The role and mechanisms of mesenchymal stem cells in postoperative cognitive dysfunction via immune network regulation.

Introduction

Postoperative cognitive dysfunction (POCD) is a common and serious complication after surgery. It is more frequently observed in elderly patients, and its reported incidence ranges from about 10% to 54%. Patients with POCD usually experience declines in memory, attention, and executive function. These cognitive changes can lower postoperative quality of life. They may also extend hospital stay, increase mortality, and raise the risk of long-term cognitive decline [ 1 ]. The development of POCD is closely related to systemic inflammation and immune activation in the central nervous system (CNS) after surgical trauma. Among these pathological changes, neuroinflammation plays a key role in both the onset and progression of POCD [ 2 , 3 ].

Surgical stress can activate microglia and astrocytes. Activated glial cells then release pro-inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) [ 4 ]. These cytokines can damage the integrity of the blood-brain barrier (BBB). This process further triggers a neuroinflammatory cascade and finally affects synaptic plasticity and neurogenesis in the hippocampus [ 2 , 5 ]. The hippocampus plays an important role in learning and memory. Zheng et al. found that increased M1 polarization of microglia promoted the release of extracellular vesicles (EVsM1) with high CCR5 expression. EVsM1 can bind CCL3/4/5 to CCR5 on the neuronal surface. This interaction activates the GPCRs-Ras-MAPK signaling pathway and leads to neuronal degeneration, synaptic loss, and eventually POCD [ 6 ]. In addition, surgery and anesthesia can induce systemic inflammation. These inflammatory signals may reach the CNS through several routes, such as the vagus nerve, and then promote neuroinflammation.

MSCs are adult stem cells with multi-directional differentiation potential. Because of their low immunogenicity, strong immunomodulatory ability, and tissue repair potential, MSCs have shown broad prospects in POCD treatment [ 7 ]. Their therapeutic effects are mainly achieved through paracrine mechanisms. MSCs can secrete several active components, including growth factors, extracellular vesicles, and conditioned medium (MSC-CM). These components can regulate immune cell function and suppress excessive inflammatory responses. Among them, MSC-derived extracellular vesicles (MSC-EVs) have received increasing attention in POCD treatment. MSC-EVs are enriched with bioactive molecules, such as miRNAs, lncRNAs, proteins, lipids, and metabolites. These molecules can regulate recipient cell function through intercellular communication [ 8 ]. MiR-140-5p carried by MSC-EVs can target HDAC7. Through this mechanism, MSC-EVs regulate M1 polarization of microglia and reduce brain injury and inflammation [ 9 ]. These results indicate that MSCs may protect against POCD by acting on several targets within the immune network. They also support the development of cell-free therapeutic strategies.

Biological characteristics and immunomodulatory functions of mesenchymal stem cells

Sources and surface markers of MSCs

MSCs are adult stem cells with multipotent differentiation potential. They have shown broad application prospects in regenerative medicine. MSCs can self-renew and differentiate into several cell types. More importantly, they also have clear immunomodulatory functions [ 10 , 11 ]. Because of these biological features, MSCs have been widely studied in cell therapy. Their applications now cover many areas of disease, including immune and neurological disorders, diabetes, bone and cartilage diseases, and myocardial infarction [ 10 ], and many clinical trials in these areas are underway.

MSCs are widely distributed in various tissues, including bone marrow, adipose tissue, umbilical cord, and amniotic membrane [ 12 ]. MSCs derived from different sources have similar characteristics but exhibit variations in their proliferative capacity, immunomodulatory properties, and differentiation potential [ 13 ].

Bone Marrow-derived MSCs (BMSCs): BMSCs are the earliest studied and applied type of MSCs and are considered the “gold standard“ [ 14 ]. They possess robust proliferative capacity and multipotent differentiation potential, capable of differentiating into osteoblasts, chondrocytes, and adipocytes, among others [ 11 ]. However, the bone marrow harvesting procedure is invasive [ 13 ]. Studies indicate that BMSCs have advantages in regenerating bone and cartilage [ 11 ].

Adipose-derived MSCs (ADSCs): ADSCs have become a research focus due to their easy accessibility, abundance, and minimally invasive harvesting procedure [ 15 ]. They can also be used in intraoperative medical procedures. ADSCs share a similar multipotent differentiation potential with BMSCs, including the ability to differentiate into adipocytes, osteoblasts, and chondrocytes [ 16 ]. They demonstrate potent immunosuppressive capabilities [ 11 ].

Umbilical Cord-derived MSCs (UC-MSCs): UC-MSCs have garnered significant attention owing to their non-invasive acquisition, low immunogenicity, high proliferative capacity, and strong immunomodulatory functions [ 17 , 18 ]. Compared to MSCs derived from adults, UC-MSCs of neonatal origin generally exhibit stronger proliferative capacity, lower immunogenicity, and a lower incidence of mutations [ 18 ].

MSCs from different sources may show slight differences in marker expression. BMSCs are positive for CD73, CD90, and CD105, but show no expression of CD34, CD45, and HLA-DR [ 17 , 19 ]. ADSCs usually express high levels of CD73, CD90, and CD105, while they show low expression of CD34, CD45, and HLA-DR [ 16 ]. UC-MSCs have a similar pattern, with high expression of CD73, CD90, and CD105 and low expression of CD34, CD45, and HLA-DR [ 20 ] (Table 1 and 2 ).

Table 1 Immunomodulatory effects of MSCs in disease therapy Mesenchymal stem cell Disease Immune cells Immunomodulatory mechanism References UC-MSCs Psoriasis T cells Th17 and CD4⁺ naïve T cells reduce Cheng, Wang et al. [ 21 ] Completely subacute spinal cord injury Astrocytes TNF - α and NF - κ B reduce, leading to a decrease in the activation of A1 astrocytes Akhlaghpasand, Tavanaei et al. [ 22 ] Systemic lupus erythematosus B cells By inducing IL-10 secretion in regulatory B cells through TGF – β1, balancing Th1/Th17/Treg immune responses Chun, Tian et al. [ 23 ] Acute ischemic stroke T cells Th1 and Th17 reduce, promotes the expansion of highly inhibitory Treg cell populations, and downregulating IL-17, TNF - α, and IFN - γ. Chen, Han et al. [ 24 ] TNBS induced colitis T cells Inhibit Th1/Th17 cells and promote Treg cells to restore immune balance. Fu, Zhang et al. [ 25 ] Autoimmune hepatitis T cells Inhibit CD4 T proliferation and peripheral CD4 T cell migration to the liver Wei, Cheng et al. [ 26 ] Inflammatory bowel disease Macrophages Activates the SIRT1-FXR pathway in macrophages, reduces the acetylation level of FXR, and directly negatively regulates the activation of NLRP3 inflammasome Zhou, Pei et al. [ 27 ] Ulcerative colitis T cells 、B cells By inhibiting the interaction between T cells, B cells, and bone marrow cells, and regulating T cell-mediated immunity, Luo, Deng et al. [ 28 ] Chronic salpingitis Macrophages Promote apoptosis of macrophage cells and reduce the mRNA expression of IL-1 β, caspase-1, and MCP-1 Liao, Li et al. [ 29 ] pulmonary arterial hypertension Macrophages Promote polarization of M2 macrophages, increase IL-10 levels, inhibit IL-33/ST2 axis expression, (Liu, Zhang et al. [ 30 ] Asthma Macrophages Reduced macrophage polarization towards M2, resulting in decreased expression levels of M2 polarization and Th2 inflammation related markers. Mo, Kang et al. [ 31 ] Endometrial injury Macrophages Promote peritoneal macrophages to clear apoptotic cells, repair and enhance macrophages through the PPAR γ - HK2 pathway Wang, Li et al. [ 32 ] BMSCs allergic rhinitis Macrophages、T cells Restore Th1/Th2 immune balance, enhance Treg activity, promote macrophage polarization towards anti-inflammatory phenotype Ye, Zhao et al. [ 33 ] Kidney transplantation B cells Promote the activation of B cells and the regulation of B cell production by IL-10, induce IL-10 Bregs production Xie, Wang et al. [ 34 ] Ischemia/reperfusion injury T cells Reduce IL-2 levels and downregulate IL-2 receptors to inhibit T cell proliferation Wang, Wang et al. [ 35 ] Smoke inhalation injury Macrophages、T cells By promoting polarization of M1-M2 macrophages and balancing Th17/Treg responses, lung inflammation and tissue damage can be alleviated. Guo, Niu et al. [ 36 ] PL-MSC Diabetic nephropathy T cells Upregulation of PD-1 and reduce the proportion of Th17 cells and increase the proportion of Treg cells, thereby reversing the balance of Th17/Treg. Wang, Liu et al. [ 37 ] AD-MSC Psoriasis Monocytes、Dendritic cells and Neutrophils Inhibit the secretion of IL-17 by peripheral blood monocytes, suppress neutrophil function, and reduce the production of type I interferon (IFN-I) by dendritic cells (pDCs) Yao, Ye et al. [ 38 ]

Immunomodulatory Mechanisms of MSCs: cell contact-dependent and independent pathways

The immunomodulatory function of MSCs is one of the main reasons why they have therapeutic potential. This function is mainly achieved through two routes: cell contact-dependent mechanisms and contact-independence, or paracrine, mechanisms [ 39 ].

Cell Contact-Dependent Pathway: MSCs can directly communicate with immune cells through surface molecules. This process helps limit excessive immune activation [ 39 ]. Programmed death-ligand 1 (PD-L1) is one of the key molecules expressed on the surface of MSCs. PD-L1 binds to programmed death-1 (PD-1) on T cells and then suppresses T cell activation and cytokine secretion [ 39 , 40 ]. Intercellular adhesion molecule-1 (ICAM-1) serves as a co-receptor and also participates in the interaction between MSCs and immune cells [ 39 ]. These contact-dependent signals work together to promote immune tolerance and reduce inflammatory responses.

Contact-Independent Pathway (Paracrine Action): The paracrine pathway is also an important way for MSCs to regulate immune responses. MSCs release many different soluble factors into the local microenvironment. These factors can affect the proliferation, differentiation, and function of immune cells. They can also inhibit pro-inflammatory cytokine production, enhance anti-inflammatory cytokine release, and promote the generation of immunosuppressive cells, such as Tregs [ 7 ].

Exosome (sEV)-Mediated Immunomodulation: In recent years, exosomes, also known as small extracellular vesicles (sEVs), secreted by MSCs have attracted increasing attention. They are now considered an important part of MSC-mediated paracrine regulation. Exosomes are nano-sized (30–150 nm) membranous vesicles and can travel long distances in the body. They contain many bioactive molecules, including proteins, lipids, mRNA, and miRNA. After being taken up by recipient cells, exosomes can deliver these molecules to immune cells. In this way, they regulate immune cell function and reshape the immune microenvironment [ 41 ].

Immunomodulatory Factors Secreted by MSCs

MSCs exert anti-inflammatory and immune homeostatic effects through a variety of immunomodulatory factors. Upon exposure to inflammatory signals, MSCs can dynamically adjust their paracrine profiles and the expression of surface immunomodulatory molecules. Therefore, the action of MSCs should not be understood as a linear response of a single factor targeting a single receptor, but rather as a networked regulation in response to multiple inflammatory signals.

Transforming Growth Factor-β (TGF-β): TGF-β is an important immunosuppressive cytokine secreted by MSCs. It can inhibit T cell activation and proliferation [ 39 ]. At the same time, TGF-β promotes the differentiation and function of Tregs. Tregs are important for maintaining immune tolerance and limiting autoimmune responses [ 39 , 42 ].

Interleukin-10 (IL-10): IL-10 is an important anti-inflammatory cytokine. However, in MSC-mediated immune regulation, IL-10 should not be understood solely as a factor directly secreted by MSCs. Instead, MSCs can enhance IL-10-driven anti-inflammatory responses by modulating Tregs, regulatory B cells, and M2-like macrophages or microglia, thereby reducing the release of pro-inflammatory factors and restoring immune homeostasis [ 43 ].

Indoleamine 2,3-Dioxygenase (IDO): IDO is a rate-limiting enzyme expressed by MSCs. Under resting conditions, IDO expressions in MSCs may be low; however, upon exposure to inflammatory signals such as IFN-γ, TNF-α, or IL-1β, IDO expression can be induced or enhanced. It suppresses T cell proliferation and function by degrading the essential amino acid tryptophan [ 44 ]. In addition, the accumulation of tryptophan metabolites can induce T cell apoptosis. This effect further strengthens the immunosuppressive activity of MSCs [ 39 ].

