Иммуномодулирующие свойства месенхимальных стволовых клеток и их внеклеточных везиков: потенциальные клинические применения в аутоиммунных заболеваниях.

Introduction and background

Therapeutic interest in mesenchymal stem cells (MSCs)/mesenchymal stromal cells has grown considerably over the past decade, yet their translation into routine clinical practice still faces substantial challenges [ 1 ]. Among the different stem cell populations, MSCs have gained considerable attention because of their biological properties and their role in regenerative medicine [ 2 ]. MSCs are multipotent cells characterized by their self-renewal capacity, relatively low immunogenicity in their resting state, homing ability, and immunomodulatory properties, although their immunogenicity can be enhanced under inflammatory conditions or in allogeneic settings. Among these biological features, immunomodulation has emerged as one of the principal mechanisms underlying their therapeutic potential, allowing MSCs to regulate both innate and adaptive immune responses. Consequently, these cells have emerged as therapeutic candidates for the treatment of immune-mediated disorders, particularly autoimmune and inflammatory diseases [ 3 , 4 ]. A substantial part of this activity is exerted through secreted products rather than through direct cell-to-cell contact, including extracellular vesicles (EVs) that transfer proteins, lipids, and nucleic acids to recipient cells and are increasingly explored as cell-free therapeutic alternatives [ 5 ].

Throughout this review, the MSC abbreviation is used in line with current nomenclature discussions, encompassing both "mesenchymal stem cells" and "mesenchymal stromal cells," given that the therapeutic effects of these cells are now widely attributed primarily to paracrine and immunomodulatory mechanisms rather than to stemness or durable engraftment [ 6 , 7 ]. The abbreviation is retained consistently throughout the manuscript in this stromal/paracrine sense.

Autoimmune diseases are a heterogeneous group of conditions caused by the immune system's response to self-antigens, resulting in self-tissue damage or dysfunction [ 8 ]. The age-standardized prevalence of autoimmune diseases has nearly doubled between 1990 and 2021 [ 9 ]. However, prevalence estimates vary considerably across diseases and populations, with population-based studies reporting a prevalence of approximately 3-5% in the general population [ 10 , 11 ]. Current therapeutic strategies include corticosteroids, non-steroidal anti-inflammatory drugs, biologic agents, resolvins, and other immunomodulatory medications [ 12 ]. Although these treatments have substantially improved disease management, long-term therapy may be associated with renal, gastrointestinal, and cardiovascular toxicity. Consequently, there remains a need for therapeutic strategies capable of controlling inflammation while minimizing systemic toxicity and providing more selective immunomodulatory effects [ 13 ]. These considerations, together with the immunomodulatory properties of MSCs and the evidence generated by preclinical and clinical studies, have prompted the investigation of MSC-based therapy in autoimmune and inflammatory diseases [ 14 ].

Despite the progress summarized above, a clinically relevant knowledge gap persists. Although the immunomodulatory properties of MSCs and MSC-EVs have been extensively characterized in experimental models, the evidence supporting their clinical application remains heterogeneous and, in some cases, inconsistent, with variable outcomes largely attributed to differences in cell sources, manufacturing processes, and routes of administration [ 15 ]. Furthermore, MSC-EV-based therapies remain predominantly confined to the preclinical stage, with unresolved challenges related to large-scale production, isolation, and characterization [ 16 ]. Importantly, the available evidence is fragmented across individual diseases and therapeutic modalities, and an integrated synthesis that connects the mechanistic basis of MSC- and MSC-EV-mediated immunomodulation with the current status of clinical translation in autoimmune diseases is still lacking. This review was conceived to address this gap.

The aim of the present narrative review is to provide a synthesis of the immunomodulatory properties of MSCs and their clinical implications for the treatment of autoimmune and inflammatory diseases, from a translational perspective that integrates mechanistic understanding with the available preclinical and clinical evidence. Rather than providing a systematic appraisal of trial data, this review offers a mechanism-informed overview of how MSC-mediated immunomodulation has been - and could be - translated into therapeutic strategies. Given the marked heterogeneity of the included studies in terms of study populations, MSC sources, manufacturing methods, dosing regimens, routes of administration, and outcome measures, no formal meta-analysis or statistical pooling was performed; findings are therefore presented descriptively. The manuscript first reviews the biological characteristics of MSCs and their secretome, then examines the molecular and cellular mechanisms of MSC- and MSC-EV-mediated immunomodulation, and finally appraises the preclinical and clinical evidence across four representative diseases (multiple sclerosis (MS), type 1 diabetes mellitus (T1D), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA)), together with the current limitations, challenges, and future perspectives of MSC-based therapies.

