, it would be preferable and essential to have realistic expectations to the treatments and to understand the potential variability in outcomes.

The clinicians should adhere to evidence-based protocols for platelet product preparation and administration to maximize positive outcomes [ 298 , 305 ]. This includes using standardized centrifugation techniques that ensure an optimal platelet concentration, and the employment of precise injection methods. Moreover, the combination of PRP with other treatments, such as laser therapy or microneedling, may enhance the results for selected patients [ 306 , 307 ].

On the other hand, there are some specific situations where the procedure should not be used due to its unfavorable potential for the patient. Usually, the PRP therapy contraindications can be broadly classified into absolute and relative contraindications [ 298 , 308 , 309 ].

The absolute contraindications could include the Platelet Dysfunction Syndromes (e.g., the Glanzmann’s thrombasthenia) that make PRP ineffective due to functional impairment of the platelets, the severe thrombocytopenia which is featured by the significantly depleted number of platelets, that making thrombocytes numerically incompatible with an effective treatment [ 310 , 311 ]. Supplementary, the acute infections (or sepsis) will make PRP treatments inadvisable due to the risk of infections spreading or exacerbation of the patient’s condition(s). Moreover, the anticoagulant therapy using different molecules (e.g., heparin, warfarin, etc.) may increase susceptibility to bleeding and bruising at the injection site [ 312 , 313 ]. Different neoplasms, especially the hematologic malignancies, disallow PRP since theoretically, containing growth factors, PRP could potentially accelerate the cancer cell growth [ 314 ].

Some of relative contraindications include the chronic infections that could pose a risk (thus a detailed evaluation could be necessary), or pregnancy/breastfeeding that, due to limited data, suggest caution. On the other hand, autoimmune diseases (e.g., lupus, dermatomyositis or rheumatoid arthritis) could be accompanied by paradoxical response to PRP administration [ 315 ]. The (uncontrolled) diabetes could interfere with the recovery after PRP administration, impairing the wound healing and the immune response, thus favoring the risk of complications [ 316 , 317 ]. Also, since corticosteroids are interfering with the efficacy of PRP treatments, steroid injections should be avoided several weeks before such treatments [ 318 ].

13. Limitations of PRP Therapy

In dermatology, and in aesthetic medicine, PRP therapy has gained popularity for treating various conditions such as hair loss, acne scars, and skin rejuvenation. However, it has several limitations considering that the results can be inconsistent, varying significantly between patients due to individual differences in platelet concentration and overall health. Additionally, PRP therapy typically requires multiple serial sessions that can last several months and can be time-consuming and costly.

The PRP preparation and administration process also lack standardization, leading to variability in outcomes. To date, there is no universally accepted protocol for PRP products preparation and administration [ 319 ]. Thus, differences in centrifugation techniques, platelet concentrations, and injection methods can result in inconsistent results. The optimal dosing and the frequency of PRP administration are not well standardized and established. While some conditions may require a single treatment, others may benefit from multiple sessions, and the ideal interval between treatments is not well defined [ 320 ].

Moreover, PRP therapy may not be effective for advanced cases of hair loss or severe skin conditions, limiting its applicability. The placebo effect can play a significant role in perceived improvements following PRP therapy. Blinded, controlled studies are necessary to distinguish actual therapeutic benefits from placebo responses [ 321 , 322 ].

While PRP therapy shows promise and exhibits excellent results (at least in regenerative dermatology), many studies suffer from small sample sizes, lack of control groups, and short follow-up periods [ 323 ]. More robust, high-quality research is needed to confirm its efficacy and safety across various applications [ 324 ]. Perhaps, long-term exhaustive studies are needed to fully understand the efficacy and safety of PRP therapy in dermatology, as current evidence is still somewhat limited and not universally accepted [ 325 ].

Although PRP is derived from the patient’s own blood, there is still a risk of infection at the injection site if proper sterile techniques are not followed [ 315 ]. Incorrect injection technique can lead to tissue damage, nerve injury, or other complications, highlighting the importance of skilled practitioners [ 326 ]. The procedure can also cause temporary side effects such as pain, swelling, and bruising at the injection site. While typically temporary, these symptoms can be distressing for patients [ 327 ].

Regarding the economic aspects of these procedures, PRP therapy can be expensive, as it involves specialized equipment and multiple clinic visits. The cost can be prohibitive for many patients, especially since it is often not covered by insurance. Thus, in many situations the access to PRP therapy may be limited in certain states, depending on their region or healthcare laws and rigors, restricting its availability to patients who might benefit from it [ 328 , 329 ]. However, patients may receive different levels of care depending on where they seek treatment. The promotion of PRP therapy for unproven or off-label uses raises ethical concerns. Clinicians must balance enthusiasm for new treatments with a commitment to evidence-based practice [ 330 ]. The regulation of PRP therapy varies by country and region, leading to inconsistent standards of practice and quality control [ 331 ].

14. Conclusions and Perspectives

PRP therapy represents a promising treatment modality across various medical fields, offering potential benefits for patients with a range of conditions. However, its use is not without contraindications and limitations. Absolute contraindications such as platelet dysfunction syndromes, severe thrombocytopenia, active infections, active cancer, and anticoagulant therapy must be carefully considered to avoid adverse outcomes. Relative contraindications, including chronic infections, autoimmune diseases, uncontrolled diabetes, pregnancy, breastfeeding, and recent corticosteroid injections, require thorough evaluation and patient-specific considerations.

The limitations of PRP therapy, including variable outcomes, lack of standardization, insufficient high-quality evidence, cost, accessibility, procedure-related risks, and regulatory and ethical concerns, must be addressed to optimize its use and ensure patient safety. Continued research and clinical trials are essential to establish standardized protocols, determine optimal treatment regimens, and confirm the efficacy and safety of PRP therapy across its various applications. By recognizing and addressing these challenges, healthcare providers can better navigate the complexities of PRP treatment and enhance patient outcomes.

On the other hand, currently the advanced therapy medicinal products (ATMPs) represent the cutting-edge medical treatments that include gene therapies, cell therapies, and tissue-engineered products [ 332 ]. These technically refined and more powerful treatments offer potential cures for complex diseases by repairing, replacing, or regenerating human cells, tissues, or genes [ 333 ]. For regulatory reasons, PRP is not considered an ATMP [ 334 ]. Both PRP therapy and ATMPs represent significant advancements in personalized and regenerative medicine, offering innovative solutions to previously challenging medical conditions.

Presently, the field of PRP therapy is evolving, with ongoing research aimed at better understanding its mechanisms and optimizing its use in dermatology. Future studies are needed to establish standardized protocols and identify biomarkers that predict patient response to PRP. Additionally, advancements in technology may lead to more refined PRP formulations and delivery methods, further improving the efficacy and consistency of this treatment.

Considering all mentioned regarding PRP and interstitial TCs, further perspectives could be hypothesized in regard with TCs roles and their regenerative potential. TCs are a distinctive population of resident cells with particular relations with dermal structural elements and elements of the epidermal stem cell niche.

To date, a broad range of dermatologic therapies have reported a series of good results in skin resurfacing/rejuvenation/repair after minimally invasive procedures. Usually, producing inflammation within the dermis (by different means) aims to to finally produce collagen and other dermal structural elements that could repair a skin defect.

Currently, there is also a lack of detailed studies of the cellular/molecular milieu elicited by PRP administration, moreover from the perspective of dermal TCs. Additionally, a cytochemical and physical collaboration between TCs and stem cells with implications in tissue regeneration in other organs (e.g., heart, lung, etc.) was indicated in previous published results [ 11 ]. To date, there are so many microscopical and biochemical confirmations that TCs represent a dermal resident cell population that is immunophenotypically and ultrastructurally distinct and being totally different from any other known dermal resident cell population. Considering the gross implications in skin homeostasis and skin pathology, the study of its behavior in reparatory/regeneration instances is an intriguing way of research. It comes naturally to investigate the presumptive ways of managing dermal TC distribution/density that could help achieve a swift and natural recovery of skin lesions.

According to published data, there is a great body of evidence indicating the regenerative potential of TCs, and their presumptive roles in the structural and ultrastructural rehabilitation of damaged tissue. There is also a great expectation for these cells with respect to regenerative medicine or tissue renewal. Thus, it is tempting to postulate implications of dermal TCs in the renewal/repair/regeneration/remodeling development after administering PRP. Thus, we may perceive PRP (only) or combined with other regeneration/renewal procedures as promising candidates with stunning potential for replacing conventional therapeutic approaches [ 328 ].

However, experimental studies on the heart after experimental acute myocardial infarction indicated the important involvement of TCs in lesion recovery within the border zone of myocardial infarction [ 12 , 292 ]. Considering these results, and the entire sequence of tissue repair, it would be unimaginative and prosaic to consider fibroblasts as the only key players in tissue regeneration.

Hitherto, there are few studies conducted on different platelet concentration derivatives: plasma, PRP, PRP-derived exosomes (PRP-Exos)/PRP-derived extracellular vesicles (PRP-EVs), and platelet-poor plasma (PPP) [ 335 ]. As we previously mentioned, the administration of PRP provides the interior of the tissue a higher concentration of GFs with angiogenic, mitogenic, and anabolic properties, which represents a routine, alternative, less invasive treatment [ 303 ]. To date, many studies have involved the administration of PRP to follow-up patients at different time intervals—from 4 weeks to 4 years [ 336 ]. All these studies indicated a great potential of PRP in treating various structural alterations of skin integrity and normal structure. Using the administration of the biologically active molecules from the plasma secretome leads to new approaches for wound closures [ 337 ]. The wound healing studies using PRP-EV indicated safety for usage in humans but no net difference between PRP-EV treated wounds and placebo [ 338 ].

PPP usually encompasses plasma that is normally discarded after the preparation of PRP. PPP is autologous plasma with a low platelet concentration that can act as a sealant and scaffold for those migrating cells involved in wound healing and tissue regeneration [ 339 ]. However, it has been proven to contain great amounts of various bioactive proteins (fibrinogen, VEGF, PDGF, SDF-1α, etc.) [ 340 ]. The studies on PPP have demonstrated that it is a good hemostatic agent for wounds, but its efficacy in regeneration should be precisely documented by further studies [ 336 , 341 ].

Currently, clear detailed structural and ultrastructural studies on mechanisms induced by PRP are rare, and there is a persisting vagueness in the presented data. Further studies on PRP cellular phenomena with respect to TCs’ presence within the dermis that are based on strong microscopical evidence could facilitate unique, valuable, and challenging research on the ultrastructure of the reparatory cellular environment provided by the administration of PRP.

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding authors, C.G.M. and M.E.H.

Conflicts of Interest

The authors declare no conflict of interest.

References

1. Gawaz M. Vogel S. Platelets in Tissue Repair: Control of Apoptosis and Interactions with Regenerative Cells Blood 2013 122 2550 2554 10.1182/blood-2013-05-468694 23963043

2. Gong T. Liu Y.-T. Fan J. Exosomal Mediators in Sepsis and Inflammatory Organ Injury: Unraveling the Role of Exosomes in Intercellular Crosstalk and Organ Dysfunction Mil. Med. Res. 2024 11 24 10.1186/s40779-024-00527-6 38644472 PMC11034107

3. Wang Q. Liu J. Li R. Wang S. Xu Y. Wang Y. Zhang H. Zhou Y. Zhang X. Chen X. Assessing the Role of Programmed Cell Death Signatures and Related Gene TOP2A in Progression and Prognostic Prediction of Clear Cell Renal Cell Carcinoma Cancer Cell Int. 2024 24 164 10.1186/s12935-024-03346-w 38730293 PMC11084013

4. An N. Chen Z. Zhao P. Yin W. Extracellular Vesicles in Sepsis: Pathogenic Roles, Organ Damage, and Therapeutic Implications Int. J. Med. Sci. 2023 20 1722 1731 10.7150/ijms.86832 37928875 PMC10620861

5. Effah C.Y. Ding X. Drokow E.K. Li X. Tong R. Sun T. Bacteria-Derived Extracellular Vesicles: Endogenous Roles, Therapeutic Potentials and Their Biomimetics for the Treatment and Prevention of Sepsis Front. Immunol. 2024 15 1296061 10.3389/fimmu.2024.1296061 38420121 PMC10899385

6. Crisci A. De Crescenzo U. Crisci M. Platelet-Rich Concentrates (L-PRF, PRP) in Tissue Regeneration: Control of Apoptosis and Interactions with Regenerative Cells J. Clin. Mol. Med. 2018 1 1000116 10.15761/JCMM.1000116

7. Ludwig N. Hilger A. Zarbock A. Rossaint J. Platelets at the Crossroads of Pro-Inflammatory and Resolution Pathways during Inflammation Cells 2022 11 1957 10.3390/cells11121957 35741086 PMC9221767

8. Cozzi M.R. Guglielmini G. Battiston M. Momi S. Lombardi E. Miller E.C. De Zanet D. Mazzucato M. Gresele P. De Marco L. Visualization of Nitric Oxide Production by Individual Platelets during Adhesion in Flowing Blood Blood 2015 125 697 705 10.1182/blood-2014-06-579474 25480660

9. Andrabi S.M. Sharma N.S. Karan A. Shahriar S.M.S. Cordon B. Ma B. Xie J. Nitric Oxide: Physiological Functions, Delivery, and Biomedical Applications Adv. Sci. 2023 10 e2303259 10.1002/advs.202303259 37632708 PMC10602574

10. Kang Y. Zhu Z. Zheng Y. Wan W. Manole C.G. Zhang Q. Skin Telocytes versus Fibroblasts: Two Distinct Dermal Cell Populations J. Cell. Mol. Med. 2015 19 2530 2539 10.1111/jcmm.12671 26414534 PMC4627559

11. Manole C.G. Gherghiceanu M. Ceafalan L.C. Hinescu M.E. Dermal Telocytes: A Different Viewpoint of Skin Repairing and Regeneration Cells 2022 11 3903 10.3390/cells11233903 36497161 PMC9736852

12. Manole C.G. Cismaşiu V. Gherghiceanu M. Popescu L.M. Experimental Acute Myocardial Infarction: Telocytes Involvement in Neo-Angiogenesis J. Cell. Mol. Med. 2011 15 2284 2296 10.1111/j.1582-4934.2011.01449.x 21895968 PMC3822940

13. Blair P. Flaumenhaft R. Platelet α-Granules: Basic Biology and Clinical Correlates Blood Rev. 2009 23 177 189 10.1016/j.blre.2009.04.001 19450911 PMC2720568