Prostaglandin E2 (PGE2): MSCs can also secrete PGE2, which is a lipid mediator with broad immunomodulatory effects [ 39 , 42 ]. PGE2 can inhibit T cell proliferation, B cell activation, and NK cell cytotoxicity. It can also promote M2 macrophage polarization, thereby reducing inflammation [ 44 ].

Hepatocyte growth factor (HGF): HGF is also an important factor in the paracrine effects of MSCs. Compared with immune-suppressive molecules such as IDO and PGE2, HGF is more inclined toward tissue repair, endothelial protection, and neural recovery [ 45 ].

These immunomodulatory factors form a complex regulatory network. Through this network, MSCs can produce therapeutic effects in several immune-related conditions. These conditions include inflammatory diseases, autoimmune diseases, and graft-versus-host disease [ 39 ] and MSCs are undergoing such testing in clinical trials.

Immune-inflammatory mechanisms of postoperative cognitive dysfunction

The inflammatory response in POCD follows a distinct temporal sequence. Following surgical trauma, tissue damage immediately triggers the release of damage-associated molecular patterns (DAMPs). Within 1–3 h postoperatively, peripheral innate immune responses are activated, and pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 begin to rise. Approximately 3–6 h later, systemic inflammation can impair the integrity of the blood-brain barrier (BBB), allowing peripheral inflammatory signals to more easily affect the central nervous system. During the subsequent 6–12 h, microglia and astrocytes become activated. By 24–48 h, reactive oxygen species (ROS) production, mitochondrial damage, and activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome further amplify neuroinflammation. Over the next 5–7 days, inflammation may gradually subside; however, if repair mechanisms are insufficient, it could progress into persistent neuroinflammation and cognitive impairment.

Systemic inflammatory response and blood-brain barrier disruption induced by surgical trauma

Tissue damage during surgery can release DAMPs, including high mobility group box 1 (HMGB1), mitochondrial DNA, and S100 proteins, etc. These DAMPs can activate the innate immune pathway through pattern recognition receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE), inducing a systemic inflammatory response, and manifesting as elevated levels of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 in the peripheral nervous system [ 46 ]. This systemic inflammatory response further damages the integrity of BBB.

The BBB is mainly formed by tightly connected endothelial cells. It controls the exchange of substances between the blood and the central nervous system (CNS). When the BBB is damaged, peripheral inflammatory factors and immune cells can enter the brain more easily or influence the brain microenvironment. This process may further activate microglia and astrocytes. Clinical studies have shown that patients undergoing gastrointestinal surgery have increased serum HMGB1 levels after surgery. This increase is associated with cognitive decline. These findings suggest that HMGB1 is not only an inflammatory marker of tissue injury but may also participate in the development of postoperative cognitive impairment [ 47 ].

Microglial activation and the neuroinflammatory cascade

Microglia, as the resident immune cells of the central nervous system, plays a core role in the neuroinflammatory cascade associated with POCD. Surgical trauma and systemic inflammatory responses can prompt microglia to shift from a resting state to an activated state, releasing various inflammatory mediators, including TNF-α, IL-1β, IL-6, and ROS, thereby contributing to hippocampal neuroinflammation, synaptic dysfunction, and cognitive decline [ 48 ].

Aging may further increase the vulnerability of microglia to postoperative inflammatory stimulation. In elderly individuals, microglia often show a stronger and more prolonged inflammatory response. This age-related microglial priming may partly explain why older patients are more susceptible to POCD.

The balance between the pro-inflammatory and reparative phenotypes of microglia also affects the pathological process of POCD. Pro-inflammatory M1-like microglia mainly secrete pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, participating in neurotoxic reactions; while M2-like microglia can secrete protective factors such as TGF-β, IL-10, and insulin-like growth factor-1 (IGF-1), participating in inflammation resolution and neural repair [ 49 ].

Pro-inflammatory cytokines and IL-17 A/MMP-9 axis-mediated barrier disruption and cognitive impairment

Pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6, play a key role in the pathophysiological process of POCD. These cytokines mainly originate from activated microglia, infiltrating peripheral immune cells and damaged tissues, and can further exacerbate and maintain postoperative neuroinflammatory responses [ 50 ]. TNF-α and IL-1β can directly damage neuronal function by influencing synaptic plasticity, glutamatergic transmission and neural network homeostasis [ 51 ]. Among them, IL-1β can enhance NMDA receptor function, especially by promoting GluN2B/NR2B-related signaling to enhance NMDA receptor-mediated excitotoxicity, thereby increasing the risk of neuronal damage [ 52 ]. IL-6, as an important mediator of systemic inflammation, is closely related to BBB dysfunction, the spread of peripheral inflammation to the central nervous system and postoperative cognitive decline [ 53 ]. However, the role of IL-6 may be context-dependent. Although MSCs can secrete IL-6, the overall effect of MSCs is usually anti-inflammatory because transplanted cells are limited in number and survival time, and their therapeutic effect mainly depends on broader paracrine immune regulation.

In addition, the IL-17 A/MMP-9 axis may further aggravate BBB damage. IL-17 A can induce the expression of matrix metalloproteinase 9 (MMP-9), and MMP-9 can degrade BBB-related extracellular matrix and tight junction structures, increase BBB permeability, and make peripheral inflammatory signals more likely to enter the central nervous system [ 54 ].

Oxidative stress, mitochondrial injury and sustained neuroimmune activation

During the progression of POCD, postoperative inflammation is closely linked to oxidative stress and mitochondrial dysfunction. Surgical trauma, anesthetic exposure, and systemic inflammation can increase ROS production. Excessive ROS may impair mitochondrial function and disturb synaptic transmission and neuronal network stability, especially in the hippocampus, which is highly sensitive to energy metabolic stress [ 55 ].

Mitochondrial injury can further amplify neuroinflammation. Damaged mitochondria may release mitochondrial DNA, cardiolipin, and other mitochondria-derived DAMPs. These signals can activate innate immune pathways and promote inflammasome-related responses. In a mouse model of POCD induced by hepatectomy, MSC treatment reduced IL-1β, IL-6, TNF-α, and oxidative stress markers in brain tissue. It also increased BDNF expression and improved cognitive function [ 56 ].

Inflammasome activation and pyroptosis-mediated inflammatory amplification

Under the combined effects of DAMP release, increased ROS production, and mitochondrial injury, the NLRP3 inflammasome can be activated. The NLRP3 inflammasome is an important platform through which the innate immune system senses danger signals. Once activated, it recruits and activates caspase-1, thereby promoting the maturation and release of IL-1β and IL-18 and converting early injury signals into stronger inflammatory effector responses [ 57 ]. Previous studies have suggested that NLRP3 inflammasome activation and NLRP3-mediated IL-1β release are closely associated with learning and memory impairment in POCD, indicating that this pathway may represent a key node in maintaining postoperative neuroinflammation [ 58 ].

Caspase-1 can also cleave gasdermin D (GSDMD) and induce pyroptosis, a pro-inflammatory form of programmed cell death. Pyroptotic cells release intracellular contents and new DAMPs, which can further activate surrounding glial cells and immune cells and form a sustained inflammatory amplification loop. In an aged mouse model of sevoflurane-induced cognitive impairment, hippocampal microglial pyroptosis was associated with activation of the ROS-NLRP3 pathway. Inhibition of pyroptosis or ROS reduced microglial pyroptosis and improved cognitive function [ 59 ] (Figs. 1 and 2 ).

Fig. 1 Surgery or tissue injury induces the release of DAMPs, including HMGB1, mitochondrial DNA, and S100 proteins, which activate peripheral immune cells through TLR4 and RAGE and promote the production of TNF-α, IL-1β, and IL-6. Systemic inflammation disrupts BBB integrity, while the IL-17 A/MMP-9 axis further increases BBB permeability, allowing peripheral immune cells and inflammatory mediators to enter the CNS. These signals activate microglia toward a pro-inflammatory M1-like phenotype, leading to ROS production, oxidative stress, mitochondrial dysfunction, synaptic impairment, and neuronal death. DAMPs, ROS, and mitochondrial injury can also activate the NLRP3 inflammasome, promoting caspase-1 activation, IL-1β/IL-18 release, and GSDMD-mediated pyroptosis, thereby amplifying neuroinflammation and contributing to POCD/PND-related cognitive impairment. In contrast, M2-like microglia secrete TGF-β, IL-10, and IGF-1, which may support inflammation resolution and neural repair. The timeline below shows the approximate sequence of these events from immediate injury to 5–7 days after surgery. (This figure was independently created by the authors using Microsoft PowerPoint)

Experimental evidence of MSCs regulating the immune network to ameliorate POCD

Effects of MSCs on modulating peripheral immune cells

MSCs exert immunomodulatory effects by regulating the balance of peripheral immune cells, particularly the ratio of Treg to Th17 cells. Previous studies have shown that MSCs can promote the generation of Treg cells and inhibit the differentiation of Th17 cells, thereby reducing IL-17 A-related inflammatory responses and restoring immune homeostasis [ 60 ]. MSC-derived extracellular vesicles can also regulate T cell proliferation, activation and differentiation by delivering active molecules such as miRNA, suppressing pro-inflammatory Th1/Th17 responses and promoting Treg generation [ 61 ].

MSCs metabolize tryptophan into kynurenine through the secretion of IDO [ 62 ]. Kynurenine is a profound immunometabolite that can activate the aryl hydrocarbon receptor (AHR). The activation of AHR is considered a critical molecular switch that promotes the generation of Treg and inhibits Th17 cells [ 62 ]. Th17 and Treg cells play antagonistic roles in immune balance, with Treg cells capable of suppressing the proliferation of Th17 cells and the production of IL-17 A [ 63 ]. It can therefore be predicted that MSCs may bias T cell differentiation towards Treg via the IDO-kynurenine-AHR axis, thereby reducing IL-17 A production. One study indicated that MSCs suppress Th17 cell responses within lymph nodes via L-amino-acid oxidase. Furthermore, the CD73-IFNγ signaling axis is crucial for MSC-mediated inhibition of inflammatory macrophages; CD73-deficient MSCs were unresponsive to IFNγ-mediated “licensing”, suggesting that the CD73-IFNγ-IDO1 signaling axis is key for MSC-mediated suppression of M1 macrophages [ 64 ].

Mechanisms by which MSCs Suppress central microglia and peripheral macrophages

The mechanism by which MSCs inhibit the M1-type polarization (pro-inflammatory phenotype) of central microglia is a crucial pathway for improving POCD. Microglia play a dual role in CNS diseases, and their M1/M2 polarization is critical for disease progression [ 65 ]. M1-like pro-inflammatory microglia mainly release pro-inflammatory mediators such as TNF-α, IL-1β, IL-6 and ROS, thereby causing neuroallergy and neuronal damage; conversely, M2-like anti-inflammatory and reparative microglia can provide protective factors such as IL-10, TGF-β, and IGF-1participating in neuroregression, tissue repair and protection [ 66 ].

Furthermore, human amniotic membrane-derived MSCs (hAMSCs), after pre-activation with IFN-γ, promoted the polarization of microglia towards the M2-type (anti-inflammatory phenotype) and increased IL-10 production by upregulating PDL-1 expression and immunomodulatory miRNAs [ 67 ]. M2-type microglia possess anti-inflammatory and tissue healing functions [ 68 ].

In drug-induced liver injury models, following MSC or MSC-derived exosome intervention, a decrease in the activation markers of the cGAS-STING pathway (p-STING, p-TBK1, p-IRF3) and a reduction in IFN-β and ISG expression were detected in peripheral macrophages [ 69 ]. Concurrently, the expression of M2 macrophage markers was upregulated, and stress granule formation was observed [ 70 ]. It can therefore be predicted that MSCs may induce M2 macrophages to form stress granules, which in turn inhibit the cGAS-STING pathway, thereby reducing the inflammatory response [ 69 ]. MSCs can also regulate macrophage cytokine production by activating the Akt/mTORC1 pathway0 [ 71 ]. In summary, these studies indicate that MSCs suppress neuroinflammation and ameliorate the pathological progression of POCD by regulating the phenotypic transition and related signaling pathways of microglia and macrophages.

Mechanisms by which MSCs suppress natural killer (NK) cells

MSCs can suppress the proliferation and cytotoxicity of NK cells [ 72 , 73 ]. The effect is mainly related to cytokines and soluble molecules released by MSCs, including PGE2, TGF-β, and IDO [ 74 ]. These factors can change the phenotype of NK cells and inhibit cytokine-induced NK cell proliferation. As a result, the cytotoxic activity of NK cells is reduced. For example, in COVID-19-related studies, MSCs were reported to help clear hyperactivated cytokine-secreting NK cells. This effect may contribute to the recovery of immune balance and reduce excessive inflammatory responses, such as the “cytokine storm” [ 75 ]. This regulatory effect is especially important under strong inflammatory conditions. It may help prevent NK cell-mediated injury to healthy tissues, including neurons.