Review design and scope

This article is a narrative review, and its scope and methodological identity are defined accordingly. The principal questions addressed are which immunomodulatory mechanisms underlie the therapeutic effects of MSCs and their EVs, and how these mechanisms have been - and could be - translated into clinical application in autoimmune and inflammatory diseases. The emphasis of the review is mechanistic and translational rather than epidemiological or trial-methodological in isolation, and the four diseases discussed - MS, T1D, SLE, and RA - were selected because, together, they represent distinct target tissues, distinct pathogenic mechanisms, and the full range of clinical evidence currently available in this setting, from randomized controlled trials to open-label cohorts and individual clinical observations. In accordance with the narrative design of this article, study selection was not systematic. Publications were identified and selected on the basis of thematic relevance and the strength of the available evidence, with priority given to the most representative studies for each disease. No formal risk-of-bias assessment, predefined protocol, or quantitative synthesis was performed, and the available evidence is presented descriptively, with its strengths and limitations explicitly noted where clinical outcomes are discussed. This review therefore does not constitute a systematic or exhaustive synthesis of all available evidence, and it does not claim to follow systematic review methodology.

Literature identification and selection

A literature search was conducted in PubMed and Google Scholar, without date restriction, covering publications from 1966 to August 2026 (last search conducted in September 2026), using combinations of the terms “mesenchymal stem cells,” “mesenchymal stromal cells,” “extracellular vesicles,” “exosomes,” “immunomodulation,” “autoimmune diseases,” “multiple sclerosis,” “type 1 diabetes mellitus,” “systemic lupus erythematosus,” and “rheumatoid arthritis.” Consistent with the narrative design of this review, the search is reported descriptively, and no single reproducible Boolean search string, record count, or duplicate-screening procedure was used. Foundational studies on MSC biology and immunomodulatory properties were identified through broader searches of the MSC literature also performed without date restriction, which accounts for the historical range of the publications cited. Preclinical studies, clinical trials, case reports, systematic reviews, and meta-analyses published in English were considered. Recent systematic reviews, randomized trials, and key consensus/guideline documents were specifically sought and incorporated. Where findings were conflicting or heterogeneous, the discrepancies were acknowledged and discussed in the corresponding sections, with the strengths and limitations of the available evidence taken into account. The restriction to English-language publications may have excluded relevant non-English studies.

Review

Biological characteristics of MSCs

MSCs are multipotent progenitor cells with broad anti-inflammatory and immunomodulatory properties, and they remain among the most extensively studied adult stem cell populations in clinical testing [ 17 ]. Friedenstein et al. reported and identified clonogenic progenitor cells capable of generating fibroblast colonies and differentiating into other mesodermal cell lineages, laying the foundations for the subsequent characterization of MSCs [ 18 , 19 ]. The first clinical trial using autologous MSCs was conducted by Lazarus et al. in 1995. The procedure was performed in 15 patients, with no serious adverse events or significant toxicity reported following the intravenous infusion of culture-expanded MSCs [ 20 ].

MSCs are multipotent cells capable of differentiating into several mesodermal lineages, including osteoblasts, chondrocytes, and adipocytes, while differentiation toward ectodermal and endodermal lineages has also been reported under specific experimental conditions. Their ability to modulate immune responses and promote tissue regeneration distinguishes MSCs from other cell populations and supports their therapeutic potential [ 21 ]. Due to their immunomodulatory, paracrine, and regenerative properties, MSCs have been extensively investigated for potential clinical applications [ 22 ]. Although the biological characteristics of MSCs vary according to their tissue of origin, they generally share self-renewal ability, immune regulatory properties, clonogenic capacity, and similar morphological features [ 23 ]. To establish standardized criteria for their identification, the International Society for Cellular Therapy (ISCT) proposed the following criteria: 1) Adherence to plastic in standard conditions; 2) Phenotype positive for CD105, CD73, CD90 and negative for CD45, CD34, CD14, CD11b, CD79α, CD19, and human leukocyte antigen (HLA)-DR; 3) In vitro differentiation into osteoblasts, adipocytes, and chondroblasts (demonstrated by staining of in vitro cell culture) [ 24 ]. However, the 2006 minimal criteria are now considered insufficient to determine the clinical potency of MSCs, and the ISCT has promoted the development of mechanism-of-action-based functional potency assays as a criterion for product release, as discussed in its recent workshops on the use of MSCs in autoimmune diseases [ 25 ].