14. Noetzli L.J. Italiano J.E. Unlocking the Molecular Secrete(s) of α-Granule Biogenesis Arter. Thromb. Vasc. Biol. 2018 38 2539 2541 10.1161/ATVBAHA.118.311614 30354241 PMC6287256

15. Woods V.M.A. Latorre-Rey L.J. Schenk F. Rommel M.G.E. Moritz T. Modlich U. Targeting Transgenic Proteins to Alpha Granules for Platelet-Directed Gene Therapy Mol. Ther. Nucleic Acids 2022 27 774 786 10.1016/j.omtn.2021.12.038 35116189 PMC8783114

16. Wu J. Heemskerk J.W.M. Baaten C.C.F.M.J. Platelet Membrane Receptor Proteolysis: Implications for Platelet Function Front. Cardiovasc. Med. 2021 7 608391 10.3389/fcvm.2020.608391 33490118 PMC7820117

17. Chaudhary P.K. Kim S. Kim S. Shedding Light on the Cell Biology of Platelet-Derived Extracellular Vesicles and Their Biomedical Applications Life 2023 13 1403 10.3390/life13061403 37374185 PMC10326820

18. Puricelli C. Boggio E. Gigliotti C.L. Stoppa I. Sutti S. Giordano M. Dianzani U. Rolla R. Platelets, Protean Cells with All-Around Functions and Multifaceted Pharmacological Applications Int. J. Mol. Sci. 2023 24 4565 10.3390/ijms24054565 36901997 PMC10002540

19. Kook S. Wang P. Young L.R. Schwake M. Saftig P. Weng X. Meng Y. Neculai D. Marks M.S. Gonzales L. Impaired Lysosomal Integral Membrane Protein 2-Dependent Peroxiredoxin 6 Delivery to Lamellar Bodies Accounts for Altered Alveolar Phospholipid Content in Adaptor Protein-3-Deficient Pearl Mice J. Biol. Chem. 2016 291 8414 8427 10.1074/jbc.M116.720201 26907692 PMC4861416

20. Hajdú G. Somogyvári M. Csermely P. Sőti C. Lysosome-Related Organelles Promote Stress and Immune Responses in C. Elegans Commun. Biol. 2023 6 936 10.1038/s42003-023-05246-7 37704756 PMC10499889

21. Heijnen H. van der Sluijs P. Platelet Secretory Behaviour: As Diverse as the Granules … or Not? J. Thromb. Haemost. 2015 13 2141 2151 10.1111/jth.13147 26391322

22. Pokrovskaya I.D. Yadav S. Rao A. McBride E. Kamykowski J.A. Zhang G. Aronova M.A. Leapman R.D. Storrie B. 3D Ultrastructural Analysis of A-granule, Dense Granule, Mitochondria, and Canalicular System Arrangement in Resting Human Platelets Res. Pract. Thromb. Haemost. 2020 4 72 85 10.1002/rth2.12260 31989087 PMC6971324

23. Smith C.W. Release of α-Granule Contents during Platelet Activation Platelets 2022 33 491 502 10.1080/09537104.2021.1913576 34569425

24. Jo S. Lee S.H. Park J. Nam B. Kim H. Youn J. Lee S. Kim T.-J. Sung I.-H. Choi S.H. Platelet-Derived Growth Factor B Is a Key Element in the Pathological Bone Formation of Ankylosing Spondylitis J. Bone Miner. Res. 2020 38 300 312 10.1002/jbmr.4751 36422470

25. Everts P. Onishi K. Jayaram P. Lana J.F. Mautner K. Platelet-Rich Plasma: New Performance Understandings and Therapeutic Considerations in 2020 Int. J. Mol. Sci. 2020 21 7794 10.3390/ijms21207794 33096812 PMC7589810

26. Cheng Y.-W. Zhang Z.-B. Lan B.-D. Lin J.-R. Chen X.-H. Kong L.-R. Xu L. Ruan C.-C. Gao P.-J. PDGF-D Activation by Macrophage-Derived UPA Promotes AngII-Induced Cardiac Remodeling in Obese Mice J. Exp. Med. 2021 218 e20210252 10.1084/jem.20210252 34236404 PMC8273546

27. Juhl P. Bondesen S. Hawkins C.L. Karsdal M.A. Bay-Jensen A.-C. Davies M.J. Siebuhr A.S. Dermal Fibroblasts Have Different Extracellular Matrix Profiles Induced by TGF-β, PDGF and IL-6 in a Model for Skin Fibrosis Sci. Rep. 2020 10 17300 10.1038/s41598-020-74179-6 33057073 PMC7560847

28. Rodrigues-Junior D.M. Tsirigoti C. Lim S.K. Heldin C.-H. Moustakas A. Extracellular Vesicles and Transforming Growth Factor β Signaling in Cancer Front. Cell Dev. Biol. 2022 10 849938 10.3389/fcell.2022.849938 35493080 PMC9043557

29. Sonker A. Dubey A. Bhatnagar A. Chaudhary R. Platelet Growth Factors from Allogeneic Platelet-Rich Plasma for Clinical Improvement in Split-Thickness Skin Graft Asian J. Transfus. Sci. 2015 9 155 10.4103/0973-6247.162712 26420935 PMC4562136

30. Karolczak K. Watala C. Blood Platelets as an Important but Underrated Circulating Source of TGFβ Int. J. Mol. Sci. 2021 22 4492 10.3390/ijms22094492 33925804 PMC8123509

31. Wang L. Zhao C. Zheng T. Zhang Y. Liu H. Wang X. Tang X. Zhao B. Liu P. Torin 1 Alleviates Impairment of TFEB-Mediated Lysosomal Biogenesis and Autophagy in TGFBI (p.G623_H626del)-Linked Thiel-Behnke Corneal Dystrophy Autophagy 2022 18 765 782 10.1080/15548627.2021.1955469 34403298 PMC9037417

32. Kim H.-J. Kim P.-K. Bae S.M. Son H.-N. Thoudam D.S. Kim J.-E. Lee B.-H. Park R.-W. Kim I.-S. Transforming Growth Factor-β–Induced Protein (TGFBIp/β Ig-H3) Activates Platelets and Promotes Thrombogenesis Blood 2009 114 5206 5215 10.1182/blood-2009-03-212415 19738031

33. Takemoto A. Okitaka M. Takagi S. Takami M. Sato S. Nishio M. Okumura S. Fujita N. A Critical Role of Platelet TGF-β Release in Podoplanin-Mediated Tumour Invasion and Metastasis Sci. Rep. 2017 7 42186 10.1038/srep42186 28176852 PMC5297242

34. Chen L. Pronk E. van Dijk C. Bian Y. Feyen J. van Tienhoven T. Yildirim M. Pisterzi P. de Jong M.M.E. Bastidas A. A Single-Cell Taxonomy Predicts Inflammatory Niche Remodeling to Drive Tissue Failure and Outcome in Human AML Blood Cancer Discov. 2023 4 394 417 10.1158/2643-3230.BCD-23-0043 37470778 PMC10472197

35. Xu R. Wu M. Wang Y. Li C. Zeng L. Wang Y. Xiao M. Chen X. Geng S. Lai P. Mesenchymal Stem Cells Reversibly De-Differentiate Myofibroblasts to Fibroblast-like Cells by Inhibiting the TGF-β-SMAD2/3 Pathway Mol. Med. 2023 29 59 10.1186/s10020-023-00630-9 37098464 PMC10131436

36. Ma J. Sanchez-Duffhues G. Goumans M.-J. ten Dijke P. TGF-β-Induced Endothelial to Mesenchymal Transition in Disease and Tissue Engineering Front. Cell Dev. Biol. 2020 8 260 10.3389/fcell.2020.00260 32373613 PMC7187792

37. Gui T. Sun Y. Shimokado A. Muragaki Y. The Roles of Mitogen-Activated Protein Kinase Pathways in TGF- β -Induced Epithelial-Mesenchymal Transition J. Signal Transduct. 2012 2012 289243 10.1155/2012/289243 22363839 PMC3272823

38. Ferrari G. Cook B.D. Terushkin V. Pintucci G. Mignatti P. Transforming Growth Factor-beta 1 (TGF-β1) Induces Angiogenesis through Vascular Endothelial Growth Factor (VEGF)-mediated Apoptosis J. Cell. Physiol. 2009 219 449 458 10.1002/jcp.21706 19180561 PMC2749291

39. Deng Z. Fan T. Xiao C. Tian H. Zheng Y. Li C. He J. TGF-β Signaling in Health, Disease, and Therapeutics Signal Transduct. Target. Ther. 2024 9 61 10.1038/s41392-024-01764-w 38514615 PMC10958066

40. Rong H. Zhang H. Ning L. Wu K. Limbu S.M. Shi Q. Qin C. Wen X. The Transforming Growth Factor Beta (TGF-β/Smads) Pathway Regulates Collagen Synthesis and Deposition in Swim Bladder of Chu’s Croaker (Nibea Coibor) Stimulated by Proline Aquaculture 2022 558 738360 10.1016/j.aquaculture.2022.738360

41. Fontemaggi G. Non-coding RNA Regulatory Networks in Post-transcriptional Regulation of VEGFA in Cancer IUBMB Life 2023 75 30 39 10.1002/iub.2620 35467790 PMC10084289

42. Ferrara N. Vascular Endothelial Growth Factor Arter. Thromb. Vasc. Biol. 2009 29 789 791 10.1161/ATVBAHA.108.179663 19164810

43. Ghalehbandi S. Yuzugulen J. Pranjol M.Z.I. Pourgholami M.H. The Role of VEGF in Cancer-Induced Angiogenesis and Research Progress of Drugs Targeting VEGF Eur. J. Pharmacol. 2023 949 175586 10.1016/j.ejphar.2023.175586 36906141

44. Li Q.-Q. Guo M. He G.-H. Xi K.-H. Zhou M.-Y. Shi R.-Y. Chen G.-Q. VEGF-Induced Nrdp1 Deficiency in Vascular Endothelial Cells Promotes Cancer Metastasis by Degrading Vascular Basement Membrane Oncogene 2024 43 1836 1851 10.1038/s41388-024-03038-9 38654108

45. Yarjoo S. Siampour H. Khalilipour M. Sajedi R.H. Bagheri H. Moshaii A. Gold Nanostructure-Enhanced Immunosensing: Ultra-Sensitive Detection of VEGF Tumor Marker for Early Disease Diagnosis Sci. Rep. 2024 14 10450 10.1038/s41598-024-60447-2 38714678 PMC11608251

46. Negahdari B. Shahosseini Z. Baniasadi V. Production of Human Epidermal Growth Factor Using Adenoviral Based System Res. Pharm. Sci. 2016 11 43 48 27051431 PMC4794936

47. Zeng F. Harris R.C. Epidermal Growth Factor, from Gene Organization to Bedside Semin. Cell Dev. Biol. 2014 28 2 11 10.1016/j.semcdb.2014.01.011 24513230 PMC4037350

48. Pereira V.B.S. Lago C.A.P. Almeida R.d.A.C. Barbirato D.d.S. Vasconcelos B.C.d.E. Biological and Cellular Properties of Advanced Platelet-Rich Fibrin (A-PRF) Compared to Other Platelet Concentrates: Systematic Review and Meta-Analysis Int. J. Mol. Sci. 2023 25 482 10.3390/ijms25010482 38203653 PMC10779223

49. Farooq M. Khan A.W. Kim M.S. Choi S. The Role of Fibroblast Growth Factor (FGF) Signaling in Tissue Repair and Regeneration Cells 2021 10 3242 10.3390/cells10113242 34831463 PMC8622657

50. Prudovsky I. Cellular Mechanisms of FGF-Stimulated Tissue Repair Cells 2021 10 1830 10.3390/cells10071830 34360000 PMC8304273

51. Teven C.M. Farina E.M. Rivas J. Reid R.R. Fibroblast Growth Factor (FGF) Signaling in Development and Skeletal Diseases Genes. Dis. 2014 1 199 213 10.1016/j.gendis.2014.09.005 25679016 PMC4323088

52. Czyz M. Fibroblast Growth Factor Receptor Signaling in Skin Cancers Cells 2019 8 540 10.3390/cells8060540 31167513 PMC6628025

53. Zhao H. Duan L. Cyclic Adenosine Monophosphate Regulates Connective Tissue Growth Factor Expression in Myocardial Fibrosis after Myocardial Infarction J. Int. Med. Res. 2021 49 030006052110155 10.1177/03000605211015586 34082585 PMC8182188

54. Chen Z. Zhang N. Chu H.Y. Yu Y. Zhang Z.-K. Zhang G. Zhang B.-T. Connective Tissue Growth Factor: From Molecular Understandings to Drug Discovery Front. Cell Dev. Biol. 2020 8 593269 10.3389/fcell.2020.593269 33195264 PMC7658337

55. Arnott J.A. Lambi A.G. Mundy C. Hendesi H. Pixley R.A. Owen T.A. Safadi F.F. Popoff S.N. The Role of Connective Tissue Growth Factor (CTGF/CCN2) in Skeletogenesis Crit. Rev. Eukaryot. Gene Expr. 2011 21 43 69 10.1615/CritRevEukarGeneExpr.v21.i1.40 21967332 PMC3357314

56. Hall-Glenn F. Lyons K.M. Roles for CCN2 in Normal Physiological Processes Cell. Mol. Life Sci. 2011 68 3209 3217 10.1007/s00018-011-0782-7 21858450 PMC3670951

57. Schenkl C. Schrepper A. Heyne E. Doenst T. Schwarzer M. The IGF-1R Inhibitor NVP-AEW541 Causes Insulin-Independent and Reversible Cardiac Contractile Dysfunction Biomedicines 2022 10 2022 10.3390/biomedicines10082022 36009569 PMC9406171

58. Ndandala C.B. Zhou Q. Li Z. Guo Y. Li G. Chen H. Identification of Insulin-like Growth Factor (IGF) Family Genes in the Golden Pompano, Trachinotus Ovatus: Molecular Cloning, Characterization and Gene Expression Int. J. Mol. Sci. 2024 25 2499 10.3390/ijms25052499 38473747 PMC10931442

59. Kiernan K. Alwarawrah Y. Nichols A.G. Danzaki K. MacIver N.J. Insulin and IGF-1 Have Both Overlapping and Distinct Effects on CD4+ T Cell Mitochondria, Metabolism, and Function Sci. Rep. 2024 14 4331 10.1038/s41598-024-54836-w 38383709 PMC10881490