Regulatory effects of MSCs on B Cells

MSCs can inhibit the proliferation of B lymphocytes and reduce their ability to produce antibodies [ 72 ]. This effect may help control autoimmune responses and chronic inflammation. MSCs may suppress B cell proliferation by secreting factors such as PGE2 and C-C motif chemokine ligand 2 (CCL-2). This mechanism is particularly relevant in diseases such as multiple myeloma, because abnormal B cell activation and antibody production may contribute to disease progression [ 76 , 77 ]. In advanced multiple myeloma, B cells can also release immunosuppressive cytokines, including IL-10 and TGFβ. This change may further enhance the immunosuppressive state [ 76 ].

MSCs can also regulate IDO expressions and promote the conversion of tryptophan into the kynurenine metabolic pathway [ 78 ]. Kynurenine is an endogenous ligand for the aryl hydrocarbon receptor (AhR). It can activate AhR in B cells and induce B cells to shift from a pro-inflammatory effector phenotype toward a regulatory or tolerogenic phenotype [ 79 ]. This phenotypic change is usually accompanied by increased IL-10 expression, reduced pro-inflammatory cytokine production, and decreased antigen-presenting capacity [ 80 ]. The interaction between B cells and microglia may form a regulatory loop. Secretions from pro-inflammatory B cells can induce human microglia/macrophages to increase IL-12, IL-6, and TNF-α expression. At the same time, these secretions can reduce the expression of homeostatic molecules and weaken myelin phagocytic capacity. In contrast, secretions from IL-10-expressing B cells can enhance homeostatic molecule expression and phagocytic capacity in microglia/macrophages [ 81 ]. IL-10 can also promote macrophage polarization toward the M2 anti-inflammatory phenotype, which may support tissue healing and regeneration [ 82 ].

Regulatory effects of MSCs on neutrophils

Surgical stress or injury activates neutrophils, leading to the release of neutrophil extracellular traps (NETs), which are primarily composed of DNA and granular protein complexes [ 83 ]. Excessive NETs not only cause tissue damage but also promote sustained inflammation and may directly or indirectly disrupt biological barriers, including the BBB [ 84 ]. Neutrophils are the primary producers of NETs, while monocytes/macrophages and microglia may be secondarily activated by NET components, and endothelial cells are closely related to BBB structure and adhesion molecule expression [ 85 ]. Therefore, MSCs regulating the activities of these immune cells, particularly by inhibiting neutrophil NETosis, may be a key strategy for alleviating POCD.

Recent studies have shown that human amniotic membrane-derived mesenchymal stem cells (hAM-MSCs) can inhibit NET formation by secreting tumor necrosis factor-stimulated gene 6 (TSG-6). TSG-6 is an important mediator for the immunomodulatory effects of MSCs [ 86 ]. Specifically, prostaglandin E2 (PGE2) secreted by hAM-MSCs can regulate NET release by affecting peptidyl arginine deiminase 4 (PAD4) and NF-κB activity in neutrophils via EP2 and EP4 receptors [ 87 ]. This mechanism provides a clear molecular-level explanation for MSC-mediated inhibition of neutrophil NETosis.

TSG-6 has demonstrated immunomodulatory effects in various pathological conditions, including inhibiting neutrophil chemotaxis and transendothelial migration, and modulating inflammatory responses in dendritic cells, macrophages, monocytes, and T cells. In a rat model of spinal cord injury, intrathecally transplanted Wharton’s jelly MSCs were able to inhibit the NLRP1 inflammasome, further underscoring the role of MSCs in inflammation regulation [ 88 ].

Fig. 2 MSCs regulate immune responses through cell contact-dependent mechanisms, including PD-L1/PD-1 and ICAM-1 signaling, and paracrine mechanisms involving TGF-β, IL-10, IDO, PGE2, HGF, and MSC-sEVs. (a). MSCs suppress neutrophil NET release via the PGE2-EP2/EP4-PAD4/NF-κB axis. (b). MSC-derived PGE2, TGF-β, and IDO inhibit NK-cell proliferation and cytotoxicity. (c). MSCs promote macrophage and microglial transition toward an anti-inflammatory M2-like phenotype through TSG-6, PGE2, MSC-EVs, and the IDO-kynurenine-AHR axis, while suppressing TLR2/TLR4-MyD88-NF-κB signaling. (d). MSCs induce tolerogenic B-cell responses, increase Breg and IL-10 production, and reduce the pro-inflammatory B-cell secretome. (e). MSCs promote Treg generation, inhibit Th17 differentiation, and reduce IL-17 A production through JAK-STAT modulation and the IDO-kynurenine-AHR axis, with LAAO and CD73-IFNγ-IDO1 also contributing to immune homeostasis. Together, these mechanisms may restore peripheral immune balance and reduce POCD-associated neuroinflammation. (This figure was independently created by the authors using Microsoft PowerPoint)

Table 2 Advantages of MSCs treatment for Postoperative cognitive impairment MSCs type/source Immune cells Main pathway Mechanism Neural repair result/advantage References BM-MSC Macrophages 、T cells and Neutrophils HMGB1-RAGE axis mediation Inhibit the activity of macrophages and T cells, enhance mitochondrial phagocytosis of neutrophils Improving POCD through anti-inflammatory and neural repair Guo, Niu et al. [ 36 ] DPSC T cells 、B cells IDO-Kynurenine- AHR axis, not specifically revealed Secreting IDO and TGF - β to inhibit inflammation, directly differentiating into neural like cells the neural repair efficiency of POCD is better. Mottaghi, Kianbakht et al. [ 89 ] hWJ-MSC Microglias、Macrophages The TLR4/CD14 signaling pathway Inhibit pro-inflammatory cytokines and educe the transcription of Il6 and Tnf in macrophages Inhibiting the transcription and secretion of pro-inflammatory cytokines Thomi, Surbek et al. [ 90 ] hUC-MSC-EVs + NLRP3 inhibitor Microglia and infiltrating macrophages the HMGB-1/TLR4/NF-κB pathway Inhibiting microglia and infiltrating macrophages, thereby reducing IL-1 β Promote neural repair Ma, Jiang et al. [ 91 ] UC-MSC + PAD4 inhibition Neutrophils、monocytes Wnt3/β-catenin/TCF4 signaling PAD4 inhibition reduces BBB damage and secondary release of DAMPs; MSCs more effectively reshape monocytes/macrophages Protecting BBB permeability and cognitive function Yue, Mo et al. [ 92 ]

Challenges in clinical translation and future directions

Optimization of administration routes and dosage for MSCs

Optimizing the administration route, timing, dosage and frequency of MSCs and their derivatives is a key issue for promoting their clinical transformation in the prevention and treatment of POCD. Currently, preclinical studies mostly use intravenous injections, which are simple to operate, have low invasiveness and is suitable for repeated administration [ 93 ]. However, after intravenous administration, MSCs or MSC-EVs may be rapidly intercepted or cleared by the lungs, liver, spleen and mononuclear phagocytic system, thereby limiting the effective dose that enters the central nervous system [ 94 ]. As cell-free therapeutic carriers, MSC-EVs can enter recipient cells through membrane fusion, endocytosis or ligand-receptor interactions, and deliver active molecules such as miRNA, proteins, lipids and metabolites [ 95 ]. Their nanoscale structure, biocompatibility and potential ability to cross the blood-brain barrier give them certain advantages in the treatment of neurological diseases.

Artificial intelligence (AI) may play an important role in optimizing the administration route and dosage of MSCs. By combining multidimensional biological signals with neurofunctional indicators, AI may help build a more personalized and real-time treatment strategy. AI can analyze dynamic time-series data, including plasma inflammatory cytokine profiles, changes in immune cell subsets, microglial/astrocytic markers, and blood-brain barrier leakage indicators. It can also process neurofunctional metrics, such as electroencephalogram (EEG) spectra, functional connectivity, and event-related potentials [ 96 , 97 ]. Based on these data, AI may predict the postoperative inflammatory peak, key turning points in immune responses, and changes in neurofunctional status. This information can help identify the optimal MSC administration time window, route, and dosage curve for each patient. Compared with the traditional model of “fixed dose → delayed clinical response”, this strategy may make MSC therapy more individualized and timelier [ 98 , 99 ].

Brain-computer interfaces (BCIs) can serve as real-time monitoring tools. They can continuously track the recovery of brain network function before and after MSC administration [ 100 ]. AI models can then adjust MSC dosage and dosing intervals according to real-time neural states captured by BCIs. In this way, treatment optimization can form a dual-layer closed-loop system that includes both immune dynamics and neural function [ 101 ]. This administration strategy is jointly guided by neural electrical activity and immune responses. Compared with adjustment methods based only on a single immune parameter or a single neural indicator, this approach may better reflect the complex pathological network of POCD.

VLong-term safety assessment and immunorejection risks

Long-term safety and possible immunorejection are still important issues in the clinical translation of MSCs and their derivatives for POCD. MSCs are usually considered to have relatively low immunogenicity. However, they are not completely immune-privileged. Their immunogenicity and therapeutic effects may be affected by several factors, including donor variability, tissue source, culture expansion, inflammatory priming, MHC compatibility, and repeated administration [ 102 ]. MSCs act through multiple mechanisms.

However, MSC heterogeneity, tissue source, and preparation procedures may change host immune responses [ 103 ]. For instance, induced pluripotent stem cell (iPSC) derived MSCs possess unlimited self-renewal capacity but may involve tumorigenic risks or immune activation during long-term use [ 103 ]. In addition, exosomes are a cell-free therapeutic strategy. They can reduce some risks related to live-cell transplantation. However, the long-term effects of the miRNAs carried by exosomes still need further validation [ 104 ].

Future efforts should involve large-scale animal models and clinical trials to monitor immune markers and histopathological changes, ensuring the safety and tolerability of MSC-based therapies for POCD [ 105 ]. The composition and function of exosomes change according to their parental MSCs; therefore, their therapeutic efficacy largely depends on the MSC donor, tissue source, and culture conditions. Aging can also induce fundamental changes in the MSC secretome, which has significant implications for the therapeutic application of exosomes [ 106 ].

Combined therapeutic strategies

The combined use of MSCs and anti-inflammatory drugs may provide a useful strategy for POCD management. This approach may improve therapeutic efficacy because POCD is not caused by a single pathological process, but by several interacting mechanisms [ 81 ].

AI and brain-computer interface (BCI) technologies may help integrate MSCs with other therapeutic approaches. This combination could support a more flexible multimodal intervention system. For example, MSC therapy may be combined with transcranial alternating current stimulation (tACS) or transcranial direct current stimulation (tDCS) [ 107 ]. BCI can record EEG features, including the θ/γ power ratio, network synchronization/desynchronization indices, and microstate analysis. These features can then be used as AI inputs to adjust stimulation parameters and treatment timing. This strategy is designed to strengthen the interaction between neuromodulation and MSC-mediated immunomodulation [ 108 ]. In this process, MSCs may regulate inflammatory networks, promote M2-type polarization, and reduce the release of pro-inflammatory cytokines. At the same time, tACS can be applied at specific frequency bands to enhance hippocampal-prefrontal functional connectivity. This effect may help restore synaptic plasticity and cognitive function [ 109 ]. AI models may further identify the optimal time window for electrical stimulation according to BCI feedback. Therefore, this “dual neuro-immune targeting” strategy may overcome some limitations of MSC-based immunomodulation alone.

Summary

The therapeutic value of mesenchymal stem cells (MSCs) in POCD has received broad attention. MSCs can regulate immune responses through several targets, so they may provide a useful strategy for treating neuroinflammation-related disorders. Their immunomodulatory effects are mainly reflected in suppressing the release of pro-inflammatory cytokines [ 110 , 111 ]. For example, MSCs reduce the infiltration and activation of M1-type macrophages. This effect further decreases the production of pro-inflammatory factors. Inflammatory models, such as the LPS (Lipopolysaccharide) induced mouse model, MSCs markedly reduce IL-1β and TNF-α levels in brain tissue.

MSCs also help form an anti-inflammatory microenvironment by increasing IL-10 and TGF-β production [ 112 ]. IL-10 is an important immunosuppressive factor. It can limit the production of pro-inflammatory cytokines. TGF-β is also involved in immune regulation, cell growth, and differentiation. It has anti-inflammatory and anti-fibrotic effects [ 113 ]. Under TNF-α stimulation, MSCs can increase the expression of TGF-β and IL-10, which strengthens their immunosuppressive activity [ 114 ]. In this way, MSCs reduce pro-inflammatory signals and enhance anti-inflammatory responses at the same time. This process may help relieve neuroinflammation, protect neurons, and support cognitive recovery [ 56 ]. Although MSCs show clear potential in POCD treatment, their clinical translation still faces several problems.