In this context, the ISCT has proposed that immune functional potency testing for advanced-phase trials should rely on a matrix of analytic methods, including quantitative RNA analysis, flow cytometry of functionally relevant surface markers, and protein-based assays of the MSC secretome [ 26 ]. Nevertheless, potency assays and biomarkers for MSC-based advanced therapy medicinal products remain an active area of methodological development [ 27 ].

MSCs can be isolated from a wide variety of adult tissues, including bone marrow, adipose tissue, peripheral blood, lungs, and heart [ 28 ]. MSCs have also been associated with perivascular cells, particularly pericytes, supporting the presence of MSC populations in perivascular niches throughout the body [ 29 ]. In addition, perinatal tissues represent important sources of MSCs, including the umbilical cord, umbilical cord blood, and Wharton's jelly [ 30 ]. Among the multiple available sources, this review focuses primarily on adipose tissue-derived mesenchymal stem cells (ADSCs), bone marrow-derived mesenchymal stem cells (BM-MSCs), and umbilical cord-derived mesenchymal stem cells (UC-MSCs).

ADSCs represent an attractive source of MSCs because sufficient amounts of adipose tissue can be obtained through relatively simple and minimally invasive procedures [ 31 ]. In addition, adipose tissue generally provides a higher yield of MSCs than bone marrow, potentially facilitating the procurement of larger numbers of cells for expansion and therapeutic applications [ 32 ]. Interest in ADSCs has progressively increased because of their anti-apoptotic, anti-inflammatory, immunomodulatory, and pro-angiogenic properties, as well as the biological activity of their secreted products [ 33 ].

BM-MSCs are a population of multipotent stromal cells present within the bone marrow and characterized by relatively low immunogenicity [ 34 ]. These cells can contribute to regenerative processes in different tissues through several mechanisms, including the secretion of growth factors, differentiation into specialized cell types, and modulation of immune responses [ 35 ]. However, the procurement of BM-MSCs generally requires an invasive and potentially painful procedure, and the number of MSCs obtained from bone marrow aspirates may be relatively limited, representing practical disadvantages compared with other tissue sources [ 36 ].

UC-MSCs are found in several compartments of the umbilical cord, particularly within Wharton's jelly and perivascular regions [ 37 ]. One of their distinctive biological characteristics is their high proliferative capacity, reflected by a shorter population doubling time compared with that of several other MSC populations [ 38 ]. UC-MSCs also exhibit relevant immunomodulatory properties through both direct interactions with immune cells and the secretion of paracrine factors, characteristics that have contributed to growing interest in their potential therapeutic application across a variety of diseases [ 39 ].

MSCs can be obtained from either autologous sources (in which cells are derived from the same patient who will receive them) or allogeneic sources (in which cells are obtained from a donor). Both approaches present distinct advantages and limitations. Autologous MSCs minimize the risk of immune rejection and generally do not require concomitant immunosuppressive therapy; however, their clinical application may be limited by the time required for cell isolation and expansion, reduced immediate availability, and the potential influence of patient-specific characteristics or underlying disease on cell quality and functionality. In contrast, allogeneic MSCs enable donor selection, can be manufactured and stored in advance for immediate “off-the-shelf” availability, and generally exhibit relatively low immunogenicity [ 40 ]. Nevertheless, allogeneic cell-based therapeutic approaches may involve immunological and treatment-related risks [ 41 ]. In the specific setting of allogeneic MSC therapy, donor-related variability, host immune recognition, limited persistence after administration, and potential alloimmune responses represent additional considerations that may influence therapeutic efficacy and safety [ 40 ]. This concern is particularly relevant for the treatment of chronic autoimmune diseases, in which repeated infusions are commonly required. Although allogeneic MSCs were initially considered immune privileged due to their low expression of major histocompatibility complex (MHC) and co-stimulatory molecules, they can be recognized by the host immune system and have been shown to elicit anti-donor immune responses involving dendritic cells (DCs), T cells, and B-cell-mediated alloantibodies [ 42 ]. In clinical studies, donor-specific antibodies developed in a mean of 11.51% of patients treated with allogeneic MSCs; however, neither the production of donor-specific antibodies after treatment nor the presence of donor-specific antibodies at baseline (presensitization) correlated with the safety or tolerability of the therapy, and the generation of alloantibodies might not have clinical relevance [ 43 ].

As discussed throughout this narrative review, a substantial proportion of the biological and therapeutic effects attributed to MSCs may be mediated through the secretion of paracrine factors [ 44 ]. Among these secreted components, MSC-derived exosomes (MSC-Exos) have attracted considerable attention because they transport biologically active cargo, including proteins, nucleic acids, lipids, and microRNAs (miRNAs), thereby contributing to intercellular communication and potentially mediating anti-inflammatory effects within inflammatory microenvironments [ 45 ]. Given this, the following section examines the MSC secretome and its major components, with particular emphasis on EVs and exosomes.