60. Del Amo C. Fernández-San Argimiro X. Cascajo-Castresana M. Perez-Valle A. Madarieta I. Olalde B. Andia I. Wound-Microenvironment Engineering through Advanced-Dressing Bioprinting Int. J. Mol. Sci. 2022 23 2836 10.3390/ijms23052836 35269978 PMC8911091

61. Mayfosh A.J. Nguyen T.K. Hulett M.D. The Heparanase Regulatory Network in Health and Disease Int. J. Mol. Sci. 2021 22 11096 10.3390/ijms222011096 34681753 PMC8541136

62. Matwiejuk M. Myśliwiec H. Chabowski A. Flisiak I. An Overview of Growth Factors as the Potential Link between Psoriasis and Metabolic Syndrome J. Clin. Med. 2023 13 109 10.3390/jcm13010109 38202116 PMC10780265

63. Li L. Ngo H.T.T. Hwang E. Wei X. Liu Y. Liu J. Yi T.-H. Conditioned Medium from Human Adipose-Derived Mesenchymal Stem Cell Culture Prevents UVB-Induced Skin Aging in Human Keratinocytes and Dermal Fibroblasts Int. J. Mol. Sci. 2019 21 49 10.3390/ijms21010049 31861704 PMC6981944

64. Li J.-F. Duan H.-F. Wu C.-T. Zhang D.-J. Deng Y. Yin H.-L. Han B. Gong H.-C. Wang H.-W. Wang Y.-L. HGF Accelerates Wound Healing by Promoting the Dedifferentiation of Epidermal Cells through β1-Integrin/ILK Pathway Biomed. Res. Int. 2013 2013 470418 10.1155/2013/470418 24490163 PMC3899705

65. Yen T. Thao D. Thuoc T. An Overview on Keratinocyte Growth Factor: From the Molecular Properties to Clinical Applications Protein Pept. Lett. 2014 21 306 317 10.2174/09298665113206660115 24188496

66. Liu H. Wu Q.-F. Li J.-Y. Liu X.-J. Li K.-C. Zhong Y.-Q. Wu D. Wang Q. Lu Y.-J. Bao L. Fibroblast Growth Factor 7 Is a Nociceptive Modulator Secreted via Large Dense-Core Vesicles J. Mol. Cell Biol. 2015 7 466 475 10.1093/jmcb/mjv019 25782913

67. Sonar S.A. Watanabe M. Nikolich J.Ž. Disorganization of Secondary Lymphoid Organs and Dyscoordination of Chemokine Secretion as Key Contributors to Immune Aging Semin. Immunol. 2023 70 101835 10.1016/j.smim.2023.101835 37651849 PMC10840697

68. Zheng H. Choi H. Oh D. Kim M. Cai L. Jawad A. Kim S. Lee J. Hyun S.-H. Supplementation with Fibroblast Growth Factor 7 during in Vitro Maturation of Porcine Cumulus-Oocyte Complexes Improves Oocyte Maturation and Early Embryonic Development Front. Vet. Sci. 2023 10 1250551 10.3389/fvets.2023.1250551 38026656 PMC10662523

69. Ferguson H.R. Smith M.P. Francavilla C. Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling Cells 2021 10 1201 10.3390/cells10051201 34068954 PMC8156822

70. Seeger M.A. Paller A.S. The Roles of Growth Factors in Keratinocyte Migration Adv. Wound Care 2015 4 213 224 10.1089/wound.2014.0540 25945284 PMC4397993

71. Thapa K. Khan H. Kaur G. Kumar P. Singh T.G. Therapeutic Targeting of Angiopoietins in Tumor Angiogenesis and Cancer Development Biochem. Biophys. Res. Commun. 2023 687 149130 10.1016/j.bbrc.2023.149130 37944468

72. Brouwers J. Noviyanti R. Fijnheer R. de Groot P.G. Trianty L. Mudaliana S. Roest M. Syafruddin D. van der Ven A. de Mast Q. Platelet Activation Determines Angiopoietin-1 and VEGF Levels in Malaria: Implications for Their Use as Biomarkers PLoS ONE 2013 8 e64850 10.1371/journal.pone.0064850 23755151 PMC3670845

73. Sun P. Bartlett C.S. Zheng C. Bigwarfe T. Grant J.M. MacDougall M. Berger V. Kerr S. Qian H.S. McHugh M. Effect of Novel Biotherapeutic Elevating Angiopoietin 1 on Progression of Diabetic Nephropathy in Diabetic/Obese Mice J. Pharmacol. Exp. Ther. 2022 382 266 276 10.1124/jpet.121.001067 35779860

74. Keskin D. Kim J. Cooke V.G. Wu C.-C. Sugimoto H. Gu C. De Palma M. Kalluri R. LeBleu V.S. Targeting Vascular Pericytes in Hypoxic Tumors Increases Lung Metastasis via Angiopoietin-2 Cell Rep. 2015 10 1066 1081 10.1016/j.celrep.2015.01.035 25704811 PMC4342328

75. Chi Y. Yu S. Yin J. Liu D. Zhuo M. Li X. Role of Angiopoietin/Tie2 System in Sepsis: A Potential Therapeutic Target Clin. Appl. Thromb./Hemost. 2024 30 10.1177/10760296241238010 38449088 PMC10921858

76. Thurston G. Rudge J.S. Ioffe E. Zhou H. Ross L. Croll S.D. Glazer N. Holash J. McDonald D.M. Yancopoulos G.D. Angiopoietin-1 Protects the Adult Vasculature against Plasma Leakage Nat. Med. 2000 6 460 463 10.1038/74725 10742156

77. Flad H.-D. Brandt E. Platelet-Derived Chemokines: Pathophysiology and Therapeutic Aspects Cell. Mol. Life Sci. 2010 67 2363 2386 10.1007/s00018-010-0306-x 20213276 PMC11115602

78. Collinson R.J. Mazza-Parton A. Fuller K.A. Linden M.D. Erber W.N. Guo B.B. Gene Expression of CXCL1 (GRO-α) and EGF by Platelets in Myeloproliferative Neoplasms Hemasphere 2020 4 e490 10.1097/HS9.0000000000000490 33134870 PMC7592996

79. Greinacher A. Warkentin T.E. Platelet Factor 4 Triggers Thrombo-inflammation by Bridging Innate and Adaptive Immunity Int. J. Lab. Hematol. 2023 45 11 22 10.1111/ijlh.14075 37150909

80. Alhanshani A.A. Heparin Induced Thrombocytopenia—Pathophysiology, Diagnosis and Treatment: A Narrative Review Int. J. Gen. Med. 2023 16 3947 3953 10.2147/IJGM.S420327 37667778 PMC10475297

81. Arepally G.M. Padmanabhan A. Heparin-Induced Thrombocytopenia Arter. Thromb. Vasc. Biol. 2020 41 141 152 10.1161/ATVBAHA.120.315445 33267665 PMC7769912

82. Kowalska M.A. Rauova L. Poncz M. Role of the Platelet Chemokine Platelet Factor 4 (PF4) in Hemostasis and Thrombosis Thromb. Res. 2010 125 292 296 10.1016/j.thromres.2009.11.023 20004006

83. Singh A.J. Gray J.W. Chemokine Signaling in Cancer-Stroma Communications J. Cell Commun. Signal. 2021 15 361 381 10.1007/s12079-021-00621-7 34086259 PMC8222467

84. Cai Z. Greene M.I. Zhu Z. Zhang H. Structural Features and PF4 Functions That Occur in Heparin-Induced Thrombocytopenia (HIT) Complicated by COVID-19 Antibodies 2020 9 52 10.3390/antib9040052 33050376 PMC7709132

85. Krauel K. Pötschke C. Weber C. Kessler W. Fürll B. Ittermann T. Maier S. Hammerschmidt S. Bröker B.M. Greinacher A. Platelet Factor 4 Binds to Bacteria, Inducing Antibodies Cross-Reacting with the Major Antigen in Heparin-Induced Thrombocytopenia Blood 2011 117 1370 1378 10.1182/blood-2010-08-301424 20959601

86. Guo L. Li N. Yang Z. Li H. Zheng H. Yang J. Chen Y. Zhao X. Mei J. Shi H. Role of CXCL5 in Regulating Chemotaxis of Innate and Adaptive Leukocytes in Infected Lungs Upon Pulmonary Influenza Infection Front. Immunol. 2021 12 785457 10.3389/fimmu.2021.785457 34868067 PMC8637413

87. Wu T. Yang W. Sun A. Wei Z. Lin Q. The Role of CXC Chemokines in Cancer Progression Cancers 2022 15 167 10.3390/cancers15010167 36612163 PMC9818145

88. Wang X. Jia Y. Li D. Guo X. Zhou Z. Qi M. Wang G. Wang F. The Abundance and Function of Neutrophils in the Endometriosis Systemic and Pelvic Microenvironment Mediat. Inflamm. 2023 2023 1481489 10.1155/2023/1481489 36762287 PMC9904898

89. Brown A. Sepuru K. Rajarathnam K. Structural Basis of Native CXCL7 Monomer Binding to CXCR2 Receptor N-Domain and Glycosaminoglycan Heparin Int. J. Mol. Sci. 2017 18 508 10.3390/ijms18030508 28245630 PMC5372524

90. Brown A.J. Sepuru K.M. Sawant K.V. Rajarathnam K. Platelet-Derived Chemokine CXCL7 Dimer Preferentially Exists in the Glycosaminoglycan-Bound Form: Implications for Neutrophil–Platelet Crosstalk Front. Immunol. 2017 8 1248 10.3389/fimmu.2017.01248 29038657 PMC5630695

91. Metzemaekers M. Gouwy M. Proost P. Neutrophil Chemoattractant Receptors in Health and Disease: Double-Edged Swords Cell. Mol. Immunol. 2020 17 433 450 10.1038/s41423-020-0412-0 32238918 PMC7192912

92. Cambier S. Gouwy M. Proost P. The Chemokines CXCL8 and CXCL12: Molecular and Functional Properties, Role in Disease and Efforts towards Pharmacological Intervention Cell. Mol. Immunol. 2023 20 217 251 10.1038/s41423-023-00974-6 36725964 PMC9890491

93. Ji H. Chen L. Ren M. Li S. Liu T. Chen H. Yu H. Sun Y. CXCL8 Promotes Endothelial-to-Mesenchymal Transition of Endothelial Cells and Protects Cells from Erastin-Induced Ferroptosis via CXCR2-Mediated Activation of the NF-ΚB Signaling Pathway Pharmaceuticals 2023 16 1210 10.3390/ph16091210 37765018 PMC10536478

94. Schall N. Daubeuf F. Marsol C. Gizzi P. Frossard N. Bonnet D. Galzi J.-L. Muller S. A Selective Neutraligand for CXCL12/SDF-1α With Beneficial Regulatory Functions in MRL/Lpr Lupus Prone Mice Front. Pharmacol. 2021 12 752194 10.3389/fphar.2021.752194 34744730 PMC8566942

95. Saeidi S. Mohammadi-Asl J. Far M.A.J. Asnafi A.A. Dehuri F. Tavakolifar Y. Saki N. Is There a Relationship Between CXCR4 Gene Expression and Prognosis of Immune Thrombocytopenia in Children? Indian J. Hematol. Blood Transfus. 2017 33 216 221 10.1007/s12288-016-0648-0 28596654 PMC5442042

96. Aghajanova L. Zhang A. Lathi R.B. Huddleston H.G. Platelet-Rich Plasma Infusion as an Adjunct Treatment for Persistent Thin Lining in Frozen Embryo Transfer Cycles: First US Experience Report J. Assist. Reprod. Genet. 2024 41 483 491 10.1007/s10815-023-02993-8 37996549 PMC10894781

97. Rath D. Chatterjee M. Borst O. Muller K. Stellos K. Mack A.F. Bongartz A. Bigalke B. Langer H. Schwab M. Expression of Stromal Cell-Derived Factor-1 Receptors CXCR4 and CXCR7 on Circulating Platelets of Patients with Acute Coronary Syndrome and Association with Left Ventricular Functional Recovery Eur. Heart J. 2014 35 386 394 10.1093/eurheartj/eht448 24168792

98. Zhang Z. Zheng Y. Zu J. Zhuang J. Xu G. Yan J. Liu X. Stromal Cell-Derived Factor (SDF)-1α and Platelet-Rich Plasma Enhance Bone Regeneration and Angiogenesis Simultaneously in Situ in Rabbit Calvaria J. Mater. Sci. Mater. Med. 2021 32 125 10.1007/s10856-021-06600-z 34524548 PMC8443516

99. Swaminath D. Penn B.M. Penn M.S. SDF-1 for Cardiac Repair Stem Cell and Gene Therapy for Cardiovascular Disease Elsevier Amsterdam, The Netherlands 2016 401 407

100. Camps J. Rodríguez-Gallego E. García-Heredia A. Triguero I. Riera-Borrull M. Hernández-Aguilera A. Luciano-Mateo F. Fernández-Arroyo S. Joven J. Paraoxonases and Chemokine (C–C Motif) Ligand-2 in Noncommunicable Diseases Adv. Clin. Chem. 2014 63 247 308 24783356 10.1016/b978-0-12-800094-6.00007-8

101. Yoshimura T. Li C. Wang Y. Matsukawa A. The Chemokine Monocyte Chemoattractant Protein-1/CCL2 Is a Promoter of Breast Cancer Metastasis Cell. Mol. Immunol. 2023 20 714 738 10.1038/s41423-023-01013-0 37208442 PMC10310763

102. Bhavsar I. Miller C.S. Al-Sabbagh M. Macrophage Inflammatory Protein-1 Alpha (MIP-1 Alpha)/CCL3: As a Biomarker Gen. Methods Biomark. Res. Their Appl. 2015 223 223 249

103. Baba T. Mukaida N. Role of Macrophage Inflammatory Protein (MIP)-1α/CCL3 in Leukemogenesis Mol. Cell. Oncol. 2014 1 e29899 10.4161/mco.29899 27308309 PMC4905173

104. Marín Oyarzún C.P. Glembotsky A.C. Goette N.P. Lev P.R. De Luca G. Baroni Pietto M.C. Moiraghi B. Castro Ríos M.A. Vicente A. Marta R.F. Platelet Toll-Like Receptors Mediate Thromboinflammatory Responses in Patients with Essential Thrombocythemia Front. Immunol. 2020 11 705 10.3389/fimmu.2020.00705 32425934 PMC7203216