Cell source and heterogeneity remain important issues. MSCs can be obtained from bone marrow (BM-MSCs), adipose tissue (AD-MSCs), and umbilical cord (UC-MSCs). MSCs from different tissues may not have the same biological features or immunomodulatory ability. In addition, culture conditions, passage number, transplantation route, and dosage can all affect therapeutic outcomes [ 115 ]. These factors make study results less consistent. They also make it difficult to build a unified treatment protocol. Future studies need to improve cell preparation and administration strategies. This work may increase the reliability and repeatability of MSC-based therapy.

The timing and duration of MSC action also needs more study. It is still unclear whether the anti-inflammatory effect of MSCs is only a short-term response or a long-term remodeling of the immune microenvironment. This question is important because it directly affects clinical treatment design. Some studies suggest that MSCs may have lasting effects through paracrine mechanisms. However, researchers still need to explain how MSCs survive and maintain their function in vivo over a longer period.

Patient differences may also influence MSC efficacy. Age, disease status, and immune background can change the response to MSC treatment. For example, elderly patients may not respond to MSCs in the same way as younger patients. Therefore, future studies need to identify reliable biomarkers. These biomarkers may help select patients who are more likely to benefit from MSC therapy [ 116 ].

At the same time, single-cell sequencing and proteomics may help clarify how MSCs regulate immune networks. These methods can reveal cytokine profiles, gene expression patterns, and cell-cell interactions. They may also help explain how MSCs affect host immune responses and neural plasticity [ 117 ]. Future studies should further examine the interaction between MSCs and other immune cells, including Treg cells and macrophages. More attention should also be paid to how MSC-secreted components cooperate in neuroimmune regulation. This line of evidence may help promote the clinical translation and application of MSC-based therapies.

In summary, MSCs have promising prospects for POCD treatment. However, several barriers still need to be addressed, including cell source, standardization, duration of action, and patient variability. Future work should combine engineering strategies, biomaterials, and multi-omics analysis. These approaches may help clarify the mechanisms of MSCs and support their wider clinical application.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Xuehao Liu and Chengran Wang contributed equally to this work.

Acknowledgements

The authors thank the scientific researchers for their help in human medical careers. This article uses ChatGPT to polish some paragraphs.

Author contributions

XL and CW contributed to the conceptualization and methodology. XL also conducted an investigation and verification. LH and HS contributed to supervision and software. SY offered financial support and worked on visualization. XL wrote the original draft, and CW also made significant contributions during the manuscript writing process. FH and JJ jointly completed the review and editing of the manuscript.

Funding

Financial support was received for the research and publication of this article. This research was funded by the Jilin Provincial Natural Science Foundation General Program (Medical Sciences Field) (YDZJ202501ZYTS109).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Abbreviations

Postoperative cognitive dysfunction

Mesenchymal stem cells

Central nervous system

Interleukin-1β

Interleukin-6

Tumor necrosis factor-α

The blood-brain barrier

Extracellular vesicles

MSC-derived extracellular vesicles

Bone Marrow-derived MSCs

Adipose-derived MSCs

Umbilical Cord-derived MSCs

Dendritic cells

I Interferon

Programmed death-ligand 1

Programmed death-1

Intercellular adhesion molecule-1

Regulatory T cells

Transforming Growth Factor-β

Interleukin-10

Indoleamine 2,3-Dioxygenase

Prostaglandin E2

Hepatocyte Growth Factor

Alzheimer’s disease

Damage-associated molecular patterns

High mobility group box 1

Toll-like receptor 4

The receptor for advanced glycation end products

Central nervous system

Pathogen-associated molecular patterns

Reactive oxygen species

Insulin-like growth factor 1

Colony-stimulating factor 1 receptor

Myocyte enhancer factor 2 C

Triggering receptor expressed on myeloid cells 2

Phosphatidylinositol 3-kinase

N-methyl-D-aspartate

Interleukin-17 A

Matrix metalloproteinase-9

Induced pluripotent stem cell

Toll-like receptor 2

MSC-conditioned medium

T helper 17

Aryl hydrocarbon receptor

Human amniotic membrane-derived MSCs

Natural killer

MSC-derived extracellular vesicles

Artificial intelligence

Brain-computer interfaces

References

1. Yang X Huang X Li M Identification of individuals at risk for postoperative cognitive dysfunction (POCD) [J] Ther Adv Neurol Disord 2022 15 17562864221114356 10.1177/17562864221114356 35992893 PMC9386869 Yang X, Huang X, Li M, et al. Identification of individuals at risk for postoperative cognitive dysfunction (POCD) [J]. Ther Adv Neurol Disord. 2022;15:17562864221114356. 10.1177/17562864221114356 PMC9386869 35992893

2. He L Duan X Li S Unveiling the role of astrocytes in postoperative cognitive dysfunction [J] Ageing Res Rev 2024 95 102223 10.1016/j.arr.2024.102223 38325753 He L, Duan X, Li S, et al. Unveiling the role of astrocytes in postoperative cognitive dysfunction [J]. Ageing Res Rev. 2024;95:102223. 10.1016/j.arr.2024.102223 38325753

3. Liu Y Yang W Xue J Neuroinflammation: The central enabler of postoperative cognitive dysfunction [J] Biomed Pharmacother 2023 167 115582 10.1016/j.biopha.2023.115582 37748409 Liu Y, Yang W, Xue J, et al. Neuroinflammation: The central enabler of postoperative cognitive dysfunction [J]. Biomed Pharmacother. 2023;167:115582. 10.1016/j.biopha.2023.115582 37748409

4. Wang Y Meng F Shen J Secukinumab ameliorates postoperative cognitive dysfunction in aged mice by reducing meningeal aggregation of γδT cell [J] Mol Cell Toxicol 2025 21 4 843 55 10.1007/s13273-024-00489-9 Wang Y, Meng F, Shen J, et al. Secukinumab ameliorates postoperative cognitive dysfunction in aged mice by reducing meningeal aggregation of γδT cell [J]. Mol Cell Toxicol. 2025;21(4):843–55.

5. Liu Y, Yin Y. Emerging roles of immune cells in postoperative cognitive dysfunction [J]. Mediators Inflamm. 2018;6215350. 10.1155/2018/6215350 PMC5835271 29670465

6. Qi Z Peng J Wang H Modulating neuroinflammation and cognitive function in postoperative cognitive dysfunction via CCR5-GPCRs-Ras-MAPK pathway targeting with microglial EVs [J] CNS Neurosci Ther 2024 30 8 e14924 10.1111/cns.14924 39143678 PMC11324532 Qi Z, Peng J, Wang H, et al. Modulating neuroinflammation and cognitive function in postoperative cognitive dysfunction via CCR5-GPCRs-Ras-MAPK pathway targeting with microglial EVs [J]. CNS Neurosci Ther. 2024;30(8):e14924. 10.1111/cns.14924 PMC11324532 39143678

7. Zhou Y, Yamamoto Y, Xiao Z, et al. The immunomodulatory functions of mesenchymal stromal/stem cells mediated via paracrine activity [J]. J Clin Med. 2019;8(7). 10.3390/jcm8071025 PMC6678920 31336889

8. Lang HL Zhao YZ Xiao RJ Small extracellular vesicles secreted by induced pluripotent stem cell-derived mesenchymal stem cells improve postoperative cognitive dysfunction in mice with diabetes [J] Neural Regen Res 2023 18 3 609 17 10.4103/1673-5374.350205 36018185 PMC9727445 Lang HL, Zhao YZ, Xiao RJ, et al. Small extracellular vesicles secreted by induced pluripotent stem cell-derived mesenchymal stem cells improve postoperative cognitive dysfunction in mice with diabetes [J]. Neural Regen Res. 2023;18(3):609–17. 10.4103/1673-5374.350205 PMC9727445 36018185

9. Qian Y Chen B Sun E Mesenchymal Stem Cell-Derived Extracellular Vesicles Alleviate Brain Damage Following Subarachnoid Hemorrhage via the Interaction of miR-140-5p and HDAC7 [J] Mol Neurobiol 2024 61 11 9136 54 10.1007/s12035-024-04118-3 38592585 Qian Y, Chen B, Sun E, et al. Mesenchymal Stem Cell-Derived Extracellular Vesicles Alleviate Brain Damage Following Subarachnoid Hemorrhage via the Interaction of miR-140-5p and HDAC7 [J]. Mol Neurobiol. 2024;61(11):9136–54. 10.1007/s12035-024-04118-3 38592585

10. Christoffers S Seiler L Wiebe E Possibilities and efficiency of MSC co-transfection for gene therapy [J] Stem Cell Res Ther 2024 15 1 150 10.1186/s13287-024-03757-6 38783353 PMC11119386 Christoffers S, Seiler L, Wiebe E, et al. Possibilities and efficiency of MSC co-transfection for gene therapy [J]. Stem Cell Res Ther. 2024;15(1):150. 10.1186/s13287-024-03757-6 PMC11119386 38783353

11. Lv Z, Cai X, Bian Y, et al. Advances in mesenchymal stem cell therapy for osteoarthritis: from preclinical and clinical perspectives [J]. Bioeng (Basel).2023;10(2). 10.3390/bioengineering10020195 PMC9952673 36829689

12. Cen J Zhang Y Bai Y Research progress of stem cell therapy for endometrial injury [J] Mater Today Bio 2022 16 100389 10.1016/j.mtbio.2022.100389 36033375 PMC9403503 Cen J, Zhang Y, Bai Y, et al. Research progress of stem cell therapy for endometrial injury [J]. Mater Today Bio. 2022;16:100389. 10.1016/j.mtbio.2022.100389 PMC9403503 36033375

13. Abu-El-Rub E Khaswaneh RR Almahasneh FA Adipose Tissue and Bone Marrow-Derived Mesenchymal Stem Cells are not Really the Same: Investigating the Differences in Their Immunomodulatory, Migratory, and Adhesive Profile [J] Biochem Genet 2025 63 1 378 92 10.1007/s10528-024-10724-6 38441812 Abu-El-Rub E, Khaswaneh RR, Almahasneh FA, et al. Adipose Tissue and Bone Marrow-Derived Mesenchymal Stem Cells are not Really the Same: Investigating the Differences in Their Immunomodulatory, Migratory, and Adhesive Profile [J]. Biochem Genet. 2025;63(1):378–92. 10.1007/s10528-024-10724-6 38441812

14. Bárcia RN, Santos JM, Filipe M, et al. What makes umbilical cord tissue-derived mesenchymal stromal cells superior immunomodulators when compared to bone marrow derived mesenchymal stromal cells? [J]. Stem Cells Int. 2015;583984. 10.1155/2015/583984 PMC4443932 26064137

15. Mazini L, Rochette L, Amine M, et al. Regenerative capacity of adipose derived stem cells (ADSCs), comparison with mesenchymal stem cells (MSCs) [J]. Int J Mol Sci. 2019;20(10). 10.3390/ijms20102523 PMC6566837 31121953

16. Wu L Tang Q Yin X The Therapeutic Potential of Adipose Tissue-Derived Mesenchymal Stem Cells to Enhance Radiotherapy Effects on Hepatocellular Carcinoma [J] Front Cell Dev Biol 2019 7 267 10.3389/fcell.2019.00267 31781559 PMC6861425 Wu L, Tang Q, Yin X, et al. The Therapeutic Potential of Adipose Tissue-Derived Mesenchymal Stem Cells to Enhance Radiotherapy Effects on Hepatocellular Carcinoma [J]. Front Cell Dev Biol. 2019;7:267. 10.3389/fcell.2019.00267 PMC6861425 31781559

17. Hori A, Takahashi A, Miharu Y, et al. Superior migration ability of umbilical cord-derived mesenchymal stromal cells (MSCs) toward activated lymphocytes in comparison with those of bone marrow and adipose-derived MSCs [J]. Front Cell Dev Biology. 2024;12–2024. 10.3389/fcell.2024.1329218 PMC10961348 38529405

18. Ma J Wu J Han L Comparative analysis of mesenchymal stem cells derived from amniotic membrane, umbilical cord, and chorionic plate under serum-free condition [J] Stem Cell Res Ther 2019 10 1 19 10.1186/s13287-018-1104-x 30635045 PMC6330472 Ma J, Wu J, Han L, et al. Comparative analysis of mesenchymal stem cells derived from amniotic membrane, umbilical cord, and chorionic plate under serum-free condition [J]. Stem Cell Res Ther. 2019;10(1):19. 10.1186/s13287-018-1104-x PMC6330472 30635045