The MSC secretome and its components

The cell secretome comprises a complex repertoire of biologically active products released by cells into the extracellular environment, including soluble factors, such as growth factors, cytokines, chemokines, and hormones, as well as EVs carrying a variety of bioactive molecules [ 46 ]. Among the soluble components, the MSC secretome contains several cytokines, including IL-10, CCL2, IL-6, and IL-7, which contribute to the paracrine and immunomodulatory activity of MSCs. In addition, MSCs secrete a broad range of growth factors and anti-inflammatory mediators that further support the biological activity of the secretome [ 47 , 48 ]. Regarding EVs, according to the Minimal Information for Studies of Extracellular Vesicles 2023 (MISEV2023) guidelines, EVs can be classified based on their physical characteristics, such as size, into "small EVs" and "medium/large EVs," with size ranges of <100 nm or <200 nm for small EVs and >200 nm for medium/large EVs, respectively [ 49 ].

Exosomes are nanoscale EVs (small EVs) enclosed by a lipid bilayer and naturally released by cells. They function as key mediators of intercellular communication through the transfer of proteins, nucleic acids, lipids, and other bioactive molecules to recipient cells [ 50 ]. Through the delivery of this molecular cargo, exosomes can transmit biological signals to recipient cells throughout the body, playing an important role in cell signaling and the modulation of cellular functions [ 51 ]. Among their bioactive components, MSC-Exos are particularly enriched in miRNAs and contain a complex molecular composition including lipids, enzymes, nucleic acids, proteins, and pro- and anti-inflammatory cytokines, which contributes to protecting miRNAs from degradation by ribonucleases in body fluids. Following the uptake of MSC-Exos by recipient cells, miRNAs are released and can target and silence specific mRNAs, thereby modulating gene expression and influencing the physiological functions of recipient cells [ 52 ]. MSC-Exos and their miRNA cargo have been investigated for their therapeutic potential in several preclinical models, including acute kidney injury, hepatic injury, and myocardial ischemia-reperfusion injury [ 53 - 55 ]. Furthermore, MSC-Exos have been associated with the regulation and attenuation of inflammatory responses through the transfer of bioactive cargo (including miRNAs) to recipient cells, supporting their potential contribution to the immunomodulatory effects attributed to MSCs [ 56 ].

EVs and exosomes secreted by MSCs can exert paracrine effects on various immune cell populations, contributing to the modulation of both innate and adaptive immune responses [ 57 ]. MSC-Exos retain many of the potential therapeutic properties attributed to their cells of origin, including anti-inflammatory, immunomodulatory, and regenerative effects [ 58 ]. Consequently, MSC-Exos and MSC-EVs have attracted considerable interest in biomedical research because of their ability to influence tissue responses to injury and disease, representing a promising alternative for the development of cell-free regenerative medicine strategies [ 44 ].

Immunomodulatory properties of MSCs and MSC-EVs

Several biological characteristics appear to contribute to the immunomodulatory and immunoregulatory properties of MSCs. MSCs are considered hypoimmunogenic due to their low expression of MHC/HLA class I, negligible expression of MHC/HLA class II, and low expression of co-stimulatory molecules, including CD40, CD40 ligand, CD80, and CD86 [ 59 , 60 ]. MSCs also secrete several soluble factors, such as indoleamine 2,3-dioxygenase (IDO), nitric oxide, and IL-6, which contribute through paracrine mechanisms to the modulation and inhibition of immune responses [ 61 - 63 ]. MSCs exert extensive immunomodulatory effects on both innate and adaptive immune responses [ 64 ]. In addition, MSC-EVs can modulate these responses by suppressing pro-inflammatory cytokines and influencing the activity of macrophages and T cells [ 65 ].

The immunomodulatory properties of MSCs are not entirely constitutive but are strongly influenced by the surrounding inflammatory microenvironment. The crosstalk between MSCs and the inflammatory microenvironment is bidirectional, and the characteristics of the inflammatory milieu can drive MSCs toward either immunosuppressive or immune-enhancing functions [ 66 ]. A study conducted by Li et al. demonstrated that pro-inflammatory cytokines play a crucial role in determining the immunomodulatory functions of MSCs. The co-presence of interferon-γ (IFN-γ) and another pro-inflammatory cytokine, such as tumor necrosis factor-α (TNF-α), was required for MSCs to exert their immunosuppressive effects [ 67 ]. Similarly, Ren et al. showed that the immunosuppressive function of MSCs is induced by pro-inflammatory cytokines and requires nitric oxide. Furthermore, pro-inflammatory cytokines induce MSCs to produce soluble factors that are crucial for their immunosuppressive activity [ 68 ]. However, this same inflammatory licensing can also raise MSC immunogenicity by increasing MHC expression, so the balance between immunomodulatory activation and immunogenic risk should be considered, particularly in allogeneic settings [ 69 ].