105. Deshauer C. Morgan A.M. Ryan E.O. Handel T.M. Prestegard J.H. Wang X. Interactions of the Chemokine CCL5/RANTES with Medium-Sized Chondroitin Sulfate Ligands Structure 2015 23 1066 1077 10.1016/j.str.2015.03.024 25982530 PMC4456249

106. Harrison P. Platelet Alpha-Granular Fibrinogen Platelets 1992 3 1 10 10.3109/09537109209013161 21043893

107. Zhou Y. Dong J. Wang M. Liu Y. New Insights of Platelet Endocytosis and Its Implication for Platelet Function Front. Cardiovasc. Med. 2024 10 8170 10.3389/fcvm.2023.1308170 38264257 PMC10803655

108. Peters C.G. Flaumenhaft R. Localization of VAMP Isoforms in Platelets Reveals Separate Granule Populations with Distinct Functions Blood 2010 116 2015 10.1182/blood.V116.21.2015.2015

109. Swinkels M. Hordijk S. Bürgisser P.E. Slotman J.A. Carter T. Leebeek F.W.G. Jansen A.J.G. Voorberg J. Bierings R. Quantitative Super-Resolution Imaging of Platelet Degranulation Reveals Differential Release of von Willebrand Factor and von Willebrand Factor Propeptide from Alpha-Granules J. Thromb. Haemost. 2023 21 1967 1980 10.1016/j.jtha.2023.03.041 37061132

110. Gkouvi A. Tsiogkas S.G. Bogdanos D.P. Gika H. Goulis D.G. Grammatikopoulou M.G. Proteomics in Patients with Fibromyalgia Syndrome: A Systematic Review of Observational Studies Curr. Pain. Headache Rep. 2024 28 565 586 10.1007/s11916-024-01244-4 38652420 PMC11271354

111. Aburima A. Berger M. Spurgeon B.E.J. Webb B.A. Wraith K.S. Febbraio M. Poole A.W. Naseem K.M. Thrombospondin-1 Promotes Hemostasis through Modulation of CAMP Signaling in Blood Platelets Blood 2021 137 678 689 10.1182/blood.2020005382 33538796

112. Mereuta O.M. Agarwal T. Ghozy S. Dai D. Arul S. Brinjikji W. Kallmes D.F. Kadirvel R. Shell Versus Core Architecture and Biology of Thrombi in Acute Ischemic Stroke: A Systematic Review Clin. Appl. Thromb./Hemost. 2023 29 10760296231213632 10.1177/10760296231213632 37960892 PMC10647960

113. Denorme F. Vanhoorelbeke K. De Meyer S.F. Von Willebrand Factor and Platelet Glycoprotein Ib: A Thromboinflammatory Axis in Stroke Front. Immunol. 2019 10 2881 10.3389/fimmu.2019.02884 31921147 PMC6928043

114. Zou J. Swieringa F. de Laat B. de Groot P.G. Roest M. Heemskerk J.W.M. Reversible Platelet Integrin AIIbβ3 Activation and Thrombus Instability Int. J. Mol. Sci. 2022 23 12512 10.3390/ijms232012512 36293367 PMC9604507

115. Ellis M.L. Alwis I. Smythe R. Yuan Y. Jackson S.P. Megakaryocyte Buds Are Distinct from Microvesicles and Likely to Represent Platelet Precursors Blood Adv. 2023 7 982 986 10.1182/bloodadvances.2022008850 36355836 PMC10027498

116. Lavergne M. Janus-Bell E. Schaff M. Gachet C. Mangin P. Platelet Integrins in Tumor Metastasis: Do They Represent a Therapeutic Target? Cancers 2017 9 133 10.3390/cancers9100133 28956830 PMC5664072

117. Li R. Emsley J. The Organizing Principle of the Platelet Glycoprotein Ib–IX–V Complex J. Thromb. Haemost. 2013 11 605 614 10.1111/jth.12144 23336709 PMC3696474

118. Bendas G. Schlesinger M. The GPIb-IX Complex on Platelets: Insight into Its Novel Physiological Functions Affecting Immune Surveillance, Hepatic Thrombopoietin Generation, Platelet Clearance and Its Relevance for Cancer Development and Metastasis Exp. Hematol. Oncol. 2022 11 19 10.1186/s40164-022-00273-2 35366951 PMC8976409

119. Colonna M. The Biology of TREM Receptors Nat. Rev. Immunol. 2023 23 580 594 10.1038/s41577-023-00837-1 36750615 PMC9904274

120. Schmoker A.M. Perez Pearson L.M. Cruz C. Colon Flores L.G. Branfeild S. Pagán Torres F.D. Fonseca K. Cantres Y.M. Salgado Ramirez C.A. Melendez L.M. Defining the TLT-1 Interactome from Resting and Activated Human Platelets J. Proteom. 2020 215 103638 10.1016/j.jprot.2020.103638 31923473 PMC7044047

121. Heijnen H.F.G. WPBs and α-Granules: More and More Look-Alike? Blood 2019 133 2634 2636 10.1182/blood-2019-02-900878 31221793

122. Pluthero F.G. Kahr W.H.A. Evaluation of Human Platelet Granules by Structured Illumination Laser Fluorescence Microscopy Platelets 2023 34 2157808 10.1080/09537104.2022.2157808 36572649

123. Stolla M.C. Leyens K. Catherman S.C. McGrath K.E. Palis J. P-Selectin Expression and Platelet Function Are Developmentally Regulated Blood 2014 124 1439 10.1182/blood.V124.21.1439.1439

124. Russo V. Falco L. Tessitore V. Mauriello A. Catapano D. Napolitano N. Tariq M. Caturano A. Ciccarelli G. D’Andrea A. Anti-Inflammatory and Anticancer Effects of Anticoagulant Therapy in Patients with Malignancy Life 2023 13 1888 10.3390/life13091888 37763292 PMC10532829

125. Rossaint J. Zarbock A. Platelets in Leucocyte Recruitment and Function Cardiovasc. Res. 2015 107 386 395 10.1093/cvr/cvv048 25712962

126. Dehghani T. Panitch A. Endothelial Cells, Neutrophils and Platelets: Getting to the Bottom of an Inflammatory Triangle Open Biol. 2020 10 200161 10.1098/rsob.200161 33050789 PMC7653352

127. Lehwald N. Duhme C. Pinchuk I. Kirchner J. Wieferich K. Schmelzle M. Jurk K. Windmöller B.A. Hübner W. Homey B. Platelets Boost Recruitment of CD133+ Bone Marrow Stem Cells to Endothelium and the Rodent Liver—The Role of P-Selectin/PSGL-1 Interactions Int. J. Mol. Sci. 2020 21 6431 10.3390/ijms21176431 32899390 PMC7504029

128. De Pablo-Moreno J.A. Miguel-Batuecas A. de Sancha M. Liras A. The Magic of Proteases: From a Procoagulant and Anticoagulant Factor V to an Equitable Treatment of Its Inherited Deficiency Int. J. Mol. Sci. 2023 24 6243 10.3390/ijms24076243 37047215 PMC10093859

129. Ren M. Li R. Chen N. Pang N. Li Y. Deng X. Wang L. Luo M. Liu Y. Hao H. Platelet-Derived Factor V Is a Critical Mediator of Arterial Thrombosis J. Am. Heart Assoc. 2017 6 e006345 10.1161/JAHA.117.006345 28673898 PMC5586322

130. Orlova N.A. Kovnir S.V. Vorobiev I.I. Gabibov A.G. Coagulation Factor IX for Hemophilia B Therapy Acta Naturae 2012 4 62 73 10.32607/20758251-2012-4-2-62-73 22872812 PMC3408704

131. Misenheimer T.M. Lasarev M.R. Kumfer K.T. Sheehan J.P. Schwartz B.S. A Novel Factor IXa–Specific Enzyme-Linked Immunosorbent Assay Detects Factor IXa in Human Plasma Res. Pr. Thromb. Haemost. 2024 8 102338 10.1016/j.rpth.2024.102338 38433974 PMC10907220

132. Chamarthy S. Normal Coagulation and Hemostasis Pathobiology of Human Disease Elsevier Amsterdam, The Netherlands 2014 1544 1552

133. Durda M.A. Wolberg A.S. Kerlin B.A. State of the Art in Factor XIII Laboratory Assessment Transfus. Apher. Sci. 2018 57 700 704 10.1016/j.transci.2018.07.006 30087086 PMC6289705

134. Shi D.-Y. Wang S.-J. Advances of Coagulation Factor XIII Chin. Med. J. 2017 130 219 223 10.4103/0366-6999.198007 28091415 PMC5282680

135. Kucuk B. Bingol-Ozakpinar O. Demir M. Uras F. Gas6 and TAM Receptors in Mouse Platelets Blood 2012 120 5199 10.1182/blood.V120.21.5199.5199

136. Breitenecker K. Heiden D. Demmer T. Weber G. Primorac A.-M. Hedrich V. Ortmayr G. Gruenberger T. Starlinger P. Herndler-Brandstetter D. Tumor-Extrinsic Axl Expression Shapes an Inflammatory Microenvironment Independent of Tumor Cell Promoting Axl Signaling in Hepatocellular Carcinoma Int. J. Mol. Sci. 2024 25 4202 10.3390/ijms25084202 38673795 PMC11050718

137. Zdżalik-Bielecka D. Poświata A. Kozik K. Jastrzębski K. Schink K.O. Brewińska-Olchowik M. Piwocka K. Stenmark H. Miączyńska M. The GAS6-AXL Signaling Pathway Triggers Actin Remodeling That Drives Membrane Ruffling, Macropinocytosis, and Cancer-Cell Invasion Proc. Natl. Acad. Sci. USA 2021 118 10.1073/pnas.2024596118 34244439 PMC8285903

138. Aquino-Domínguez A.S. Romero-Tlalolini M.d.l.A. Torres-Aguilar H. Aguilar-Ruiz S.R. Recent Advances in the Discovery and Function of Antimicrobial Molecules in Platelets Int. J. Mol. Sci. 2021 22 10230 10.3390/ijms221910230 34638568 PMC8508203

139. CL K. Jeyaraman M. Jeyaraman N. Ramasubramanian S. Khanna M. Yadav S. Antimicrobial Effects of Platelet-Rich Plasma and Platelet-Rich Fibrin: A Scoping Review Cureus 2023 15 e51360 10.7759/cureus.51360 38292974 PMC10825076

140. Portier I. Campbell R.A. Role of Platelets in Detection and Regulation of Infection Arter. Thromb. Vasc. Biol. 2020 41 70 78 10.1161/ATVBAHA.120.314645 33115274 PMC7770024

141. Ribeiro L.S. Migliari Branco L. Franklin B.S. Regulation of Innate Immune Responses by Platelets Front. Immunol. 2019 10 1320 10.3389/fimmu.2019.01320 31244858 PMC6579861

142. Ezzeroug Ezzraimi A. Hannachi N. Mariotti A. Rolain J.-M. Camoin-Jau L. Platelets and Escherichia Coli: A Complex Interaction Biomedicines 2022 10 1636 10.3390/biomedicines10071636 35884941 PMC9313189

143. Wallis S. Wolska N. Englert H. Posner M. Upadhyay A. Renné T. Eggleston I. Bagby S. Pula G. A Peptide from the Staphylococcal Protein Efb Binds P-selectin and Inhibits the Interaction of Platelets with Leukocytes J. Thromb. Haemost. 2022 20 729 741 10.1111/jth.15613 34846792

144. Antoniak S. Mackman N. Platelets and Viruses Platelets 2021 32 325 330 10.1080/09537104.2021.1887842 33615982 PMC7987802

145. Kho S. Barber B.E. Johar E. Andries B. Poespoprodjo J.R. Kenangalem E. Piera K.A. Ehmann A. Price R.N. William T. Platelets Kill Circulating Parasites of All Major Plasmodium Species in Human Malaria Blood 2018 132 1332 1344 10.1182/blood-2018-05-849307 30026183 PMC6161646

146. Chaudhary P.K. Kim S. Kim S. An Insight into Recent Advances on Platelet Function in Health and Disease Int. J. Mol. Sci. 2022 23 6022 10.3390/ijms23116022 35682700 PMC9181192

147. Ambrosio A.L. Boyle J.A. Di Pietro S.M. Mechanism of Platelet Dense Granule Biogenesis: Study of Cargo Transport and Function of Rab32 and Rab38 in a Model System Blood 2012 120 4072 4081 10.1182/blood-2012-04-420745 22927249 PMC3496959

148. Sharda A. Flaumenhaft R. The Life Cycle of Platelet Granules F1000Res 2018 7 236 10.12688/f1000research.13283.1 29560259 PMC5832915

149. Ravera S. Signorello M.G. Panfoli I. Platelet Metabolic Flexibility: A Matter of Substrate and Location Cells 2023 12 1802 10.3390/cells12131802 37443836 PMC10340290

150. Koupenova M. Ravid K. Biology of Platelet Purinergic Receptors and Implications for Platelet Heterogeneity Front. Pharmacol. 2018 9 37 10.3389/fphar.2018.00037 29441021 PMC5797577

151. Neubauer K. Zieger B. Endothelial Cells and Coagulation Cell Tissue Res. 2022 387 391 398 10.1007/s00441-021-03471-2 34014399 PMC8975780

152. Dupuis A. Bordet J.-C. Eckly A. Gachet C. Platelet δ-Storage Pool Disease: An Update J. Clin. Med. 2020 9 2508 10.3390/jcm9082508 32759727 PMC7466064

153. Hechler B. Gachet C. P2 Receptors and Platelet Function Purinergic Signal. 2011 7 293 303 10.1007/s11302-011-9247-6 21792575 PMC3166986

154. Ponomarenko E.A. Ignatova A.A. Polokhov D.M. Khismatullina R.D. Kurilo D.S. Shcherbina A. Zharkov P.A. Maschan A.A. Novichkova G.A. Panteleev M.A. Healthy Pediatric Platelets Are Moderately Hyporeactive in Comparison with Adults’ Platelets Platelets 2022 33 727 734 10.1080/09537104.2021.1981848 34749589

155. Battinelli E.M. Markens B.A. Italiano J.E. Release of Angiogenesis Regulatory Proteins from Platelet Alpha Granules: Modulation of Physiologic and Pathologic Angiogenesis Blood 2011 118 1359 1369 10.1182/blood-2011-02-334524 21680800 PMC3152500