19. Jiang Y, Wells A, Sylakowski K, et al. Adult stem cell functioning in the tumor micro-environment [J]. Int J Mol Sci. 2019;20(10). 10.3390/ijms20102566 PMC6566759 31130595

20. Kim GY, Choi GT, Park J, et al. Comparative analysis of porcine adipose- and wharton’s jelly-derived mesenchymal stem cells [J]. Animals (Basel). 2023;13(18). 10.3390/ani13182947 PMC10525484 37760347

21. Cheng L Wang S Peng C Human umbilical cord mesenchymal stem cells for psoriasis: a phase 1/2a, single-arm study [J] Signal Transduct Target Ther 2022 7 1 263 10.1038/s41392-022-01059-y 35927231 PMC9352692 Cheng L, Wang S, Peng C, et al. Human umbilical cord mesenchymal stem cells for psoriasis: a phase 1/2a, single-arm study [J]. Signal Transduct Target Ther. 2022;7(1):263. 10.1038/s41392-022-01059-y PMC9352692 35927231

22. Akhlaghpasand M Tavanaei R Hosseinpoor M Safety and potential effects of intrathecal injection of allogeneic human umbilical cord mesenchymal stem cell-derived exosomes in complete subacute spinal cord injury: a first-in-human, single-arm, open-label, phase I clinical trial [J] Stem Cell Res Ther 2024 15 1 264 10.1186/s13287-024-03868-0 39183334 PMC11346059 Akhlaghpasand M, Tavanaei R, Hosseinpoor M, et al. Safety and potential effects of intrathecal injection of allogeneic human umbilical cord mesenchymal stem cell-derived exosomes in complete subacute spinal cord injury: a first-in-human, single-arm, open-label, phase I clinical trial [J]. Stem Cell Res Ther. 2024;15(1):264. 10.1186/s13287-024-03868-0 PMC11346059 39183334

23. Chun W Tian J Zhang Y Transplantation of mesenchymal stem cells ameliorates systemic lupus erythematosus and upregulates B10 cells through TGF-β1 [J] Stem Cell Res Ther 2021 12 1 512 10.1186/s13287-021-02586-1 34563233 PMC8466915 Chun W, Tian J, Zhang Y. Transplantation of mesenchymal stem cells ameliorates systemic lupus erythematosus and upregulates B10 cells through TGF-β1 [J]. Stem Cell Res Ther. 2021;12(1):512. 10.1186/s13287-021-02586-1 PMC8466915 34563233

24. Chen S Han C Shi Z Umbilical mesenchymal stem cells mitigate T-cell compartments shift and Th17/Treg imbalance in acute ischemic stroke via mitochondrial transfer [J] Stem Cell Res Ther 2025 16 1 134 10.1186/s13287-025-04224-6 40075467 PMC11905603 Chen S, Han C, Shi Z, et al. Umbilical mesenchymal stem cells mitigate T-cell compartments shift and Th17/Treg imbalance in acute ischemic stroke via mitochondrial transfer [J]. Stem Cell Res Ther. 2025;16(1):134. 10.1186/s13287-025-04224-6 PMC11905603 40075467

25. Fu Y Zhang C Xie H Human umbilical cord mesenchymal stem cells alleviated TNBS-induced colitis in mice by restoring the balance of intestinal microbes and immunoregulation [J] Life Sci 2023 334 122189 10.1016/j.lfs.2023.122189 37865178 Fu Y, Zhang C, Xie H, et al. Human umbilical cord mesenchymal stem cells alleviated TNBS-induced colitis in mice by restoring the balance of intestinal microbes and immunoregulation [J]. Life Sci. 2023;334:122189. 10.1016/j.lfs.2023.122189 37865178

26. Wei X, Cheng X, Luo Y, et al. Umbilical cord-derived mesenchymal stem cells attenuate S100-induced autoimmune hepatitis via modulating Th1 and Th17 cell responses in mice [J]. Stem Cells Int, 2023, 2023: 9992207. 10.1155/2023/9992207 PMC10597736 37881518

27. Zhou M Pei B Cai P Human umbilical cord mesenchymal stem cell-derived exosomes repair IBD by activating the SIRT1-FXR pathway in macrophages [J] Stem Cell Res Ther 2025 16 1 233 10.1186/s13287-025-04365-8 40346712 PMC12065267 Zhou M, Pei B, Cai P, et al. Human umbilical cord mesenchymal stem cell-derived exosomes repair IBD by activating the SIRT1-FXR pathway in macrophages [J]. Stem Cell Res Ther. 2025;16(1):233. 10.1186/s13287-025-04365-8 PMC12065267 40346712

28. Luo X Deng J Jiang X Reconstitution of T cell-mediated immunity by umbilical cord-derived mesenchymal stem cells in ulcerative colitis [J] Clin Transl Med 2025 15 8 e70452 10.1002/ctm2.70452 40842289 PMC12371211 Luo X, Deng J, Jiang X, et al. Reconstitution of T cell-mediated immunity by umbilical cord-derived mesenchymal stem cells in ulcerative colitis [J]. Clin Transl Med. 2025;15(8):e70452. 10.1002/ctm2.70452 PMC12371211 40842289

29. Liao W Li X Tang X Human Umbilical Cord Mesenchymal Stem Cells Alleviate Chronic Salpingitis by Modulating Macrophage-Associated Inflammatory Factors [J] Curr Stem Cell Res Ther 2024 19 11 1442 8 10.2174/011574888X261128231108043931 38173206 Liao W, Li X, Tang X. Human Umbilical Cord Mesenchymal Stem Cells Alleviate Chronic Salpingitis by Modulating Macrophage-Associated Inflammatory Factors [J]. Curr Stem Cell Res Ther. 2024;19(11):1442–8. 10.2174/011574888X261128231108043931 38173206

30. Liu H Zhang Q Liu C Human Umbilical Cord Mesenchymal Stromal Cell-Derived Exosomes Alleviate Hypoxia-Induced Pulmonary Arterial Hypertension in Mice Via Macrophages [J] Stem Cells 2024 42 4 329 45 10.1093/stmcls/sxad098 38153856 Liu H, Zhang Q, Liu C, et al. Human Umbilical Cord Mesenchymal Stromal Cell-Derived Exosomes Alleviate Hypoxia-Induced Pulmonary Arterial Hypertension in Mice Via Macrophages [J]. Stem Cells. 2024;42(4):329–45. 10.1093/stmcls/sxad098 38153856

31. Mo Y Kang H Bang JY Intratracheal administration of mesenchymal stem cells modulates lung macrophage polarization and exerts anti-asthmatic effects [J] Sci Rep 2022 12 1 11728 10.1038/s41598-022-14846-y 35821386 PMC9276742 Mo Y, Kang H, Bang JY, et al. Intratracheal administration of mesenchymal stem cells modulates lung macrophage polarization and exerts anti-asthmatic effects [J]. Sci Rep. 2022;12(1):11728. 10.1038/s41598-022-14846-y PMC9276742 35821386

32. Wang J Li J Yin L MSCs promote the efferocytosis of large peritoneal macrophages to eliminate ferroptotic monocytes/macrophages in the injured endometria [J] Stem Cell Res Ther 2024 15 1 127 10.1186/s13287-024-03742-z 38693589 PMC11064342 Wang J, Li J, Yin L, et al. MSCs promote the efferocytosis of large peritoneal macrophages to eliminate ferroptotic monocytes/macrophages in the injured endometria [J]. Stem Cell Res Ther. 2024;15(1):127. 10.1186/s13287-024-03742-z PMC11064342 38693589

33. Ye YM Zhao YX Xiang LR The Immunomodulatory mechanism and research progress of mesenchymal stem cells in the treatment of allergic rhinitis [J] Stem Cell Res Ther 2025 16 1 188 10.1186/s13287-025-04333-2 40251675 PMC12008879 Ye YM, Zhao YX, Xiang LR, et al. The Immunomodulatory mechanism and research progress of mesenchymal stem cells in the treatment of allergic rhinitis [J]. Stem Cell Res Ther. 2025;16(1):188. 10.1186/s13287-025-04333-2 PMC12008879 40251675

34. Xie HC Wang ZG Feng YH Bone marrow mesenchymal stem cells repress renal transplant immune rejection by facilitating the APRIL phosphorylation to induce regulation B cell production [J] Physiol Genomics 2023 55 2 90 100 10.1152/physiolgenomics.00103.2022 36645668 Xie HC, Wang ZG, Feng YH, et al. Bone marrow mesenchymal stem cells repress renal transplant immune rejection by facilitating the APRIL phosphorylation to induce regulation B cell production [J]. Physiol Genomics. 2023;55(2):90–100. 10.1152/physiolgenomics.00103.2022 36645668

35. Wang H Wang K LIU B The efficacy of bone marrow mesenchymal stem cells on rat intestinal immune-function injured by ischemia/reperfusion [J] Heliyon 2023 9 5 e15585 10.1016/j.heliyon.2023.e15585 37131448 PMC10149202 Wang H, Wang K, LIU B, et al. The efficacy of bone marrow mesenchymal stem cells on rat intestinal immune-function injured by ischemia/reperfusion [J]. Heliyon. 2023;9(5):e15585. 10.1016/j.heliyon.2023.e15585 PMC10149202 37131448

36. Guo X Niu Z ZhuanG Y Bone marrow mesenchymal stromal cells attenuate smoke inhalation injury by regulating the M1/M2-Th17/Treg immune homeostasis axis [J] Int Immunopharmacol 2024 141 112986 10.1016/j.intimp.2024.112986 39182266 Guo X, Niu Z, ZhuanG Y, et al. Bone marrow mesenchymal stromal cells attenuate smoke inhalation injury by regulating the M1/M2-Th17/Treg immune homeostasis axis [J]. Int Immunopharmacol. 2024;141:112986. 10.1016/j.intimp.2024.112986 39182266

37. Wang J Liu H Yue G Human placenta-derived mesenchymal stem cells ameliorate diabetic kidney disease by modulating the T helper 17 cell/ regulatory T-cell balance through the programmed death 1 / programmed death-ligand 1 pathway [J] Diabetes Obes Metab 2024 26 1 32 45 10.1111/dom.15282 37722965 Wang J, Liu H, Yue G, et al. Human placenta-derived mesenchymal stem cells ameliorate diabetic kidney disease by modulating the T helper 17 cell/ regulatory T-cell balance through the programmed death 1 / programmed death-ligand 1 pathway [J]. Diabetes Obes Metab. 2024;26(1):32–45. 10.1111/dom.15282 37722965

38. Yao D Ye S He Z Adipose-derived mesenchymal stem cells (AD-MSCs) in the treatment for psoriasis: results of a single-arm pilot trial [J] Ann Transl Med 2021 9 22 1653 10.21037/atm-21-5028 34988162 PMC8667096 Yao D, Ye S, He Z, et al. Adipose-derived mesenchymal stem cells (AD-MSCs) in the treatment for psoriasis: results of a single-arm pilot trial [J]. Ann Transl Med. 2021;9(22):1653. 10.21037/atm-21-5028 PMC8667096 34988162

39. Shafeghat Z Dorfaki M Dehrouyeh S Mesenchymal stem cell-derived exosomes for managing graft-versus-host disease: An updated view [J] Transpl Immunol 2023 81 101957 10.1016/j.trim.2023.101957 37935319 Shafeghat Z, Dorfaki M, Dehrouyeh S, et al. Mesenchymal stem cell-derived exosomes for managing graft-versus-host disease: An updated view [J]. Transpl Immunol. 2023;81:101957. 10.1016/j.trim.2023.101957 37935319

40. Kim JY Park M Kim YH Tonsil-derived mesenchymal stem cells (T-MSCs) prevent Th17-mediated autoimmune response via regulation of the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) pathway [J] J Tissue Eng Regen Med 2018 12 2 e1022 33 10.1002/term.2423 28107610 Kim JY, Park M, Kim YH, et al. Tonsil-derived mesenchymal stem cells (T-MSCs) prevent Th17-mediated autoimmune response via regulation of the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) pathway [J]. J Tissue Eng Regen Med. 2018;12(2):e1022–33. 10.1002/term.2423 28107610

41. Kou M, Huang L, Yang J, et al. Mesenchymal stem cell-derived extracellular vesicles for immunomodulation and regeneration: a next generation therapeutic tool? [J]. Volume 13. Cell Death & Disease; 2022. p. 580. 7. 10.1038/s41419-022-05034-x PMC9252569 35787632