The elicitation of the immunosuppressive functions of MSCs requires an inflammatory environment; therefore, understanding the inflammatory milieu present in different pathological conditions may be important for optimizing their immunomodulatory function and therapeutic efficacy [ 70 ]. For instance, studies using models of inflammatory and immune-mediated diseases, including graft-versus-host disease (GVHD) and experimental autoimmune encephalomyelitis (EAE), have suggested that when MSCs are administered at the onset of disease, when inflammatory signals are still limited, their therapeutic efficacy may be reduced [ 71 , 72 ].

MSCs possess important immunoregulatory properties, acting on different immune cell populations both directly through cell-to-cell contact and indirectly through paracrine mechanisms mediated by soluble factors and MSC-EVs; accordingly, MSCs interact with T cells, B cells, macrophages, natural killer (NK) cells, and DCs [ 73 ]. Given the central role of these immune cell populations in MSC-mediated immunomodulation, their principal interactions with MSCs and MSC-EVs are schematically illustrated below (Figure 1 ), while the following sections examine their immunomodulatory effects in greater detail.

Immunomodulatory effects of MSCs and MSC-EVs on T cells

T cells are a key cellular component of the adaptive immune system, playing a fundamental role in maintaining health and preventing different types of diseases. MSCs can modulate T cell functions either indirectly, by acting on other immune cells that subsequently influence T cell responses, or directly, through their effects on T cells [ 74 ]. Regarding the indirect pathway, MSCs can maintain macrophages and DCs in an immature state, thereby preventing the activation of effector T cells and promoting the generation of Tregs [ 75 ]. Regarding the direct pathway, soluble factors secreted by MSCs can modulate T cell responses; for example, MSC-derived HLA-G5 has been shown to suppress T cell functions and promote the generation of CD4+CD25highFOXP3+ Tregs [ 76 ].

Although MSCs themselves generally do not secrete the inflammatory cytokines TNF-α and IFN-γ, these cytokines - produced by surrounding immune cells - act as licensing signals that enhance the secretion of immunosuppressive mediators such as prostaglandin E2 (PGE2) and IDO, thereby inhibiting T cell proliferation and modulating the adaptive immune response [ 77 ]. Furthermore, MSCs produce immunosuppressive molecules such as heme oxygenase-1 (HO-1), leukemia inhibitory factor (LIF), programmed death-ligand 1 (PD-L1), and galectins, which contribute to the inhibition of T cell differentiation and proliferation [ 78 - 82 ].

MSCs can also influence the balance between pro-inflammatory and regulatory T cell subsets. They can suppress Th17 differentiation through downregulation of RORγt while promoting the Treg phenotype through increased Foxp3 expression, thereby contributing to the regulation of the Th17/Treg balance and attenuation of inflammatory responses [ 52 ].

MSC-EVs can reduce T cell activation and enhance Treg cell activity [ 83 ]. In a study conducted by Yeganeh et al., MSC-EVs were associated with an increased frequency of CD4+CD25+FOXP3+ T cells, together with upregulation of Foxp3 mRNA expression [ 84 ].

Immunomodulatory effects of MSCs and MSC-EVs on B cells

B cells mediate humoral immunity primarily via the synthesis and secretion of antibodies; they also serve as antigen-presenting cells and regulate the function of other immune cells [ 85 ].

In a study conducted by Corcione et al., MSCs inhibited B cell proliferation through G0/G1 cell cycle arrest; additionally, IgM, IgA, and IgG production was significantly reduced in B cells co-cultured with MSCs compared with control B cells [ 86 ]. Inflammatory stimulation can enhance the inhibitory effects of MSCs on B cells, with IFN-γ playing an important role in this response [ 87 ]. MSCs can also induce the generation of CD23+CD43+ regulatory B cells (Bregs), which are capable of suppressing T cell proliferation and pro-inflammatory cytokine production, suggesting a potential therapeutic role in inflammation-related diseases [ 88 ].

MSC-EVs can suppress B cell proliferation, with a more pronounced inhibitory effect observed when EVs are derived from inflammatory-primed MSCs [ 89 ]. BMSC-Exos can modulate B cell function by regulating the expression of genes involved in B cell maturation and differentiation [ 90 ].