156. Kubacka M. Mogilski S. Bednarski M. Pociecha K. Świerczek A. Nicosia N. Schabikowski J. Załuski M. Chłoń-Rzepa G. Hockemeyer J. Antiplatelet Effects of Selected Xanthine-Based Adenosine A2A and A2B Receptor Antagonists Determined in Rat Blood Int. J. Mol. Sci. 2023 24 13378 10.3390/ijms241713378 37686188 PMC10487961

157. Gündüz D. Tanislav C. Sedding D. Parahuleva M. Santoso S. Troidl C. Hamm C. Aslam M. Uridine Triphosphate Thio Analogues Inhibit Platelet P2Y12 Receptor and Aggregation Int. J. Mol. Sci. 2017 18 269 10.3390/ijms18020269 28146050 PMC5343805

158. Aslam M. Sedding D. Koshty A. Santoso S. Schulz R. Hamm C. Gündüz D. Nucleoside Triphosphates Inhibit ADP, Collagen, and Epinephrine-Induced Platelet Aggregation: Role of P2Y1 and P2Y12 Receptors Thromb. Res. 2013 132 548 557 10.1016/j.thromres.2013.08.021 24071464

159. Kassouf N. Ambily A. Watson S. Hassock S. Authi H.S. Srivastava S. Watson S.P. Authi K.S. Phosphatidylinositol-3,4,5-Trisphosphate Stimulates Ca 2+ Elevation and Akt Phosphorylation to Constitute a Major Mechanism of Thromboxane A2 Formation in Human Platelets Cell Signal. 2015 27 1488 1498 10.1016/j.cellsig.2015.03.008 25797048

160. Maclean J.A. Schoenwaelder S.M. Serotonin in Platelets Serotonin Elsevier Amsterdam, The Netherlands 2019 91 119

161. Mammadova-Bach E. Mauler M. Braun A. Duerschmied D. Immuno-Thrombotic Effects of Platelet Serotonin Serotonin—A Chemical Messenger between All Types of Living Cells InTech Houston, TX, USA 2017

162. Briones-Aranda A. Corzo-Gómez J. Casique-Aguirre D. Megchún-Hernández M. The Platelet Serotonergic System and the Search for New Biomarkers and Therapeutic Options for Diverse Diseases Serotonin—Neurotransmitter and Hormone of Brain, Bowels and Blood [Working Title] IntechOpen Houston, TX, USA 2023

163. Rieder M. Gauchel N. Bode C. Duerschmied D. Serotonin: A Platelet Hormone Modulating Cardiovascular Disease J. Thromb. Thrombolysis 2021 52 42 47 10.1007/s11239-020-02331-0 33155668 PMC8282555

164. Jiang S.Z. To J.L. Hughes M.R. McNagny K.M. Kim H. Platelet Signaling at the Nexus of Innate Immunity and Rheumatoid Arthritis Front. Immunol. 2022 13 977828 10.3389/fimmu.2022.977828 36505402 PMC9732516

165. Sage S.O. Harper A.G.S. Calcium Sequestration by Human Platelet Acidic Organelles Is Regulated by the Actin Cytoskeleton and Autocrine 5-Hydroxytryptamine Cell Calcium 2022 101 102522 10.1016/j.ceca.2021.102522 34968774

166. Weitz J.I. Fredenburgh J.C. Platelet Polyphosphate: The Long and the Short of It Blood 2017 129 1574 1575 10.1182/blood-2017-01-761593 28336732

167. Docampo R. Advances in the Cellular Biology, Biochemistry, and Molecular Biology of Acidocalcisomes Microbiol. Mol. Biol. Rev. 2024 88 e0004223 10.1128/mmbr.00042-23 38099688 PMC10966946

168. Bernhard E. Nitschke Y. Khursigara G. Sabbagh Y. Wang Y. Rutsch F. A Reference Range for Plasma Levels of Inorganic Pyrophosphate in Children Using the ATP Sulfurylase Method J. Clin. Endocrinol. Metab. 2022 107 109 118 10.1210/clinem/dgab615 34498693 PMC8684482

169. Fitch-Tewfik J.L. Flaumenhaft R. Platelet Granule Exocytosis: A Comparison with Chromaffin Cells Front. Endocrinol. 2013 4 77 10.3389/fendo.2013.00077 PMC3693082 23805129

170. Flaumenhaft R. Sharda A. Platelet Secretion Platelets Elsevier Amsterdam, The Netherlands 2019 349 370

171. Feng M. Hechler B. Adam F. Gachet C. Eckly A. Kauskot A. Denis C.V. Bryckaert M. Bobe R. Rosa J.-P. ADP Receptor P2Y12 Is the Capstone of the Cross-Talk between Ca 2+ Mobilization Pathways Dependent on Ca 2+ ATPases Sarcoplasmic/Endoplasmic Reticulum Type 3 and Type 2b in Platelets Res. Pr. Thromb. Haemost. 2023 7 100004 10.1016/j.rpth.2022.100004 PMC10031336 36970741

172. Karampini E. Bierings R. Voorberg J. Orchestration of Primary Hemostasis by Platelet and Endothelial Lysosome-Related Organelles Arter. Thromb. Vasc. Biol. 2020 40 1441 1453 10.1161/ATVBAHA.120.314245 32375545

173. Södergren A.L. Svensson Holm A.-C.B. Ramström S. Lindström E.G. Grenegård M. Öllinger K. Thrombin-Induced Lysosomal Exocytosis in Human Platelets Is Dependent on Secondary Activation by ADP and Regulated by Endothelial-Derived Substances Platelets 2016 27 86 92 10.3109/09537104.2015.1042446 25970449

174. Koupenova M. Livada A.C. Morrell C.N. Platelet and Megakaryocyte Roles in Innate and Adaptive Immunity Circ. Res. 2022 130 288 308 10.1161/CIRCRESAHA.121.319821 35050690 PMC8852355

175. Thon J.N. Peters C.G. Machlus K.R. Aslam R. Rowley J. Macleod H. Devine M.T. Fuchs T.A. Weyrich A.S. Semple J.W. T Granules in Human Platelets Function in TLR9 Organization and Signaling J. Cell Biol. 2012 198 561 574 10.1083/jcb.201111136 22908309 PMC3514030

176. Khan A.B. Siddiqui U. Fatima S. Rehman A.A. Jairajpuri M.A. Naringin Binds to Protein Disulfide Isomerase to Inhibit Its Activity and Modulate the Blood Coagulation Rates: Implications in Controlling Thrombosis Int. J. Biol. Macromol. 2023 252 126241 10.1016/j.ijbiomac.2023.126241 37567521

177. Seifert A.W. Monaghan J.R. Voss S.R. Maden M. Skin Regeneration in Adult Axolotls: A Blueprint for Scar-Free Healing in Vertebrates PLoS ONE 2012 7 e32875 10.1371/journal.pone.0032875 22485136 PMC3317654

178. Richardson R. Slanchev K. Kraus C. Knyphausen P. Eming S. Hammerschmidt M. Adult Zebrafish as a Model System for Cutaneous Wound-Healing Research J. Investig. Dermatol. 2013 133 1655 1665 10.1038/jid.2013.16 23325040 PMC3644348

179. Yokoyama H. Maruoka T. Aruga A. Amano T. Ohgo S. Shiroishi T. Tamura K. Prx-1 Expression in Xenopus Laevis Scarless Skin-Wound Healing and Its Resemblance to Epimorphic Regeneration J. Investig. Dermatol. 2011 131 2477 2485 10.1038/jid.2011.223 21776009

180. Bohaud C. Johansen M.D. Jorgensen C. Ipseiz N. Kremer L. Djouad F. The Role of Macrophages During Zebrafish Injury and Tissue Regeneration Under Infectious and Non-Infectious Conditions Front. Immunol. 2021 12 707824 10.3389/fimmu.2021.707824 34367168 PMC8334857

181. Naomi R. Bahari H. Yazid M.D. Embong H. Othman F. Zebrafish as a Model System to Study the Mechanism of Cutaneous Wound Healing and Drug Discovery: Advantages and Challenges Pharmaceuticals 2021 14 1058 10.3390/ph14101058 34681282 PMC8539578

182. Chen N. Quan Y. Chen M. Lu Y. Yang L. Wang S. Chen F. Xu Y. Shen M. Zeng H. Melanocortin/MC5R Axis Regulates the Proliferation of Hematopoietic Stem Cells in Mice after Ionizing Radiation Injury Blood Adv. 2023 7 3199 3212 10.1182/bloodadvances.2022009249 36920787 PMC10338215

183. Li L. Rutlin M. Abraira V.E. Cassidy C. Kus L. Gong S. Jankowski M.P. Luo W. Heintz N. Koerber H.R. The Functional Organization of Cutaneous Low-Threshold Mechanosensory Neurons Cell 2011 147 1615 1627 10.1016/j.cell.2011.11.027 22196735 PMC3262167

184. Lansdown A.B.G. Calcium: A Potential Central Regulator in Wound Healing in the Skin Wound Repair Regen. 2002 10 271 285 10.1046/j.1524-475X.2002.10502.x 12406163

185. Sorg H. Sorg C.G.G. Skin Wound Healing: Of Players, Patterns, and Processes Eur. Surg. Res. 2023 64 141 157 10.1159/000528271 36417847

186. van der Vliet A. Janssen-Heininger Y.M.W. Hydrogen Peroxide as a Damage Signal in Tissue Injury and Inflammation: Murderer, Mediator, or Messenger? J. Cell. Biochem. 2014 115 427 435 10.1002/jcb.24683 24122865 PMC4363740

187. Su Y. Richmond A. Chemokine Regulation of Neutrophil Infiltration of Skin Wounds Adv. Wound Care 2015 4 631 640 10.1089/wound.2014.0559 PMC4620531 26543677

188. Gillitzer R. Goebeler M. Chemokines in Cutaneous Wound Healing J. Leukoc. Biol. 2001 69 513 521 10.1189/jlb.69.4.513 11310836

189. Othman A. Sekheri M. Filep J.G. Roles of Neutrophil Granule Proteins in Orchestrating Inflammation and Immunity FEBS J. 2022 289 3932 3953 10.1111/febs.15803 33683814 PMC9546106

190. Wilgus T.A. Roy S. McDaniel J.C. Neutrophils and Wound Repair: Positive Actions and Negative Reactions Adv. Wound Care 2013 2 379 388 10.1089/wound.2012.0383 PMC3763227 24527354

191. Rawat K. Syeda S. Shrivastava A. Neutrophil-Derived Granule Cargoes: Paving the Way for Tumor Growth and Progression Cancer Metastasis Rev. 2021 40 221 244 10.1007/s10555-020-09951-1 33438104 PMC7802614

192. Romejko K. Markowska M. Niemczyk S. The Review of Current Knowledge on Neutrophil Gelatinase-Associated Lipocalin (NGAL) Int. J. Mol. Sci. 2023 24 10470 10.3390/ijms241310470 37445650 PMC10341718

193. Zhou Y. Bréchard S. Neutrophil Extracellular Vesicles: A Delicate Balance between Pro-Inflammatory Responses and Anti-Inflammatory Therapies Cells 2022 11 3318 10.3390/cells11203318 36291183 PMC9600967

194. Immler R. Nadolni W. Bertsch A. Morikis V. Rohwedder I. Masgrau-Alsina S. Schroll T. Yevtushenko A. Soehnlein O. Moser M. The Voltage-Gated Potassium Channel KV1.3 Regulates Neutrophil Recruitment during Inflammation Cardiovasc. Res. 2022 118 1289 1302 10.1093/cvr/cvab133 33881519 PMC8953450

195. Domon H. Nagai K. Maekawa T. Oda M. Yonezawa D. Takeda W. Hiyoshi T. Tamura H. Yamaguchi M. Kawabata S. Neutrophil Elastase Subverts the Immune Response by Cleaving Toll-Like Receptors and Cytokines in Pneumococcal Pneumonia Front. Immunol. 2018 9 732 10.3389/fimmu.2018.00732 29922273 PMC5996908

196. Segel G.B. Halterman M.W. Lichtman M.A. The Paradox of the Neutrophil’s Role in Tissue Injury J. Leukoc. Biol. 2011 89 359 372 10.1189/jlb.0910538 21097697 PMC6608002

197. Yipp B.G. Kubes P. NETosis: How Vital Is It? Blood 2013 122 2784 2794 10.1182/blood-2013-04-457671 24009232

198. Jorch S.K. Kubes P. An Emerging Role for Neutrophil Extracellular Traps in Noninfectious Disease Nat. Med. 2017 23 279 287 10.1038/nm.4294 28267716

199. He L. Marneros A.G. Macrophages Are Essential for the Early Wound Healing Response and the Formation of a Fibrovascular Scar Am. J. Pathol. 2013 182 2407 2417 10.1016/j.ajpath.2013.02.032 23602833 PMC3668032

200. Yanez D.A. Lacher R.K. Vidyarthi A. Colegio O.R. The Role of Macrophages in Skin Homeostasis Pflug. Arch. 2017 469 455 463 10.1007/s00424-017-1953-7 PMC5663320 28233123

201. Dash S.P. Gupta S. Sarangi P.P. Monocytes and Macrophages: Origin, Homing, Differentiation, and Functionality during Inflammation Heliyon 2024 10 e29686 10.1016/j.heliyon.2024.e29686 38681642 PMC11046129

202. Chen Y.-L. Wang H.-T. Lin P.-T. Chuang J.-H. Yang M.-Y. Macrophage Inflammatory Protein-1 Alpha, a Potential Biomarker for Predicting Left Atrial Remodeling in Patients with Atrial Fibrillation Front. Cardiovasc. Med. 2021 8 784792 10.3389/fcvm.2021.784792 34957262 PMC8695724

203. Georgakis M.K. van der Laan S.W. Asare Y. Mekke J.M. Haitjema S. Schoneveld A.H. de Jager S.C.A. Nurmohamed N.S. Kroon J. Stroes E.S.G. Monocyte-Chemoattractant Protein-1 Levels in Human Atherosclerotic Lesions Associate with Plaque Vulnerability Arter. Thromb. Vasc. Biol. 2021 41 2038 2048 10.1161/ATVBAHA.121.316091 33827260

204. Goren I. Allmann N. Yogev N. Schürmann C. Linke A. Holdener M. Waisman A. Pfeilschifter J. Frank S. A Transgenic Mouse Model of Inducible Macrophage Depletion Am. J. Pathol. 2009 175 132 147 10.2353/ajpath.2009.081002 19528348 PMC2708801