42. Lee HK Lim SH Chung IS Preclinical efficacy and mechanisms of mesenchymal stem cells in animal models of autoimmune diseases [J] Immune Netw 2014 14 2 81 8 10.4110/in.2014.14.2.81 24851097 PMC4022782 Lee HK, Lim SH, Chung IS, et al. Preclinical efficacy and mechanisms of mesenchymal stem cells in animal models of autoimmune diseases [J]. Immune Netw. 2014;14(2):81–8. 10.4110/in.2014.14.2.81 PMC4022782 24851097

43. Chen X Cai C Xu D Human Mesenchymal Stem Cell-Treated Regulatory CD23(+)CD43(+) B Cells Alleviate Intestinal Inflammation [J] Theranostics 2019 9 16 4633 47 10.7150/thno.32260 31367246 PMC6643430 Chen X, Cai C, Xu D, et al. Human Mesenchymal Stem Cell-Treated Regulatory CD23(+)CD43(+) B Cells Alleviate Intestinal Inflammation [J]. Theranostics. 2019;9(16):4633–47. 10.7150/thno.32260 PMC6643430 31367246

44. Wassmer CH Berishvili E Immunomodulatory Properties of Amniotic Membrane Derivatives and Their Potential in Regenerative Medicine [J] Curr Diab Rep 2020 20 8 31 10.1007/s11892-020-01316-w 32519069 PMC7283202 Wassmer CH, Berishvili E. Immunomodulatory Properties of Amniotic Membrane Derivatives and Their Potential in Regenerative Medicine [J]. Curr Diab Rep. 2020;20(8):31. 10.1007/s11892-020-01316-w PMC7283202 32519069

45. Wang H Zheng R Chen Q Mesenchymal stem cells microvesicles stabilize endothelial barrier function partly mediated by hepatocyte growth factor (HGF) [J] Stem Cell Res Ther 2017 8 1 211 10.1186/s13287-017-0662-7 28969681 PMC5623961 Wang H, Zheng R, Chen Q, et al. Mesenchymal stem cells microvesicles stabilize endothelial barrier function partly mediated by hepatocyte growth factor (HGF) [J]. Stem Cell Res Ther. 2017;8(1):211. 10.1186/s13287-017-0662-7 PMC5623961 28969681

46. Saxena S, Kruys V, De Jongh R, et al. High-mobility group box-1 and its potential role in perioperative neurocognitive disorders [J]. Cells. 2021;10(10). 10.3390/cells10102582 PMC8533835 34685561

47. Lin GX Wang T Chen MH Serum high-mobility group box 1 protein correlates with cognitive decline after gastrointestinal surgery [J] Acta Anaesthesiol Scand 2014 58 6 668 74 10.1111/aas.12320 24754551 Lin GX, Wang T, Chen MH, et al. Serum high-mobility group box 1 protein correlates with cognitive decline after gastrointestinal surgery [J]. Acta Anaesthesiol Scand. 2014;58(6):668–74. 10.1111/aas.12320 24754551

48. Feng X Valdearcos M Uchida Y Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice [J] JCI Insight 2017 2 7 e91229 10.1172/jci.insight.91229 28405620 PMC5374063 Feng X, Valdearcos M, Uchida Y, et al. Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice [J]. JCI Insight. 2017;2(7):e91229. 10.1172/jci.insight.91229 PMC5374063 28405620

49. Sun J Lei D CD200-CD200R Pathway: A Regulator of Microglial Polarization in Postoperative Cognitive Dysfunction [J] J Inflamm Res 2024 17 8421 7 10.2147/JIR.S489895 39530002 PMC11552426 Sun J, Lei D. CD200-CD200R Pathway: A Regulator of Microglial Polarization in Postoperative Cognitive Dysfunction [J]. J Inflamm Res. 2024;17:8421–7. 10.2147/JIR.S489895 PMC11552426 39530002

50. Safavynia SA Goldstein PA The Role of Neuroinflammation in Postoperative Cognitive Dysfunction: Moving From Hypothesis to Treatment [J] Front Psychiatry 2018 9 752 10.3389/fpsyt.2018.00752 30705643 PMC6345198 Safavynia SA, Goldstein PA. The Role of Neuroinflammation in Postoperative Cognitive Dysfunction: Moving From Hypothesis to Treatment [J]. Front Psychiatry. 2018;9:752. 10.3389/fpsyt.2018.00752 PMC6345198 30705643

51. Rizzo FR, Musella A, De Vito F, et al. Tumor necrosis factor and interleukin-1β modulate synaptic plasticity during neuroinflammation [J]. Neural Plast. 2018: 8430123. 10.1155/2018/8430123 PMC5976900 29861718

52. Viviani B Bartesaghi S Gardoni F Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases [J] J Neurosci 2003 23 25 8692 700 10.1523/JNEUROSCI.23-25-08692.2003 14507968 PMC6740426 Viviani B, Bartesaghi S, Gardoni F, et al. Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases [J]. J Neurosci. 2003;23(25):8692–700. 10.1523/JNEUROSCI.23-25-08692.2003 PMC6740426 14507968

53. Li Z, Zhu Y, Kang Y, et al. Neuroinflammation as the underlying mechanism of postoperative cognitive dysfunction and therapeutic strategies [J]. Front Cell Neurosci, 2022, Volume 16–2022. 10.3389/fncel.2022.843069 PMC8995749 35418837

54. Ni P Dong H Wang Y IL-17A contributes to perioperative neurocognitive disorders through blood-brain barrier disruption in aged mice [J] J Neuroinflammation 2018 15 1 332 10.1186/s12974-018-1374-3 30501622 PMC6267879 Ni P, Dong H, Wang Y, et al. IL-17A contributes to perioperative neurocognitive disorders through blood-brain barrier disruption in aged mice [J]. J Neuroinflammation. 2018;15(1):332. 10.1186/s12974-018-1374-3 PMC6267879 30501622

55. Ying J Deng X Du R Mitochondrial modulation treating postoperative cognitive dysfunction neuroprotection via DRP1 inhibition by Mdivi1 [J] Sci Rep 2024 14 1 26155 10.1038/s41598-024-75548-1 39478015 PMC11525678 Ying J, Deng X, Du R, et al. Mitochondrial modulation treating postoperative cognitive dysfunction neuroprotection via DRP1 inhibition by Mdivi1 [J]. Sci Rep. 2024;14(1):26155. 10.1038/s41598-024-75548-1 PMC11525678 39478015

56. Jiang Y Gao H Yuan H Amelioration of postoperative cognitive dysfunction in mice by mesenchymal stem cell-conditioned medium treatments is associated with reduced inflammation, oxidative stress and increased BDNF expression in brain tissues [J] Neurosci Lett 2019 709 134372 10.1016/j.neulet.2019.134372 31295540 Jiang Y, Gao H, Yuan H, et al. Amelioration of postoperative cognitive dysfunction in mice by mesenchymal stem cell-conditioned medium treatments is associated with reduced inflammation, oxidative stress and increased BDNF expression in brain tissues [J]. Neurosci Lett. 2019;709:134372. 10.1016/j.neulet.2019.134372 31295540

57. Zhang S Liu C Sun J Bridging the Gap: Investigating the Link between Inflammasomes and Postoperative Cognitive Dysfunction [J] Aging Dis 2023 14 6 1981 2002 10.14336/AD.2023.0501 37450925 PMC10676784 Zhang S, Liu C, Sun J, et al. Bridging the Gap: Investigating the Link between Inflammasomes and Postoperative Cognitive Dysfunction [J]. Aging Dis. 2023;14(6):1981–2002. 10.14336/AD.2023.0501 PMC10676784 37450925

58. Wang Z Meng S Cao L Critical role of NLRP3-caspase-1 pathway in age-dependent isoflurane-induced microglial inflammatory response and cognitive impairment [J] J Neuroinflammation 2018 15 1 109 10.1186/s12974-018-1137-1 29665808 PMC5904978 Wang Z, Meng S, Cao L, et al. Critical role of NLRP3-caspase-1 pathway in age-dependent isoflurane-induced microglial inflammatory response and cognitive impairment [J]. J Neuroinflammation. 2018;15(1):109. 10.1186/s12974-018-1137-1 PMC5904978 29665808

59. Zhou Y Zhang Y Wang H Microglial pyroptosis in hippocampus mediates sevolfurane-induced cognitive impairment in aged mice via ROS-NLRP3 inflammasome pathway [J] Int Immunopharmacol 2023 116 109725 10.1016/j.intimp.2023.109725 36764275 Zhou Y, Zhang Y, Wang H, et al. Microglial pyroptosis in hippocampus mediates sevolfurane-induced cognitive impairment in aged mice via ROS-NLRP3 inflammasome pathway [J]. Int Immunopharmacol. 2023;116:109725. 10.1016/j.intimp.2023.109725 36764275

60. Chen QH Wu F Liu L Mesenchymal stem cells regulate the Th17/Treg cell balance partly through hepatocyte growth factor in vitro [J] Stem Cell Res Ther 2020 11 1 91 10.1186/s13287-020-01612-y 32111238 PMC7049226 Chen QH, Wu F, Liu L, et al. Mesenchymal stem cells regulate the Th17/Treg cell balance partly through hepatocyte growth factor in vitro [J]. Stem Cell Res Ther. 2020;11(1):91. 10.1186/s13287-020-01612-y PMC7049226 32111238

61. Shi QZ Yu HM Chen HM Exosomes derived from mesenchymal stem cells regulate Treg/Th17 balance in aplastic anemia by transferring miR-23a-3p [J] Clin Exp Med 2021 21 3 429 37 10.1007/s10238-021-00701-3 33779886 Shi QZ, Yu HM, Chen HM, et al. Exosomes derived from mesenchymal stem cells regulate Treg/Th17 balance in aplastic anemia by transferring miR-23a-3p [J]. Clin Exp Med. 2021;21(3):429–37. 10.1007/s10238-021-00701-3 33779886

62. Hui Y, Jiao X, Yang L et al. Indoleamine-2, 3-dioxygenase: An important controller in maintaining mesenchymal stem cell-mediated immunomodulatory homeostasis [J]. Acta Pharm Sinica B, 2025. 10.1016/j.apsb.2025.04.022 PMC12278408 40698141

63. Ni Q Zhen L Zeng Z Mesenchymal stromal cells restrain the Th17 cell response via L-amino-acid oxidase within lymph nodes [J] Cell Death Dis 2024 15 9 640 10.1038/s41419-024-07024-7 39251573 PMC11383963 Ni Q, Zhen L, Zeng Z, et al. Mesenchymal stromal cells restrain the Th17 cell response via L-amino-acid oxidase within lymph nodes [J]. Cell Death Dis. 2024;15(9):640. 10.1038/s41419-024-07024-7 PMC11383963 39251573

64. Chandanala S Mohan G Manukonda D-L A novel role of CD73-IFNγ signalling axis in human mesenchymal stromal cell mediated inflammatory macrophage suppression [J] Regenerative Therapy 2024 26 89 101 10.1016/j.reth.2024.05.011 38845846 PMC11153905 Chandanala S, Mohan G, Manukonda D-L, et al. A novel role of CD73-IFNγ signalling axis in human mesenchymal stromal cell mediated inflammatory macrophage suppression [J]. Regenerative Therapy. 2024;26:89–101. 10.1016/j.reth.2024.05.011 PMC11153905 38845846

65. Long Y Li XQ Deng J Modulating the polarization phenotype of microglia - A valuable strategy for central nervous system diseases [J] Ageing Res Rev 2024 93 102160 10.1016/j.arr.2023.102160 38065225 Long Y, Li XQ, Deng J, et al. Modulating the polarization phenotype of microglia - A valuable strategy for central nervous system diseases [J]. Ageing Res Rev. 2024;93:102160. 10.1016/j.arr.2023.102160 38065225

66. Wang J He W Zhang J A richer and more diverse future for microglia phenotypes [J] Heliyon 2023 9 4 e14713 10.1016/j.heliyon.2023.e14713 37025898 PMC10070543 Wang J, He W, Zhang J. A richer and more diverse future for microglia phenotypes [J]. Heliyon. 2023;9(4):e14713. 10.1016/j.heliyon.2023.e14713 PMC10070543 37025898

67. You T Yang Y IFNγ preconditioning improves neuroprotection of MSC-derived vesicles on injured retinal ganglion cells by suppressing microglia activation via miRNA-dependent ribosome activity [J] Extracell Vesicles Circulating Nucleic Acids 2025 6 1 87 111 10.20517/evcna.2024.66 PMC11977360 40206798 You T, Yang Y. IFNγ preconditioning improves neuroprotection of MSC-derived vesicles on injured retinal ganglion cells by suppressing microglia activation via miRNA-dependent ribosome activity [J]. Extracell Vesicles Circulating Nucleic Acids. 2025;6(1):87–111. 10.20517/evcna.2024.66 PMC11977360 40206798