Immunomodulatory effects of MSCs and MSC-EVs on NK cells

NK cells are key effectors of innate immunity; they become activated upon encountering infected, allogeneic, and tumor cells [ 91 ]. MSCs can modulate the NK cell phenotype and inhibit their proliferation, cytokine secretion, and cytotoxic activity against HLA class I-expressing target cells [ 92 ]. MSCs can inhibit IL-2-induced NK cell proliferation and effector functions, including cytotoxic activity and cytokine production, with IDO and PGE2 acting as key mediators of MSC-induced NK cell suppression [ 93 ].

MSC-EVs can modulate NK cell functions in different inflammatory settings, suppressing their pro-inflammatory and cytotoxic activity [ 94 ]. The ADSC secretome restricts IL-2-mediated NK cell effector functions through the upregulation of cytokine-inducible SH2-containing protein (CIS) and dual-specificity phosphatase 4 (DUSP4), thereby supporting its therapeutic potential in inflammatory and autoimmune diseases [ 95 ].

Immunomodulatory effects of MSCs and MSC-EVs on macrophages and DCs

Macrophages are widely distributed immune cells that reside in tissues throughout the body and constitute an important component of the mononuclear phagocyte system, playing essential roles in immune defense, surveillance, and tissue homeostasis [ 96 ]. Given the narrative nature of this review, macrophages will be described according to the simplified M1/M2 classification, which is used here for heuristic purposes despite representing an oversimplification, as current evidence indicates that macrophage activation spans a continuous spectrum of functional states determined by the local microenvironment rather than discrete subsets. M1 macrophages are effector cells characterized by the secretion of pro-inflammatory cytokines, whereas M2 macrophages produce high levels of anti-inflammatory cytokines, including IL-10 and transforming growth factor-β (TGF-β), and play important roles in wound healing and tissue repair [ 97 ].

MSCs can promote the shift from pro-inflammatory M1-type macrophages toward an anti-inflammatory M2-type phenotype through IL-10-mediated mechanisms [ 98 ]. Injected BM-MSCs interact with macrophages, reprogramming them. MSCs produce PGE2 that acts on macrophages, stimulating IL-10 production, an anti-inflammatory cytokine [ 99 ]. A study conducted by Vasandan et al. showed that MSC-secreted PGE2 plays a crucial role in modulating macrophage activation, promoting a shift from the M1-type toward the M2-type phenotype [ 100 ]. These IL-10-secreting M2-type macrophages can suppress T cell proliferation and inhibit B cell differentiation [ 101 , 102 ].

MSCs can modulate macrophage function through soluble mediators, including IL-10, TGF-β, IDO, and PGE2 [ 63 ]. MSC-EVs play a crucial role in these mechanisms. CCR2-positive MSC-Exos can bind CCL2 and suppress its ability to recruit and activate macrophages [ 103 ]. Atorvastatin-pretreated BM-MSC-EVs can promote M2 macrophage polarization through the transfer of miR-139-3p, which suppresses the STAT1 pathway and contributes to cardiac repair following myocardial infarction [ 104 ].

DCs are innate immune cells and constitute one of the most effective types of antigen-presenting cells, playing a central role in coordinating various forms of immune responses [ 105 ]. MSCs can modulate DC phenotype, differentiation, and migration, while weakening their antigen presentation ability [ 106 ]. MSCs can promote the reversion of mature DCs toward an immature phenotype, characterized by downregulation of MHC-II and the costimulatory molecules CD80 and CD86, thereby reducing their capacity to stimulate T cell responses [ 107 ].

MSC-EVs play a crucial role in the regulation of DC functions in various inflammatory and immune-mediated diseases [ 108 ]. They can be internalized by DCs and promote a tolerogenic DC phenotype, while also inducing a shift toward an anti-inflammatory Treg profile, a finding with potential relevance for autoimmune diseases such as T1D [ 109 ].

Clinical implications of MSC- and MSC-EV-mediated immunomodulation in autoimmune and inflammatory diseases

Inflammation is a physiological response triggered by the body as a defense mechanism against infectious and injurious agents. Under normal conditions, this process is self-limited and resolves once the infectious or injurious stimulus has ceased [ 110 ]. However, despite its physiological role, when inflammation becomes chronic and unresolved, it can lead to tissue damage and perpetuate various pathological processes [ 111 ]. Chronic inflammation is associated with several health conditions and contributes to increased morbidity and mortality in diseases such as chronic kidney disease, cardiovascular disease, diabetes mellitus, neurodegenerative disorders, and autoimmune diseases [ 112 ].