205. Mirza R. DiPietro L.A. Koh T.J. Selective and Specific Macrophage Ablation Is Detrimental to Wound Healing in Mice Am. J. Pathol. 2009 175 2454 2462 10.2353/ajpath.2009.090248 19850888 PMC2789630

206. Lucas T. Waisman A. Ranjan R. Roes J. Krieg T. Müller W. Roers A. Eming S.A. Differential Roles of Macrophages in Diverse Phases of Skin Repair J. Immunol. 2010 184 3964 3977 10.4049/jimmunol.0903356 20176743

207. Zhu Z. Ding J. Ma Z. Iwashina T. Tredget E.E. Systemic Depletion of Macrophages in the Subacute Phase of Wound Healing Reduces Hypertrophic Scar Formation Wound Repair Regen. 2016 24 644 656 10.1111/wrr.12442 27169512

208. Hu M.S. Walmsley G.G. Barnes L.A. Weiskopf K. Rennert R.C. Duscher D. Januszyk M. Maan Z.N. Hong W.X. Cheung A.T.M. Delivery of Monocyte Lineage Cells in a Biomimetic Scaffold Enhances Tissue Repair JCI Insight 2017 2 e96260 10.1172/jci.insight.96260 28978794 PMC5841872

209. Godwin J.W. Pinto A.R. Rosenthal N.A. Macrophages Are Required for Adult Salamander Limb Regeneration Proc. Natl. Acad. Sci. USA 2013 110 9415 9420 10.1073/pnas.1300290110 23690624 PMC3677454

210. Wetzler C. Kämpfer H. Stallmeyer B. Pfeilschifter J. Frank S. Large and Sustained Induction of Chemokines during Impaired Wound Healing in the Genetically Diabetic Mouse: Prolonged Persistence of Neutrophils and Macrophages during the Late Phase of Repair J. Investig. Dermatol. 2000 115 245 253 10.1046/j.1523-1747.2000.00029.x 10951242

211. Khanna S. Biswas S. Shang Y. Collard E. Azad A. Kauh C. Bhasker V. Gordillo G.M. Sen C.K. Roy S. Macrophage Dysfunction Impairs Resolution of Inflammation in the Wounds of Diabetic Mice PLoS ONE 2010 5 e9539 10.1371/journal.pone.0009539 20209061 PMC2832020

212. Krzyszczyk P. Schloss R. Palmer A. Berthiaume F. The Role of Macrophages in Acute and Chronic Wound Healing and Interventions to Promote Pro-Wound Healing Phenotypes Front. Physiol. 2018 9 419 10.3389/fphys.2018.00419 29765329 PMC5938667

213. Li W. Xu Z. Zou B. Yang D. Lu Y. Zhang X. Zhang C. Li Y. Zhu C. Macrophage Regulation in Vascularization upon Regeneration and Repair of Tissue Injury and Engineered Organ Transplantation Fundam. Res. 2024 in press 10.1016/j.fmre.2023.12.015 PMC11997588 40242532

214. Di Nardo A. Yamasaki K. Dorschner R.A. Lai Y. Gallo R.L. Mast Cell Cathelicidin Antimicrobial Peptide Prevents Invasive Group A Streptococcus Infection of the Skin J. Immunol. 2008 180 7565 7573 10.4049/jimmunol.180.11.7565 18490758 PMC2664112

215. Li H. Niu J. Wang X. Niu M. Liao C. The Contribution of Antimicrobial Peptides to Immune Cell Function: A Review of Recent Advances Pharmaceutics 2023 15 2278 10.3390/pharmaceutics15092278 37765247 PMC10535326

216. Wang Z. Lai Y. Bernard J.J. MacLeod D.T. Cogen A.L. Moss B. Di Nardo A. Skin Mast Cells Protect Mice against Vaccinia Virus by Triggering Mast Cell Receptor S1PR2 and Releasing Antimicrobial Peptides J. Immunol. 2012 188 345 357 10.4049/jimmunol.1101703 22140255 PMC3244574

217. Wilgus T.A. Wulff B.C. The Importance of Mast Cells in Dermal Scarring Adv. Wound Care 2014 3 356 365 10.1089/wound.2013.0457 24757590 PMC3985512

218. Younan G. Suber F. Xing W. Shi T. Kunori Y. Åbrink M. Pejler G. Schlenner S.M. Rodewald H.-R. Moore F.D. The Inflammatory Response after an Epidermal Burn Depends on the Activities of Mouse Mast Cell Proteases 4 and 5 J. Immunol. 2010 185 7681 7690 10.4049/jimmunol.1002803 21076070 PMC3058366

219. Peña O.A. Martin P. Cellular and Molecular Mechanisms of Skin Wound Healing Nat. Rev. Mol. Cell Biol. 2024 25 599 616 10.1038/s41580-024-00715-1 38528155

220. Bacci S. Fine Regulation during Wound Healing by Mast Cells, a Physiological Role Not Yet Clarified Int. J. Mol. Sci. 2022 23 1820 10.3390/ijms23031820 35163741 PMC8836533

221. Gao M. Guo H. Dong X. Wang Z. Yang Z. Shang Q. Wang Q. Regulation of Inflammation during Wound Healing: The Function of Mesenchymal Stem Cells and Strategies for Therapeutic Enhancement Front. Pharmacol. 2024 15 1345779 10.3389/fphar.2024.1345779 38425646 PMC10901993

222. Wulff B.C. Parent A.E. Meleski M.A. DiPietro L.A. Schrementi M.E. Wilgus T.A. Mast Cells Contribute to Scar Formation during Fetal Wound Healing J. Investig. Dermatol. 2012 132 458 465 10.1038/jid.2011.324 21993557 PMC3258379

223. Wulff B.C. Wilgus T.A. Mast Cell Activity in the Healing Wound: More than Meets the Eye? Exp. Dermatol. 2013 22 507 510 10.1111/exd.12169 23802591 PMC3723719

224. Tellechea A. Leal E.C. Kafanas A. Auster M.E. Kuchibhotla S. Ostrovsky Y. Tecilazich F. Baltzis D. Zheng Y. Carvalho E. Mast Cells Regulate Wound Healing in Diabetes Diabetes 2016 65 2006 2019 10.2337/db15-0340 27207516 PMC4915574

225. Song M.-S. Nam J.-H. Noh K.-E. Lim D.-S. Dendritic Cell-Based Immunotherapy: The Importance of Dendritic Cell Migration J. Immunol. Res. 2024 2024 7827246 10.1155/2024/7827246 38628676 PMC11019573

226. Malissen B. Tamoutounour S. Henri S. The Origins and Functions of Dendritic Cells and Macrophages in the Skin Nat. Rev. Immunol. 2014 14 417 428 10.1038/nri3683 24854591

227. Yan B. Liu N. Li J. Li J. Zhu W. Kuang Y. Chen X. Peng C. The Role of Langerhans Cells in Epidermal Homeostasis and Pathogenesis of Psoriasis J. Cell. Mol. Med. 2020 24 11646 11655 10.1111/jcmm.15834 32916775 PMC7579693

228. Van den Bossche J. Malissen B. Mantovani A. De Baetselier P. Van Ginderachter J.A. Regulation and Function of the E-Cadherin/Catenin Complex in Cells of the Monocyte-Macrophage Lineage and DCs Blood 2012 119 1623 1633 10.1182/blood-2011-10-384289 22174153

229. Zhou L. Jiang A. Veenstra J. Ozog D. Mi Q.-S. The Roles of Skin Langerhans Cells in Immune Tolerance and Cancer Immunity Vaccines 2022 10 1380 10.3390/vaccines10091380 36146458 PMC9503294

230. Gregorio J. Meller S. Conrad C. Di Nardo A. Homey B. Lauerma A. Arai N. Gallo R.L. DiGiovanni J. Gilliet M. Plasmacytoid Dendritic Cells Sense Skin Injury and Promote Wound Healing through Type I Interferons J. Exp. Med. 2010 207 2921 2930 10.1084/jem.20101102 21115688 PMC3005239

231. Arroyo Hornero R. Idoyaga J. Plasmacytoid Dendritic Cells: A Dendritic Cell in Disguise Mol. Immunol. 2023 159 38 45 10.1016/j.molimm.2023.05.007 37269733 PMC10625168

232. Keyes B.E. Liu S. Asare A. Naik S. Levorse J. Polak L. Lu C.P. Nikolova M. Pasolli H.A. Fuchs E. Impaired Epidermal to Dendritic T Cell Signaling Slows Wound Repair in Aged Skin Cell 2016 167 1323 1338.e14 10.1016/j.cell.2016.10.052 27863246 PMC5364946

233. Witherden D.A. Watanabe M. Garijo O. Rieder S.E. Sarkisyan G. Cronin S.J.F. Verdino P. Wilson I.A. Kumanogoh A. Kikutani H. The CD100 Receptor Interacts with Its Plexin B2 Ligand to Regulate Epidermal Γδ T Cell Function Immunity 2012 37 314 325 10.1016/j.immuni.2012.05.026 22902232 PMC3430606

234. Kim M.K. Kim J. Properties of Immature and Mature Dendritic Cells: Phenotype, Morphology, Phagocytosis, and Migration RSC Adv. 2019 9 11230 11238 10.1039/C9RA00818G 35520256 PMC9063012

235. Jameson J.M. Cauvi G. Witherden D.A. Havran W.L. A Keratinocyte-Responsive Γδ TCR Is Necessary for Dendritic Epidermal T Cell Activation by Damaged Keratinocytes and Maintenance in the Epidermis J. Immunol. 2004 172 3573 3579 10.4049/jimmunol.172.6.3573 15004158

236. Havran W.L. Jameson J.M. Epidermal T Cells and Wound Healing J. Immunol. 2010 184 5423 5428 10.4049/jimmunol.0902733 20483798 PMC2944652

237. Marshall P.L. Nagy N. Kaber G. Barlow G.L. Ramesh A. Xie B.J. Linde M.H. Haddock N.L. Lester C.A. Tran Q.-L. Hyaluronan Synthesis Inhibition Impairs Antigen Presentation and Delays Transplantation Rejection Matrix Biol. 2021 96 69 86 10.1016/j.matbio.2020.12.001 33290836 PMC8147171

238. Iwabuchi K. Satoh M. Yoshino K. Ishimori N. Recent Advances Regarding the Potential Roles of Invariant Natural Killer T Cells in Cardiovascular Diseases with Immunological and Inflammatory Backgrounds Int. Immunol. 2024 36 377 392 10.1093/intimm/dxae019 38557824

239. Yip K.H. Papadopoulos M. Pant H. Tumes D.J. The Role of Invariant T Cells in Inflammation of the Skin and Airways Semin. Immunopathol. 2019 41 401 410 10.1007/s00281-019-00740-9 30989319

240. Tanno H. Kawakami K. Ritsu M. Kanno E. Suzuki A. Kamimatsuno R. Takagi N. Miyasaka T. Ishii K. Imai Y. Contribution of Invariant Natural Killer T Cells to Skin Wound Healing Am. J. Pathol. 2015 185 3248 3257 10.1016/j.ajpath.2015.08.012 26468976

241. Tanno H. Kawakami K. Kanno E. Suzuki A. Takagi N. Yamamoto H. Ishii K. Imai Y. Maruyama R. Tachi M. Invariant NKT Cells Promote Skin Wound Healing by Preventing a Prolonged Neutrophilic Inflammatory Response Wound Repair Regen. 2017 25 805 815 10.1111/wrr.12588 28940971

242. Govindaraju P. Todd L. Shetye S. Monslow J. Puré E. CD44-Dependent Inflammation, Fibrogenesis, and Collagenolysis Regulates Extracellular Matrix Remodeling and Tensile Strength during Cutaneous Wound Healing Matrix Biol. 2019 75–76 314 330 10.1016/j.matbio.2018.06.004 29894820 PMC6286871

243. Nguyen J.K. Austin E. Huang A. Mamalis A. Jagdeo J. The IL-4/IL-13 Axis in Skin Fibrosis and Scarring: Mechanistic Concepts and Therapeutic Targets Arch. Dermatol. Res. 2020 312 81 92 10.1007/s00403-019-01972-3 31493000 PMC7008089

244. Saw V.P.J. Schmidt E. Offiah I. Galatowicz G. Zillikens D. Dart J.K.G. Calder V.L. Daniels J.T. Profibrotic Phenotype of Conjunctival Fibroblasts from Mucous Membrane Pemphigoid Am. J. Pathol. 2011 178 187 197 10.1016/j.ajpath.2010.11.013 21224056 PMC3069913

245. Maeda D. Kubo T. Kiya K. Kawai K. Matsuzaki S. Kobayashi D. Fujiwara T. Katayama T. Hosokawa K. Periostin Is Induced by IL-4/IL-13 in Dermal Fibroblasts and Promotes RhoA/ROCK Pathway-Mediated TGF-Β1 Secretion in Abnormal Scar Formation J. Plast. Surg. Hand Surg. 2019 53 288 294 10.1080/2000656X.2019.1612752 31066603

246. Min M.S. Mazori D.R. Lee M.S. Merola J.F. Vleugels R.A. Cobos G. LaChance A.H. Successful Treatment of Keloids and Hypertrophic Scars with Systemic and Intralesional Dupilumab J. Drugs Dermatol. 2023 22 1220 1222 10.36849/JDD.6385 38051859

247. Wong V.W. Paterno J. Sorkin M. Glotzbach J.P. Levi K. Januszyk M. Rustad K.C. Longaker M.T. Gurtner G.C. Mechanical Force Prolongs Acute Inflammation via T-cell-dependent Pathways during Scar Formation FASEB J. 2011 25 4498 4510 10.1096/fj.10-178087 21911593

248. Popescu L.M. Faussone-Pellegrini M.-S. TELOCYTES—A Case of Serendipity: The Winding Way from Interstitial Cells of Cajal (ICC), via Interstitial Cajal-Like Cells (ICLC) to TELOCYTES J. Cell. Mol. Med. 2010 14 729 740 10.1111/j.1582-4934.2010.01059.x 20367664 PMC3823108

249. Xiao J. Bei Y. Decoding Telocytes Telocytes Connect. Cells 2016 913 23 39 10.1007/978-981-10-1061-3_2 27796878

250. Aleksandrovych V. Pasternak A. Basta P. Sajewicz M. Walocha J.A. Gil K. Telocytes: Facts, Speculations and Myths (Review Article) Folia Med. Cracov. 2017 57 5 22 28608858