68. Yu H Xu Z Qu G Hypoxic Preconditioning Enhances the Efficacy of Mesenchymal Stem Cells-Derived Conditioned Medium in Switching Microglia toward Anti-inflammatory Polarization in Ischemia/Reperfusion [J] Cell Mol Neurobiol 2021 41 3 505 24 10.1007/s10571-020-00868-5 32424775 PMC11448619 Yu H, Xu Z, Qu G, et al. Hypoxic Preconditioning Enhances the Efficacy of Mesenchymal Stem Cells-Derived Conditioned Medium in Switching Microglia toward Anti-inflammatory Polarization in Ischemia/Reperfusion [J]. Cell Mol Neurobiol. 2021;41(3):505–24. 10.1007/s10571-020-00868-5 PMC11448619 32424775

69. Wang Y She S Li W Inhibition of cGAS-STING pathway by stress granules after activation of M2 macrophages by human mesenchymal stem cells against drug induced liver injury [J] Mol Immunol 2024 165 42 54 10.1016/j.molimm.2023.12.005 38150981 Wang Y, She S, Li W, et al. Inhibition of cGAS-STING pathway by stress granules after activation of M2 macrophages by human mesenchymal stem cells against drug induced liver injury [J]. Mol Immunol. 2024;165:42–54. 10.1016/j.molimm.2023.12.005 38150981

70. FU SP WU X C, Yang RL The role and mechanisms of mesenchymal stem cells regulating macrophage plasticity in spinal cord injury [J] Biomed Pharmacother 2023 168 115632 10.1016/j.biopha.2023.115632 37806094 FU SP, WU X C, Yang RL, et al. The role and mechanisms of mesenchymal stem cells regulating macrophage plasticity in spinal cord injury [J]. Biomed Pharmacother. 2023;168:115632. 10.1016/j.biopha.2023.115632 37806094

71. Ko JH OH JY Mesenchymal stromal cells regulate THP-1-differentiated macrophage cytokine production by activating Akt/mammalian target of rapamycin complex 1 pathway [J] Cytotherapy 2023 25 8 858 65 10.1016/j.jcyt.2023.03.013 37125989 Ko JH, OH JY. Mesenchymal stromal cells regulate THP-1-differentiated macrophage cytokine production by activating Akt/mammalian target of rapamycin complex 1 pathway [J]. Cytotherapy. 2023;25(8):858–65. 10.1016/j.jcyt.2023.03.013 37125989

72. Wang X Guo D He C Clinical application of mesenchymal stem cells in immunosenescence: a qualitative review of their potential and challenges [J] Stem Cell Res Ther 2025 16 1 265 10.1186/s13287-025-04360-z 40437519 PMC12121065 Wang X, Guo D, He C, et al. Clinical application of mesenchymal stem cells in immunosenescence: a qualitative review of their potential and challenges [J]. Stem Cell Res Ther. 2025;16(1):265. 10.1186/s13287-025-04360-z PMC12121065 40437519

73. Cui R Rekasi H Hepner-Schefczyk M Human mesenchymal stromal/stem cells acquire immunostimulatory capacity upon cross-talk with natural killer cells and might improve the NK cell function of immunocompromised patients [J] Stem Cell Res Ther 2016 7 1 88 10.1186/s13287-016-0353-9 27388156 PMC4937587 Cui R, Rekasi H, Hepner-Schefczyk M, et al. Human mesenchymal stromal/stem cells acquire immunostimulatory capacity upon cross-talk with natural killer cells and might improve the NK cell function of immunocompromised patients [J]. Stem Cell Res Ther. 2016;7(1):88. 10.1186/s13287-016-0353-9 PMC4937587 27388156

74. Pal B Das B In vitro Culture of Naïve Human Bone Marrow Mesenchymal Stem Cells: A Stemness Based Approach [J] Front Cell Dev Biol 2017 5 69 10.3389/fcell.2017.00069 28884113 PMC5572382 Pal B, Das B. In vitro Culture of Naïve Human Bone Marrow Mesenchymal Stem Cells: A Stemness Based Approach [J]. Front Cell Dev Biol. 2017;5:69. 10.3389/fcell.2017.00069 PMC5572382 28884113

75. Kavianpour M Saleh M Verdi J The role of mesenchymal stromal cells in immune modulation of COVID-19: focus on cytokine storm [J] Stem Cell Res Ther 2020 11 1 404 10.1186/s13287-020-01849-7 32948252 PMC7499002 Kavianpour M, Saleh M, Verdi J. The role of mesenchymal stromal cells in immune modulation of COVID-19: focus on cytokine storm [J]. Stem Cell Res Ther. 2020;11(1):404. 10.1186/s13287-020-01849-7 PMC7499002 32948252

76. Cordas Dos Santos DM Toenges R Bertamini L New horizons in our understanding of precursor multiple myeloma and early interception [J] Nat Rev Cancer 2024 24 12 867 86 10.1038/s41568-024-00755-x 39414947 Cordas Dos Santos DM, Toenges R, Bertamini L, et al. New horizons in our understanding of precursor multiple myeloma and early interception [J]. Nat Rev Cancer. 2024;24(12):867–86. 10.1038/s41568-024-00755-x 39414947

77. Caro J Braunstein M Williams L Inflammation and infection in plasma cell disorders: how pathogens shape the fate of patients [J] Leukemia 2022 36 3 613 24 10.1038/s41375-021-01506-9 35110727 PMC8809233 Caro J, Braunstein M, Williams L, et al. Inflammation and infection in plasma cell disorders: how pathogens shape the fate of patients [J]. Leukemia. 2022;36(3):613–24. 10.1038/s41375-021-01506-9 PMC8809233 35110727

78. Lu J Zhang Y Hao Q IDO-Kynurenine pathway mediates NLRP3 inflammasome activation-induced postoperative cognitive impairment in aged mice [J] Int J Neurosci 2024 134 11 1309 19 10.1080/00207454.2023.2262741 37746906 Lu J, Zhang Y, Hao Q, et al. IDO-Kynurenine pathway mediates NLRP3 inflammasome activation-induced postoperative cognitive impairment in aged mice [J]. Int J Neurosci. 2024;134(11):1309–19. 10.1080/00207454.2023.2262741 37746906

79. Marszalek-Grabska M Walczak K Gawel K Kynurenine emerges from the shadows - Current knowledge on its fate and function [J] Pharmacol Ther 2021 225 107845 10.1016/j.pharmthera.2021.107845 33831481 Marszalek-Grabska M, Walczak K, Gawel K, et al. Kynurenine emerges from the shadows - Current knowledge on its fate and function [J]. Pharmacol Ther. 2021;225:107845. 10.1016/j.pharmthera.2021.107845 33831481

80. Huang W Rui K Wang X The aryl hydrocarbon receptor in immune regulation and autoimmune pathogenesis [J] J Autoimmun 2023 138 103049 10.1016/j.jaut.2023.103049 37229809 Huang W, Rui K, Wang X, et al. The aryl hydrocarbon receptor in immune regulation and autoimmune pathogenesis [J]. J Autoimmun. 2023;138:103049. 10.1016/j.jaut.2023.103049 37229809

81. Las Heras K Garcia-Orue I Rancan F Modulating the immune system towards a functional chronic wound healing: A biomaterials and Nanomedicine perspective [J] Adv Drug Deliv Rev 2024 210 115342 10.1016/j.addr.2024.115342 38797316 Las Heras K, Garcia-Orue I, Rancan F, et al. Modulating the immune system towards a functional chronic wound healing: A biomaterials and Nanomedicine perspective [J]. Adv Drug Deliv Rev. 2024;210:115342. 10.1016/j.addr.2024.115342 38797316

82. Yan Z Zhang T Wang Y Extracellular vesicle biopotentiated hydrogels for diabetic wound healing: The art of living nanomaterials combined with soft scaffolds [J] Mater Today Bio 2023 23 100810 10.1016/j.mtbio.2023.100810 37810755 PMC10550777 Yan Z, Zhang T, Wang Y, et al. Extracellular vesicle biopotentiated hydrogels for diabetic wound healing: The art of living nanomaterials combined with soft scaffolds [J]. Mater Today Bio. 2023;23:100810. 10.1016/j.mtbio.2023.100810 PMC10550777 37810755

83. Magaña-Guerrero FS Domínguez-López A Martínez-Aboytes P Human Amniotic Membrane Mesenchymal Stem Cells inhibit Neutrophil Extracellular Traps through TSG-6 [J] Sci Rep 2017 7 1 12426 10.1038/s41598-017-10962-2 28963485 PMC5622031 Magaña-Guerrero FS, Domínguez-López A, Martínez-Aboytes P, et al. Human Amniotic Membrane Mesenchymal Stem Cells inhibit Neutrophil Extracellular Traps through TSG-6 [J]. Sci Rep. 2017;7(1):12426. 10.1038/s41598-017-10962-2 PMC5622031 28963485

84. Chen L Liu Y Wang Z Mesenchymal stem cell-derived extracellular vesicles protect against abdominal aortic aneurysm formation by inhibiting NET-induced ferroptosis [J] Exp Mol Med 2023 55 5 939 51 10.1038/s12276-023-00986-2 37121969 PMC10238484 Chen L, Liu Y, Wang Z, et al. Mesenchymal stem cell-derived extracellular vesicles protect against abdominal aortic aneurysm formation by inhibiting NET-induced ferroptosis [J]. Exp Mol Med. 2023;55(5):939–51. 10.1038/s12276-023-00986-2 PMC10238484 37121969

85. Vargas-Rodríguez P, Cuenca-Martagón A, Castillo-González J, et al. Novel therapeutic opportunities for neurodegenerative diseases with mesenchymal stem cells: the focus on modulating the blood-brain barrier [J]. Int J Mol Sci. 2023;24(18). 10.3390/ijms241814117 PMC10531435 37762420

86. La Russa D, Di Santo C, Lizasoain I, et al. Tumor Necrosis Factor (TNF)-α-Stimulated Gene 6 (TSG-6): a promising immunomodulatory target in acute neurodegenerative diseases [J]. Int J Mol Sci, 2023, 24(2). 10.3390/ijms24021162 PMC9865344 36674674

87. Estúa-Acosta GA, Buentello-Volante B, Magaña-Guerrero FS et al. Human Amniotic Membrane Mesenchymal Stem Cell-Synthesized PGE(2) Exerts an Immunomodulatory Effect on Neutrophil Extracellular Trap in a PAD-4-Dependent Pathway through EP2 and EP4 [J]. Cells, 2022, 11(18). 10.3390/cells11182831 PMC9496826 36139406

88. Mohamadi Y Noori Moghahi SM H, Mousavi M Intrathecal transplantation of Wharton’s jelly mesenchymal stem cells suppresses the NLRP1 inflammasome in the rat model of spinal cord injury [J] J Chem Neuroanat 2019 97 1 8 10.1016/j.jchemneu.2019.01.011 30703433 Mohamadi Y, Noori Moghahi SM, H, Mousavi M, et al. Intrathecal transplantation of Wharton’s jelly mesenchymal stem cells suppresses the NLRP1 inflammasome in the rat model of spinal cord injury [J]. J Chem Neuroanat. 2019;97:1–8. 10.1016/j.jchemneu.2019.01.011 30703433

89. Mottaghi M Kianbakht C Samadian S Clinical applications of dental pulp stem cells-derived exosomes in oral and maxillofacial tissue regeneration and repair [J] Differentiation 2025 146 100918 10.1016/j.diff.2025.100918 41308294 Mottaghi M, Kianbakht C, Samadian S, et al. Clinical applications of dental pulp stem cells-derived exosomes in oral and maxillofacial tissue regeneration and repair [J]. Differentiation. 2025;146:100918. 10.1016/j.diff.2025.100918 41308294

90. Thomi G Surbek D Haesler V Exosomes derived from umbilical cord mesenchymal stem cells reduce microglia-mediated neuroinflammation in perinatal brain injury [J] Stem Cell Res Ther 2019 10 1 105 10.1186/s13287-019-1207-z 30898154 PMC6429800 Thomi G, Surbek D, Haesler V, et al. Exosomes derived from umbilical cord mesenchymal stem cells reduce microglia-mediated neuroinflammation in perinatal brain injury [J]. Stem Cell Res Ther. 2019;10(1):105. 10.1186/s13287-019-1207-z PMC6429800 30898154