Clinical studies of MSC-based therapies have generally shown an acceptable short-term safety profile, although most of the available evidence derives from early-phase and frequently uncontrolled studies [ 113 ]. However, the absence of serious adverse events in small or early-phase studies should not be interpreted as definitive evidence of long-term safety, and the limited follow-up and methodological heterogeneity of available trials warrant caution. Supported by their immunomodulatory and anti-inflammatory properties and by the acceptable short-term safety profile observed in early-phase trials, MSCs have been administered predominantly in clinical trials for the treatment of autoimmune diseases, particularly in patients who had exhausted other therapeutic options [ 114 ]. These therapies have been investigated across a broad spectrum of autoimmune and inflammatory conditions, including Crohn’s disease, GVHD, psoriasis, liver injury, primary Sjögren’s syndrome, T1D, MS, SLE, and RA, among others [ 57 , 115 ].

In the following sections, we will explore in depth the clinical translation of these therapies across four selected diseases - MS, T1D, SLE, and RA - whose potential therapeutic applications are illustrated below (Figure 2 ). We will analyze their pathophysiology, the therapeutic mechanisms involved, and the available clinical evidence translating the immunomodulatory properties of MSCs into clinical practice.

MS

MS is a chronic autoimmune disease that affects the central nervous system, primarily targeting myelinated axons and causing varying degrees of structural damage to both myelin and axons [ 116 ]. Multiple cellular components, including autoreactive CD4+ T cells, B cells, NK cells, macrophages, and microglia, together with soluble mediators such as IFN-γ, IL-6, and IgG1, contribute to MS pathogenesis [ 117 ]. Chronic active lesions are characterized by microglial activation, oxidative stress, mitochondrial dysfunction, and iron accumulation, which collectively contribute to progressive neuroaxonal degeneration [ 118 ]. Studies have shown that MSCs can modulate MS-associated immune responses by promoting anti-inflammatory Th2 and Treg responses while suppressing pro-inflammatory Th1 and Th17 responses and inflammatory cytokine activity [ 119 ].

In preclinical models, MSC infusion was effective in decreasing inflammation, preserving axons, promoting oligodendrogenesis, and increasing nerve conduction velocity, improving neurological functions [ 120 ]. MSC-released factors also play a crucial role in targeting MS. MSC-derived hepatocyte growth factor (HGF) promotes remyelination and modulates the inflammatory response by reducing pro-inflammatory cytokines such as IFN-γ and IL-17 [ 121 ]. Preclinical evidence has also demonstrated the neuroprotective and neuroregenerative potential of MSC-EVs, which protected neurons from apoptotic cell death and promoted remyelination through the activation of oligodendroglial precursors [ 122 ]. Exosomes have also been shown to cross the blood-brain barrier, expanding their potential therapeutic relevance in central nervous system disorders [ 123 ].

Clinical trials investigating MSC-based therapies for MS have generally reported improvements in neurological outcomes, together with an acceptable safety profile [ 124 ]. Several clinical studies have reported favorable outcomes following MSC-based therapies for MS, including fewer disease episodes, reduced annual relapse frequency, reduced Expanded Disability Status Scale (EDSS) and recurrence rates, as well as improvements in quality of life [ 125 ]. Taken together, the pooled evidence suggests that most treated patients with MS improve or remain stable after MSC-based therapy [ 119 ]. Meta-analytic evidence specifically evaluating autologous MSC transplantation in MS has reported low transplant-related mortality and encouraging rates of no evidence of disease activity, with a greater benefit observed with intrathecal administration [ 126 ]. However, efficacy has not been definitively established in controlled studies, and long-term efficacy data remain preliminary [ 127 ]. Consistent with these observations, a recent systematic review and meta-analysis of randomized controlled trials, which included five randomized trials of MSC transplantation in MS, reported that MSC therapy did not significantly improve the number of lesions, lesion volume, or EDSS scores compared with control groups, though MSC treatment did not increase the incidence of adverse events; the authors emphasized that the small number of randomized trials available warrants further confirmation or revision of these findings [ 128 ]. Connick et al. administered autologous MSCs to patients with secondary progressive MS; the study reported improvements in visual function, reduced visual evoked response latency, and increased optic nerve area, with no serious adverse events. These structural and functional findings were consistent with a potential neuroprotective effect, although the uncontrolled, proof-of-concept design precludes definitive conclusions [ 129 ]. In a randomized, sham-controlled trial enrolling patients with active progressive MS, autologous MSC administration was well tolerated and significantly reduced the proportion of patients experiencing treatment failure, while a higher proportion of treated patients exhibited no evidence of disease activity, particularly with intrathecal administration; however, these short-term findings warrant confirmation in larger phase III trials [ 130 ].