251. Vannucchi M.G. Telocytes and Macrophages in the Gut: From Morphology to Function, Do the Two Cell Types Interact with Each Other? Which Helps Which? Int. J. Mol. Sci. 2022 23 8435 10.3390/ijms23158435 35955569 PMC9369081

252. Xu T. Zhang H. Zhu Z. Telocytes and Endometriosis Arch. Gynecol. Obs. 2022 307 39 49 10.1007/s00404-022-06634-w 35668319

253. Mustafa F.E.-Z.A. The Cellular Architecture of the Primo Vascular System J. Acupunct. Meridian Stud. 2022 15 4 11 10.51507/j.jams.2022.15.1.4 35770569

254. Rosa I. Nardini P. Fioretto B.S. Guasti D. Romano E. Sgambati E. Marini M. Manetti M. Immunohistochemical and Ultrastructural Identification of Telocytes in the Lamina Propria of Human Vaginal Mucosa Acta Histochem. 2023 125 152094 10.1016/j.acthis.2023.152094 37757515

255. Vannucchi M.G. The Telocytes: Ten Years after Their Introduction in the Scientific Literature. An Update on Their Morphology, Distribution, and Potential Roles in the Gut Int. J. Mol. Sci. 2020 21 4478 10.3390/ijms21124478 32599706 PMC7352570

256. Omatsu Y. Nagasawa T. Identification of Microenvironmental Niches for Hematopoietic Stem Cells and Lymphoid Progenitors—Bone Marrow Fibroblastic Reticular Cells with Salient Features Int. Immunol. 2021 33 821 826 10.1093/intimm/dxab092 34668936

257. Aleksandrovych V. Gil A. Poniatowski A. Notes about Telocytes and Immunity Folia Medica Cracoviensia 2022 62 101 109 10.24425/fmc.2022.142373 36309835

258. Zhu Z. Ma Q. Meng X. Pan Y. Li Y. Wang J. Liu Y. Yang P. Interstitial Cell Dysregulation in Allergic Contact Dermatitis: A Morphodynamic Study of Novel Interstitial Cell Telocytes Microsc. Microanal. 2023 29 762 776 10.1093/micmic/ozad010 37749732

259. Chunhua L. Xuebing B. Yonghong S. Min Y. Haixiang H. Jianming Y. Zhenwei Z. Qiusheng C. Distribution and Ultrastructural Features of Telocytes in the Pars Distalis of the Rat Pituitary Gland Microsc. Microanal. 2023 29 658 664 10.1093/micmic/ozac047 37749715

260. Bai X. Mei L. Shi Y. Huang H. Guo Y. Liang C. Yang M. Wu R. Zhang Y. Chen Q. The Cellular Mechanism of Acupuncture for Ulcerative Colitis Based on the Communication of Telocytes Microsc. Microanal. 2023 29 1190 1204 10.1093/micmic/ozad028 37749671

261. Zhang S. Sun L. Chen B. Lin S. Gu J. Tan L. Lin M. Telocytes Protect against Lung Tissue Fibrosis through Hexokinase 2-dependent Pathway by Secreting Hepatocyte Growth Factor Clin. Exp. Pharmacol. Physiol. 2023 50 964 972 10.1111/1440-1681.13823 37715611

262. Yang M. Yang T. Mei L. Zhang Y. Liang C. Bai X. Zhang Z. Shi Y. Chen Q. The Potential of Berberine to Target Telocytes in Rabbit Heart Planta Med. 2023 90 84 95 10.1055/a-2198-5523 37714195

263. Hussein M.M. Sayed R.K.A. Mokhtar D.M. Structural and Immunohistochemical Characterization of Pancreas of Molly Fish ( Poecilia sphenops ), with a Special Reference to Its Immune Role Microsc. Res. Tech. 2023 86 1667 1680 10.1002/jemt.24407 37610072

264. Díaz-Flores L. Gutiérrez R. González-Gómez M. García M.d.P. Carrasco J.L. Madrid J.F. Díaz-Flores L. Telocytes/CD34+ Stromal Cells in the Normal, Hyperplastic, and Adenomatous Human Parathyroid Glands Int. J. Mol. Sci. 2023 24 12118 10.3390/ijms241512118 37569493 PMC10419317

265. Xiang J. Guo J. Zhang S. Wu H. Chen Y.-G. Wang J. Li B. Liu H. A Stromal Lineage Maintains Crypt Structure and Villus Homeostasis in the Intestinal Stem Cell Niche BMC Biol. 2023 21 169 10.1186/s12915-023-01667-2 37553612 PMC10408166

266. Bugajska J. Berska J. Pasternak A. Sztefko K. Biliary Amino Acids and Telocytes in Gallstone Disease Metabolites 2023 13 753 10.3390/metabo13060753 37367910 PMC10305334

267. Abd-Elhafeez H.H. Rutland C.S. Soliman S.A. Morphology of Migrating Telocytes and Their Potential Role in Stem Cell Differentiation during Cartilage Development in Catfish ( Clarias gariepinus ) Microsc. Res. Tech. 2023 86 1108 1121 10.1002/jemt.24374 37337938

268. Dama G. Hu X. Yan Y. Li Y. Li H. Yang F. Liu Y. Lin J. Identification and Protective Role of CD34+ Stromal Cells/Telocytes in Experimental Autoimmune Encephalomyelitis (EAE) Mouse Spleen Histochem. Cell Biol. 2023 160 11 25 10.1007/s00418-023-02186-5 37014442

269. Yang D. Yuan L. Chen S. Zhang Y. Ma X. Xing Y. Song J. Morphological and Histochemical Identification of Telocytes in Adult Yak Epididymis Sci. Rep. 2023 13 5295 10.1038/s41598-023-32220-4 37002252 PMC10066225

270. Pereira de Godoy J.M. Pereira de Godoy A.C. Guerreiro Godoy M.d.F. de Santi Neto D. Synthesis and Physiological Remodeling of CD34 Cells in the Skin Following the Reversal of Fibrosis through Intensive Treatment for Lower Limb Lymphedema: A Case Report Dermatopathology 2023 10 104 111 10.3390/dermatopathology10010016 36975385 PMC10047408

271. Fernandez-Flores A. Cassarino D.S. Type 2 Dermal Dendrocytes Are Telocytes and So Should They Be Called Am. J. Dermatopathol. 2023 45 351 353 10.1097/DAD.0000000000002415 36939132

272. Ding F. Hu Q. Wang Y. Jiang M. Cui Z. Guo R. Liu L. Chen F. Hu H. Zhao G. Smooth Muscle Cells, Interstitial Cells and Neurons in the Gallbladder (GB): Functional Syncytium of Electrical Rhythmicity and GB Motility (Review) Int. J. Mol. Med. 2023 51 33 10.3892/ijmm.2023.5236 36928163 PMC10035990

273. Díaz-Flores L. Gutiérrez R. González-Gómez M. García M.d.P. Palmas M. Carrasco J.L. Madrid J.F. Díaz-Flores L. Delimiting CD34+ Stromal Cells/Telocytes Are Resident Mesenchymal Cells That Participate in Neovessel Formation in Skin Kaposi Sarcoma Int. J. Mol. Sci. 2023 24 3793 10.3390/ijms24043793 36835203 PMC9962853

274. Henrot P. Blervaque L. Dupin I. Zysman M. Esteves P. Gouzi F. Hayot M. Pomiès P. Berger P. Cellular Interplay in Skeletal Muscle Regeneration and Wasting: Insights from Animal Models J. Cachexia Sarcopenia Muscle 2023 14 745 757 10.1002/jcsm.13103 36811134 PMC10067506

275. Ma Y. Ma Q.-W. Sun Y. Chen X.-F. The Emerging Role of Extracellular Vesicles in the Testis Hum. Reprod. 2023 38 334 351 10.1093/humrep/dead015 36728671

276. Ahmed A.M. Hussein M.R. Telocytes in Cutaneous Biology: A Reappraisal Actas Dermosifiliogr. 2023 114 229 239 10.1016/j.ad.2022.08.023 36690154

277. Babadag S. Çelebi-Saltik B. A Cellular Regulator of the Niche: Telocyte Tissue Barriers 2023 11 2131955 10.1080/21688370.2022.2131955 36218299 PMC10606812

278. Abe S. Behavior and Functional Roles of CD34+ Mesenchymal Cells in Mammalian Testes Int. J. Mol. Sci. 2022 23 9585 10.3390/ijms23179585 36076981 PMC9455925

279. Rosa I. Ibba-Manneschi L. Guasti D. Perigli G. Faussone-Pellegrini M. Manetti M. Morphologic Evidence of Telocytes in Human Thyroid Stromal Tissue J. Cell. Mol. Med. 2022 26 2477 2481 10.1111/jcmm.17282 35307951 PMC8995439

280. Manetti M. Molecular Morphology and Function of Stromal Cells Int. J. Mol. Sci. 2021 22 13422 10.3390/ijms222413422 34948214 PMC8703619

281. Rusu M.C. Mirancea N. Mănoiu V.S. Vâlcu M. Nicolescu M.I. Păduraru D. Skin Telocytes Ann. Anat.—Anat. Anz. 2012 194 359 367 10.1016/j.aanat.2011.11.007 22226149

282. Manole C.G. Soare C. Ceafalan L.C. Voiculescu V.M. Platelet-Rich Plasma in Dermatology: New Insights on the Cellular Mechanism of Skin Repair and Regeneration Life 2023 14 40 10.3390/life14010040 38255655 PMC10817627

283. Romano E. Rosa I. Fioretto B.S. Lucattelli E. Innocenti M. Ibba-Manneschi L. Matucci-Cerinic M. Manetti M. A Two-Step Immunomagnetic Microbead-Based Method for the Isolation of Human Primary Skin Telocytes/CD34+ Stromal Cells Int. J. Mol. Sci. 2020 21 5877 10.3390/ijms21165877 32824287 PMC7461544

284. Wang L. Xiao L. Zhang R. Jin H. Shi H. Ultrastructural and Immunohistochemical Characteristics of Telocytes in Human Scalp Tissue Sci. Rep. 2020 10 1693 10.1038/s41598-020-58628-w 32015359 PMC6997163

285. Mirancea N. Moroşanu A.-M. Mirancea G.-V. Juravle F.D. Mănoiu V.S. Infrastructure of the Telocytes from Tumor Stroma in the Skin Basal and Squamous Cell Carcinomas Rom. J. Morphol. Embryol. 2013 54 1025 1037 24398998

286. Díaz-Flores L. Gutiérrez R. Pino García M. González M. Díaz-Flores L. Francisco Madrid J. Telocytes as a Source of Progenitor Cells in Regeneration and Repair through Granulation Tissue Curr. Stem Cell Res. Ther. 2016 11 395 403 10.2174/1574888X10666151001115111 26423297

287. Manetti M. Guiducci S. Ruffo M. Rosa I. Faussone-Pellegrini M.S. Matucci-Cerinic M. Ibba-Manneschi L. Evidence for Progressive Reduction and Loss of Telocytes in the Dermal Cellular Network of Systemic Sclerosis J. Cell. Mol. Med. 2013 17 482 496 10.1111/jcmm.12028 23444845 PMC3822649

288. Cismasiu V.B. Radu E. Popescu L.M. MiR-193 Expression Differentiates Telocytes from Other Stromal Cells J. Cell. Mol. Med. 2011 15 1071 1074 10.1111/j.1582-4934.2011.01325.x 21447044 PMC3822620

289. Manole C.G. Marinescu B.G. Marta D. Nicolescu M.I. Areas of Cartilaginous and Osseous Metaplasia After Experimental Myocardial Infarction in Rats Anat. Rec. 2019 302 947 953 10.1002/ar.24010 30369066

290. Cucu I. Nicolescu M.I. Busnatu Ș.S. Manole C.G. Dynamic Involvement of Telocytes in Modulating Multiple Signaling Pathways in Cardiac Cytoarchitecture Int. J. Mol. Sci. 2022 23 5769 10.3390/ijms23105769 35628576 PMC9143034

291. Díaz-Flores L. Gutiérrez R. García M.P. González-Gómez M. Rodríguez-Rodriguez R. Hernández-León N. Díaz-Flores L. Carrasco J.L. Cd34+ Stromal Cells/Telocytes in Normal and Pathological Skin Int. J. Mol. Sci. 2021 22 7342 10.3390/ijms22147342 34298962 PMC8307573

292. Rosa I. Romano E. Fioretto B.S. Guasti D. Ibba-Manneschi L. Matucci-Cerinic M. Manetti M. Scleroderma-like Impairment in the Network of Telocytes/CD34+ Stromal Cells in the Experimental Mouse Model of Bleomycin-Induced Dermal Fibrosis Int. J. Mol. Sci. 2021 22 12407 10.3390/ijms222212407 34830288 PMC8620338

293. Matei A.E. Distler J.H.W. Response to: ‘In Search for the Ideal Anatomical Composition of Vascularised Human Skin Equivalents for Systemic Sclerosis Translational Research: Should We Recruit the Telocytes?’ By Manetti and Matucci-Cerinic Ann. Rheum. Dis. 2021 80 e150 10.1136/annrheumdis-2019-216393 31582376

294. Tey R.V. Haldankar P. Joshi V.R. Raj R. Maradi R. Variability in Platelet-Rich Plasma Preparations Used in Regenerative Medicine: A Comparative Analysis Stem Cells Int. 2022 2022 3852898 10.1155/2022/3852898 36311042 PMC9613381

295. Trevisson B. Becerro-de-Bengoa-Vallejo R. Sevillano D. González N. Losa-Iglesias M. López-López D. Alou L. Age-based Inter-subject Variability in Platelet and White Blood Cell Concentrations of Platelet-rich Plasma Prepared Using a New Application to Blood Separation System Int. Wound J. 2022 19 362 369 10.1111/iwj.13636 34114747 PMC8762541

296. Zahir H. Dehghani B. Yuan X. Chinenov Y. Kim C. Burge A. Bandhari R. Nemirov D. Fava P. Moley P. In Vitro Responses to Platelet-Rich-Plasma Are Associated with Variable Clinical Outcomes in Patients with Knee Osteoarthritis Sci. Rep. 2021 11 11493 10.1038/s41598-021-90174-x 34075069 PMC8169703

297. Patel H. Pundkar A. Shrivastava S. Chandanwale R. Jaiswal A.M. A Comprehensive Review on Platelet-Rich Plasma Activation: A Key Player in Accelerating Skin Wound Healing Cureus 2023 15 e48943 10.7759/cureus.48943 38106716 PMC10725573