91. Ma G Jiang X Meng X Inhibition of NLRP3 Inflammasome Alleviates Postoperative Cognitive Impairment by Suppressing the HMGB-1/TLR4/NF-κB Pathway [J] Neurochem Res 2025 50 3 173 10.1007/s11064-025-04416-9 40437299 Ma G, Jiang X, Meng X, et al. Inhibition of NLRP3 Inflammasome Alleviates Postoperative Cognitive Impairment by Suppressing the HMGB-1/TLR4/NF-κB Pathway [J]. Neurochem Res. 2025;50(3):173. 10.1007/s11064-025-04416-9 40437299

92. Yue J Mo L Zeng G Inhibition of neutrophil extracellular traps alleviates blood–brain barrier disruption and cognitive dysfunction via Wnt3/β-catenin/TCF4 signaling in sepsis-associated encephalopathy [J] J Neuroinflamm 2025 22 1 87 10.1186/s12974-025-03395-6 PMC11917101 40102948 Yue J, Mo L, Zeng G, et al. Inhibition of neutrophil extracellular traps alleviates blood–brain barrier disruption and cognitive dysfunction via Wnt3/β-catenin/TCF4 signaling in sepsis-associated encephalopathy [J]. J Neuroinflamm. 2025;22(1):87. 10.1186/s12974-025-03395-6 PMC11917101 40102948

93. Baek G Choi H Kim Y Mesenchymal Stem Cell-Derived Extracellular Vesicles as Therapeutics and as a Drug Delivery Platform [J] Stem Cells Transl Med 2019 8 9 880 6 10.1002/sctm.18-0226 31045328 PMC6708072 Baek G, Choi H, Kim Y, et al. Mesenchymal Stem Cell-Derived Extracellular Vesicles as Therapeutics and as a Drug Delivery Platform [J]. Stem Cells Transl Med. 2019;8(9):880–6. 10.1002/sctm.18-0226 PMC6708072 31045328

94. Cieślik M Bryniarski K Nazimek K Biodelivery of therapeutic extracellular vesicles: should mononuclear phagocytes always be feared? [J] Front Cell Dev Biol 2023 11 1211833 10.3389/fcell.2023.1211833 37476156 PMC10354279 Cieślik M, Bryniarski K, Nazimek K. Biodelivery of therapeutic extracellular vesicles: should mononuclear phagocytes always be feared? [J]. Front Cell Dev Biol. 2023;11:1211833. 10.3389/fcell.2023.1211833 PMC10354279 37476156

95. Ribovski L Joshi B Gao J Breaking free: endocytosis and endosomal escape of extracellular vesicles [J] Extracell Vesicles Circ Nucl Acids 2023 4 2 283 305 10.20517/evcna.2023.26 39697985 PMC11648447 Ribovski L, Joshi B, Gao J, et al. Breaking free: endocytosis and endosomal escape of extracellular vesicles [J]. Extracell Vesicles Circ Nucl Acids. 2023;4(2):283–305. 10.20517/evcna.2023.26 PMC11648447 39697985

96. Huang M Dissanayaka WL YIU C K Y. Artificial Intelligence Driven Innovation Advancing Mesenchymal Stem Cell Therapies and Intelligent Biomaterials for Regenerative Medicine [J] Bioengineering 2025 12 12 1302 10.3390/bioengineering12121302 41463599 PMC12729526 Huang M, Dissanayaka WL, YIU C K Y. Artificial Intelligence Driven Innovation. Advancing Mesenchymal Stem Cell Therapies and Intelligent Biomaterials for Regenerative Medicine [J]. Bioengineering. 2025;12(12):1302. 10.3390/bioengineering12121302 PMC12729526 41463599

97. Gao X, Wang Y, Chen X, et al. Brain–computer interface—a brain-in-the-loop communication system [J]. Proceedings of the IEEE, 2025.

98. Chinnadurai R, Madabhushi A. Opportunities with artificial intelligence in assessing the potency of mesenchymal stromal cells [J]. Stem Cells; 2025. 10.1093/stmcls/sxaf067 PMC12790435 41159402

99. Blasiak A Tan LWJ Chong LM Personalized dose selection for the first Waldenström macroglobulinemia patient on the PRECISE CURATE.AI trial [J] npj Digit Med 2024 7 1 223 10.1038/s41746-024-01195-5 39191913 PMC11350179 Blasiak A, Tan LWJ, Chong LM, et al. Personalized dose selection for the first Waldenström macroglobulinemia patient on the PRECISE CURATE.AI trial [J]. npj Digit Med. 2024;7(1):223. 10.1038/s41746-024-01195-5 PMC11350179 39191913

100. Sun X, Li M, Li Q, et al. Poststroke cognitive impairment research progress on application of brain-computer interface [J]. Biomed Res Int. 2022;9935192. 10.1155/2022/9935192 PMC8896931 35252458

101. Henderson FC Tuchman K Angiogenic Cell Precursors and Neural Cell Precursors in Service to the Brain–Computer Interface [J] Cells 2025 14 15 1163 10.3390/cells14151163 40801596 PMC12346536 Henderson FC, Tuchman K. Angiogenic Cell Precursors and Neural Cell Precursors in Service to the Brain–Computer Interface [J]. Cells. 2025;14(15):1163. 10.3390/cells14151163 PMC12346536 40801596

102. Chen W Lv L Chen N Immunogenicity of mesenchymal stromal/stem cells [J] Scand J Immunol 2023 97 6 e13267 10.1111/sji.13267 39007962 Chen W, Lv L, Chen N, et al. Immunogenicity of mesenchymal stromal/stem cells [J]. Scand J Immunol. 2023;97(6):e13267. 10.1111/sji.13267 39007962

103. Lee HR, Kim S, Shin S et al. iPSC-Derived MSCs Are a Distinct Entity of MSCs with Higher Therapeutic Potential than Their Donor-Matched Parental MSCs [J]. Int J Mol Sci, 2023, 24(1). 10.3390/ijms24010881 PMC9821152 36614321

104. Tang X Ren Y Zeng W MicroRNA-based interventions in aberrant cell cycle diseases: Therapeutic strategies for cancers, central nervous system disorders and comorbidities [J] Biomed Pharmacother 2024 177 116979 10.1016/j.biopha.2024.116979 38906026 Tang X, Ren Y, Zeng W, et al. MicroRNA-based interventions in aberrant cell cycle diseases: Therapeutic strategies for cancers, central nervous system disorders and comorbidities [J]. Biomed Pharmacother. 2024;177:116979. 10.1016/j.biopha.2024.116979 38906026

105. Ying C, Lin F. The Role of Immune Cell Subsets in the Development of Postoperative Cognitive Dysfunction in Surgical Patients Under Anesthesia [J]. Neuroimmunomodulation, 2025: 1–28. 10.1159/000548491 41036654

106. Siraj Y Galderisi U Alessio N Senescence induces fundamental changes in the secretome of mesenchymal stromal cells (MSCs): implications for the therapeutic use of MSCs and their derivates [J] Front Bioeng Biotechnol 2023 11 1148761 10.3389/fbioe.2023.1148761 37229499 PMC10203235 Siraj Y, Galderisi U, Alessio N. Senescence induces fundamental changes in the secretome of mesenchymal stromal cells (MSCs): implications for the therapeutic use of MSCs and their derivates [J]. Front Bioeng Biotechnol. 2023;11:1148761. 10.3389/fbioe.2023.1148761 PMC10203235 37229499

107. Rudroff T Rainio O Klén R Leveraging Artificial Intelligence to Optimize Transcranial Direct Current Stimulation for Long COVID Management: A Forward-Looking Perspective [J] Brain Sci 2024 14 8 831 10.3390/brainsci14080831 39199522 PMC11353063 Rudroff T, Rainio O, Klén R. Leveraging Artificial Intelligence to Optimize Transcranial Direct Current Stimulation for Long COVID Management: A Forward-Looking Perspective [J]. Brain Sci. 2024;14(8):831. 10.3390/brainsci14080831 PMC11353063 39199522

108. Gao X Wang Y Chen X Interface, interaction, and intelligence in generalized brain-computer interfaces [J] Trends Cogn Sci 2021 25 8 671 84 10.1016/j.tics.2021.04.003 34116918 Gao X, Wang Y, Chen X, et al. Interface, interaction, and intelligence in generalized brain-computer interfaces [J]. Trends Cogn Sci. 2021;25(8):671–84. 10.1016/j.tics.2021.04.003 34116918

109. Samal P Hashmi MF Role of machine learning and deep learning techniques in EEG-based BCI emotion recognition system: a review [J] Artif Intell Rev 2024 57 3 50 10.1007/s10462-023-10690-2 Samal P, Hashmi MF. Role of machine learning and deep learning techniques in EEG-based BCI emotion recognition system: a review [J]. Artif Intell Rev. 2024;57(3):50.

110. Meng X Xiao J Wang J Mesenchymal Stem Cells Attenuates Hirschsprung diseases - Associated Enterocolitis by Reducing M1 Macrophages Infiltration via COX-2 Dependent Mechanism [J] J Pediatr Surg 2024 59 8 1498 514 10.1016/j.jpedsurg.2024.02.033 38508971 Meng X, Xiao J, Wang J, et al. Mesenchymal Stem Cells Attenuates Hirschsprung diseases - Associated Enterocolitis by Reducing M1 Macrophages Infiltration via COX-2 Dependent Mechanism [J]. J Pediatr Surg. 2024;59(8):1498–514. 10.1016/j.jpedsurg.2024.02.033 38508971

111. Huang L You J Yao Y Interleukin-13 Gene Modification Enhances Grafted Mesenchymal Stem Cells Survival After Subretinal Transplantation [J] Cell Mol Neurobiol 2020 40 5 725 35 10.1007/s10571-019-00768-3 31792777 PMC11448798 Huang L, You J, Yao Y, et al. Interleukin-13 Gene Modification Enhances Grafted Mesenchymal Stem Cells Survival After Subretinal Transplantation [J]. Cell Mol Neurobiol. 2020;40(5):725–35. 10.1007/s10571-019-00768-3 PMC11448798 31792777

112. Zhao Z Han Y Zhang Z Total glucosides of paeony improves the immunomodulatory capacity of MSCs partially via the miR-124/STAT3 pathway in oral lichen planus [J] Biomed Pharmacother 2018 105 151 8 10.1016/j.biopha.2018.05.076 29852392 Zhao Z, Han Y, Zhang Z, et al. Total glucosides of paeony improves the immunomodulatory capacity of MSCs partially via the miR-124/STAT3 pathway in oral lichen planus [J]. Biomed Pharmacother. 2018;105:151–8. 10.1016/j.biopha.2018.05.076 29852392

113. Fathy M, Okabe M, Saad Eldien HM et al. AT-MSCs Antifibrotic activity is improved by eugenol through modulation of TGF-β/Smad Signaling Pathway in Rats [J]. Molecules, 2020, 25(2). 10.3390/molecules25020348 PMC7024200 31952158

114. Putra A Ridwan FB Putridewi AI The Role of TNF-α induced MSCs on Suppressive Inflammation by Increasing TGF-β and IL-10 [J] Open Access Maced J Med Sci 2018 6 10 1779 83 10.3889/oamjms.2018.404 30455748 PMC6236029 Putra A, Ridwan FB, Putridewi AI, et al. The Role of TNF-α induced MSCs on Suppressive Inflammation by Increasing TGF-β and IL-10 [J]. Open Access Maced J Med Sci. 2018;6(10):1779–83. 10.3889/oamjms.2018.404 PMC6236029 30455748

115. Anwar MM Ali OS Rashed LA The therapeutic potential and efficiency of Intracerebroventricular transplantation and intravenous injection of Mesenchymal stem cells in relieving Aß hallmarks and improving cognitive dysfunction in AD induced model [J] Gene Rep 2021 25 101323 10.1016/j.genrep.2021.101323 Anwar MM, Ali OS, Rashed LA, et al. The therapeutic potential and efficiency of Intracerebroventricular transplantation and intravenous injection of Mesenchymal stem cells in relieving Aß hallmarks and improving cognitive dysfunction in AD induced model [J]. Gene Rep. 2021;25:101323.

116. Ahmed Kudligi SSS, Akbar N. A, et al. Intraoperative neuroplasticity: role of anesthetics in postoperative cognitive dysfunction (pocd) in young adult [j]. Paripex Indian Journal of Research; 2025.

117. Chen H Li S Xu W Interleukin-17A promotes the differentiation of bone marrow mesenchymal stem cells into neuronal cells [J] Tissue Cell 2021 69 101482 10.1016/j.tice.2020.101482 33418236 Chen H, Li S, Xu W, et al. Interleukin-17A promotes the differentiation of bone marrow mesenchymal stem cells into neuronal cells [J]. Tissue Cell. 2021;69:101482. 10.1016/j.tice.2020.101482 33418236