298. Nanda S. Chauhan K. Shetty V. Dashore S. Bhatia S. Platelet-Rich Plasma in Aesthetics Indian Dermatol. Online J. 2021 12 41 10.4103/idoj.idoj_290_21 34976880 PMC8664171

299. Buontempo M. Alhanshali L. Shapiro J. Sicco K. Garshick M. Platelet-Rich Plasma Applications, The Past 5 Years: A Review Article EMJ Dermatol. 2023 10.33590/emjdermatol/10309838

300. Maisel-Campbell A.L. Ismail A. Reynolds K.A. Poon E. Serrano L. Grushchak S. Farid C. West D.P. Alam M. A Systematic Review of the Safety and Effectiveness of Platelet-Rich Plasma (PRP) for Skin Aging Arch. Dermatol. Res. 2020 312 301 315 10.1007/s00403-019-01999-6 31628542

301. Li X. Gao J. Zheng H. Zou C. Yu Z. Wu Z. Zhang J. Study of Platelet-rich Plasma Application for Skin and Plastic Surgery in Recent 20 Years: A Bibliometric Analysis J. Cosmet. Dermatol. 2023 22 1852 1862 10.1111/jocd.15653 36762408

302. Kim J.-H. Park Y.-B. Ha C.-W. Roh Y.J. Park J.-G. Adverse Reactions and Clinical Outcomes for Leukocyte-Poor Versus Leukocyte-Rich Platelet-Rich Plasma in Knee Osteoarthritis: A Systematic Review and Meta-Analysis Orthop. J. Sports Med. 2021 9 232596712110119 10.1177/23259671211011948 34277879 PMC8255589

303. Phoebe L.K.W. Lee K.W.A. Chan L.K.W. Hung L.C. Wu R. Wong S. Wan J. Yi K. Use of Platelet Rich Plasma for Skin Rejuvenation Ski. Res. Technol. 2024 30 e13714 10.1111/srt.13714 38650371 PMC11035968

304. Sharun K. Pawde A.M. Variables Affecting the Potential Efficacy of Platelet-Rich Plasma in Dermatology J. Am. Acad. Dermatol. 2021 84 e47 e48 10.1016/j.jaad.2020.08.080 32858077

305. Peng G.L. Platelet-Rich Plasma for Skin Rejuvenation Facial Plast. Surg. Clin. N. Am. 2019 27 405 411 10.1016/j.fsc.2019.04.006 31280855

306. Yepuri V. Venkataram M. Platelet-Rich Plasma with Microneedling in Androgenetic Alopecia: Study of Efficacy of the Treatment and the Number of Sessions Required J. Cutan. Aesthet. Surg. 2021 14 184 190 10.4103/0974-2077.323638 34566361 PMC8423195

307. El-Domyati M. Abdel-Wahab H. Hossam A. Combining Microneedling with Other Minimally Invasive Procedures for Facial Rejuvenation: A Split-face Comparative Study Int. J. Dermatol. 2018 57 1324 1334 10.1111/ijd.14172 30105816

308. Jain N.K. Gulati M. Platelet-Rich Plasma: A Healing Virtuoso Blood Res. 2016 51 3 10.5045/br.2016.51.1.3 27104183 PMC4828525

309. Eymard F. Ornetti P. Maillet J. Noel É. Adam P. Legré-Boyer V. Boyer T. Allali F. Gremeaux V. Kaux J.-F. Intra-Articular Injections of Platelet-Rich Plasma in Symptomatic Knee Osteoarthritis: A Consensus Statement from French-Speaking Experts Knee Surg. Sports Traumatol. Arthrosc. 2021 29 3195 3210 10.1007/s00167-020-06102-5 32583023 PMC8458198

310. Yaman R. Kinard T.N. Platelet Rich Plasma: Hope or Hype? Ann. Blood 2022 7 6 10.21037/aob-21-57

311. Mallis P. Michalopoulos E. Panagouli E. Dimou Z. Sarri E.F. Georgiou E. Gkioka V. Stavropoulos-Giokas C. Selection Criteria of Cord Blood Units for Platelet Gel Production: Proposed Directions from Hellenic Cord Blood Bank. Comment on Mallis et al. Short Term Results of Fibrin Gel Obtained from Cord Blood Units: A Preliminary in Vitro Study. Bioengineering 2019, 6, 66 Bioengineering 2021 8 53 10.3390/bioengineering8050053 33925496 PMC8146526

312. Akbarzadeh S. McKenzie M.B. Rahman M.M. Cleland H. Allogeneic Platelet-Rich Plasma: Is It Safe and Effective for Wound Repair? Eur. Surg. Res. 2021 62 1 9 10.1159/000514223 33621973

313. Oneto P. Zubiry P.R. Schattner M. Etulain J. Anticoagulants Interfere with the Angiogenic and Regenerative Responses Mediated by Platelets Front. Bioeng. Biotechnol. 2020 8 223 10.3389/fbioe.2020.00223 32266247 PMC7098916

314. Eichler C. Üner J. Thangarajah F. Radosa J. Zinser M. Fischer L.A. Puppe J. Warm M. Malter W. Lenz C. Platelet-Rich Plasma (PRP) in Oncological Patients: Long-Term Oncological Outcome Analysis of the Treatment of Subcutaneous Venous Access Device Scars in 89 Breast Cancer Patients Arch. Gynecol. Obs. 2022 306 1171 1176 10.1007/s00404-022-06416-4 35377044 PMC9470624

315. Stojadinovic O. Morrison B. Tosti A. Adverse Effects of Platelet-Rich Plasma and Microneedling J. Am. Acad. Dermatol. 2020 82 501 502 10.1016/j.jaad.2019.07.109 31408684

316. Izzo P. De Intinis C. Molle M. Polistena A. Sibio S. Codacci-Pisanelli M. Biacchi D. Di Cello P. Santini D. Izzo L. Case Report: The Use of PRP in the Treatment of Diabetic Foot: Case Series and a Review of the Literature Front. Endocrinol. 2023 14 1286907 10.3389/fendo.2023.1286907 38170077 PMC10760803

317. Lambadiari V. Kountouri A. Psahoulia F. Koliou G.-A. Lazaris A. Michalopoulos E. Mallis P. Korakas E. Eleftheriadou I. Balampanis K. Treatment with Umbilical Cord Blood Platelet Lysate Gel Improves Healing of Diabetic Foot Ulcer J. Clin. Med. 2024 13 1310 10.3390/jcm13051310 38592188 PMC10932121

318. Majid I. Timungpi R. Platelet Rich Plasma in Treatment of Topical Steroid Damaged Face: A Retrospective Analytical Study Dermatol. Ther. 2022 35 e15356 10.1111/dth.15356 35118757

319. Carvalho A. Ferreira A.F. Soares M. Santos S. Tomé P. Machado-Simões J. Pais A.S. Sousa A.P. Paiva A. Almeida-Santos T. Optimization of Platelet-Rich Plasma Preparation for Regenerative Medicine: Comparison of Different Anticoagulants and Resuspension Media Bioengineering 2024 11 209 10.3390/bioengineering11030209 38534483 PMC10967741

320. Chahla J. Cinque M.E. Piuzzi N.S. Mannava S. Geeslin A.G. Murray I.R. Dornan G.J. Muschler G.F. LaPrade R.F. A Call for Standardization in Platelet-Rich Plasma Preparation Protocols and Composition Reporting J. Bone Jt. Surg. 2017 99 1769 1779 10.2106/JBJS.16.01374 29040132

321. Behrangi E. Akbarzadehpasha A. Dehghani A. Zare S. Ghassemi M. Zeinali R. Goodarzi A. Lotfi Z. Platelet-rich Plasma as a New and Successful Treatment for Lichen Planopilaris: A Controlled Blinded Randomized Clinical Trial J. Cosmet. Dermatol. 2024 23 2547 2555 10.1111/jocd.16302 38525908

322. White C. Brahs A. Dorton D. Witfill K. Platelet-Rich Plasma: A Comprehensive Review of Emerging Applications in Medical and Aesthetic Dermatology J. Clin. Aesthet. Dermatol. 2021 14 44 57 34980960 PMC8675348

323. Coulange Zavarro A. De Girolamo L. Laver L. Sánchez M. Tischer T. Filardo G. Sabatier F. Magalon J. The Top 100 Most Cited Articles on Platelet-Rich Plasma Use in Regenerative Medicine—A Bibliometric Analysis—From the ESSKA Orthobiologic Initiative Bioengineering 2022 9 580 10.3390/bioengineering9100580 36290547 PMC9598782

324. Santos L.C. Lana G.L. Santos G.S. Visoni S.B.C. Brigagão R.J. Santos N. Sobreiro R. da Cruz Silva Reis A. Rodrigues B.L. Ferrari S. The Biological Role of Platelet Derivatives in Regenerative Aesthetics Int. J. Mol. Sci. 2024 25 5604 10.3390/ijms25115604 38891792 PMC11172268

325. Lin M.-Y. Lin C.-S. Hu S. Chung W.-H. Progress in the Use of Platelet-Rich Plasma in Aesthetic and Medical Dermatology J. Clin. Aesthet. Dermatol. 2020 13 28 35 33178379 PMC7595356

326. Pixley J.N. Cook M.K. Singh R. Larrondo J. McMichael A.J. A Comprehensive Review of Platelet-Rich Plasma for the Treatment of Dermatologic Disorders J. Dermatol. Treat. 2023 34 2142035 10.1080/09546634.2022.2142035 36318219

327. Arabzadeh Bahri R. Maleki S. Shafiee A. Ghandi N. Abedini R. Ehsani A.H. Ehsani A. Razavi Z. Efficacy and Safety of Platelet-Rich Plasma Therapy in Alopecia Areata Patients: A Systematic Review Dermatol. Ther. 2023 2023 8827644 10.1155/2023/8827644

328. Verma R. Kumar S. Garg P. Verma Y.K. Platelet-Rich Plasma: A Comparative and Economical Therapy for Wound Healing and Tissue Regeneration Cell Tissue Bank. 2023 24 285 306 10.1007/s10561-022-10039-z 36222966 PMC9555256

329. Varghese J. Acharya N. Platelet-Rich Plasma: A Promising Regenerative Therapy in Gynecological Disorders Cureus 2022 14 e28998 10.7759/cureus.28998 36249659 PMC9549690

330. Murray I.R. Chahla J. Wordie S.J. Shapiro S.A. Piuzzi N.S. Frank R.M. Halbrecht J. Okada K. Nakamura N. Mandelbaum B. Regulatory and Ethical Aspects of Orthobiologic Therapies Orthop. J. Sports Med. 2022 10 232596712211016 10.1177/23259671221101626 36479465 PMC9720812

331. Codorean I.-B. Cernat E. Popescu D. Sinescu R.D. Perlea P. Legal and Ethical Aspects of Platelet-Rich Plasma Rom. J. Leg. Med. 2017 25 405 408 10.4323/rjlm.2019.65

332. Mayoly A. Iniesta A. Curvale C. Kachouh N. Jaloux C. Eraud J. Vogtensperger M. Veran J. Grimaud F. Jouve E. Development of Autologous Platelet-Rich Plasma Mixed-Microfat as an Advanced Therapy Medicinal Product for Intra-Articular Injection of Radio-Carpal Osteoarthritis: From Validation Data to Preliminary Clinical Results Int. J. Mol. Sci. 2019 20 1111 10.3390/ijms20051111 30841510 PMC6429478

333. Frey B.M. Humpe A. ATMPs: New Challenge for Transfusion Services Transfus. Med. Hemother. 2022 49 127 128 10.1159/000525025 35813603 PMC9209980

334. Schirmann A. Boutin E. Faix A. Yiou R. Tolerance and Efficacy of Platelet-Rich Plasma Injections in Peyronie’s Disease: Pilot Study Progrès En. Urol. 2022 32 856 861 10.1016/j.purol.2022.05.004 35778315

335. Shome S. Kodieswaran M. Dadheech R. Chevella M. Sensharma S. Awasthi S. Bandyopadhyay A. Mandal B.B. Recent Advances in Platelet-Rich Plasma and Its Derivatives: Therapeutic Agents for Tissue Engineering and Regenerative Medicine Prog. Biomed. Eng. 2024 6 012004 10.1088/2516-1091/ad1338 39655847

336. Mehdipour chari K. Enderami S.E. Mansour R.N. Hasanzadeh E. Amini Mahabadi J. Abazari M. Asadi P. Hojjat A. Applications of Blood Plasma Derivatives for Cutaneous Wound Healing: A Mini-Review of Clinical Studies Regen. Ther. 2024 27 251 258 10.1016/j.reth.2024.02.011 38596823 PMC11002853

337. Anitua E. Troya M. Falcon-Pérez J.M. López-Sarrio S. González E. Alkhraisat M.H. Advances in Platelet Rich Plasma-Derived Extracellular Vesicles for Regenerative Medicine: A Systematic-Narrative Review Int. J. Mol. Sci. 2023 24 13043 10.3390/ijms241713043 37685849 PMC10488108

338. Johnson J. Law S.Q.K. Shojaee M. Hall A.S. Bhuiyan S. Lim M.B.L. Silva A. Kong K.J.W. Schoppet M. Blyth C. First-in-human Clinical Trial of Allogeneic, Platelet-derived Extracellular Vesicles as a Potential Therapeutic for Delayed Wound Healing J. Extracell. Vesicles 2023 12 e12332 10.1002/jev2.12332 37353884 PMC10290200

339. Vaidakis D. Papapanou M. Siristatidis C.S. Autologous Platelet-Rich Plasma for Assisted Reproduction Cochrane Database Syst. Rev. 2024 2024 CD013875 10.1002/14651858.CD013875.pub2 PMC11057220 38682756

340. Miroshnychenko O. Chang W. Dragoo J.L. The Use of Platelet-Rich and Platelet-Poor Plasma to Enhance Differentiation of Skeletal Myoblasts: Implications for the Use of Autologous Blood Products for Muscle Regeneration Am. J. Sports Med. 2017 45 945 953 10.1177/0363546516677547 28027451

341. Alhawari H. Jafar H. Al Soudi M. Ameereh L.A. Fawaris M. Saleh M. Aladwan S. Younes N. Awidi A. Perilesional Injections of Human Platelet Lysate versus Platelet Poor Plasma for the Treatment of Diabetic Foot Ulcers: A double-blinded Prospective Clinical Trial Int. Wound J. 2023 20 3116 3122 10.1111/iwj.14186 37140065 PMC10502275