Overall, the MS evidence remains mechanistically consistent but clinically inconclusive: preclinical data suggest anti-inflammatory, neuroprotective, and remyelinating activity, and uncontrolled human data are consistent with a potential neuroprotective effect, yet randomized evidence is limited and discordant, with pooled analyses showing no significant effect on lesion burden or EDSS and no increase in the incidence of adverse events, while the available sham-controlled trial reported reduced treatment failure, particularly with intrathecal administration. Surrogate signals such as visual evoked response latency and optic nerve area remain unlinked to clinically meaningful outcomes, and adequately powered phase III trials with standardized cell source, dose, and route of administration are still required.

T1D

T1D is a heterogeneous chronic disorder characterized by the autoimmune-mediated destruction of pancreatic β-cells [ 131 ]. T1D predominantly affects children and young individuals and accounts for approximately 5-10% of all diabetes cases [ 132 ]. The pathophysiology of T1D involves both humoral and cellular immunity. Humoral autoimmunity is characterized by the development of autoantibodies against self-antigens such as insulin, glutamic acid decarboxylase, and zinc transporter 8 [ 133 ]. Regarding cellular immunity, CD8+ cytotoxic T cells are the predominant immune cells recruited to pancreatic islets, while macrophages also play a crucial role in the pathological immune response in T1D [ 134 ]. B cells also contribute to T1D pathogenesis, with their antigen-presenting capacity representing an important pathogenic mechanism [ 135 ].

In preclinical models of T1D, MSC-based therapies have shown the potential to reverse disease progression, reduce inflammation, and suppress pathological immune responses [ 136 ]. ADSC treatment reduced pancreatic inflammation by attenuating the CD4+ Th1 immune response and promoting Treg expansion, thereby contributing to the maintenance of functional β-cells [ 137 ]. Preliminary findings showed that BM-MSCs exerted immunomodulatory effects by promoting immune tolerance in T1D [ 115 ]. Additionally, MSC-Exos have shown the ability to inhibit the development of Th1 and Th17 cells, leading to the restoration of the balance between Th1- and Th2-mediated immune responses in T1D [ 138 ].

Over the years, MSC-based therapies have gained increasing attention for the treatment of T1D due to their immunomodulatory properties and the release of bioactive products, including cytokines and EVs [ 139 ]. Across different clinical trials, MSC-based therapies showed a good safety profile, with no serious adverse events reported during treatment or follow-up [ 140 ]. A study conducted by Hu et al. showed a good safety profile of UC-MSCs in patients with new-onset T1D, with significant improvements in HbA1c and C-peptide levels, reduced insulin requirements, and no episodes of ketoacidosis during follow-up [ 141 ]. In a pilot randomized controlled open-label clinical study, Wu et al. followed patients with T1D who received UC-MSCs for eight years, reporting sustained safety during follow-up and a lower incidence of chronic diabetic complications in treated patients [ 142 ]. However, given the small sample size inherent to a pilot study and the open-label design, these long-term findings should be regarded as preliminary and warrant confirmation in larger, adequately powered controlled trials. A pilot randomized controlled open-label clinical study by Cai et al. evaluated the co-transplantation of UC-MSCs with autologous bone marrow cells in patients with established T1D, reporting an acceptable safety profile and moderate improvements in measures of insulin secretion [ 143 ]. More broadly, recent critical appraisals of cell-based therapy for T1D caution that, despite years of investigation, uncertainty persists and a definitive conclusion regarding efficacy cannot yet be drawn, reinforcing the need for adequately powered randomized trials [ 144 ]. Systematic overviews of stem cell-based clinical trials in diabetes mellitus similarly point to the limited number of completed, adequately powered randomized trials and the considerable heterogeneity in study protocols, underscoring the need for standardized evaluation [ 145 ]. In line with these observations, a meta-analysis of clinical trials concluded that MSC transplantation could represent a possible therapeutic option for diabetes, although additional well-designed randomized studies are required to confirm these findings [ 146 ].

Overall, the T1D evidence suggests biological plausibility and short-term safety but not established efficacy: preclinical models have shown the potential to reverse disease progression, reduce pancreatic inflammation, and preserve β-cell function, whereas human data derive mainly from small, open-label studies reporting reductions in HbA1c and insulin requirements, increased C-peptide, and, in a single pilot trial with long-term follow-up, a lower incidence of chronic diabetic complications. Randomized controlled evidence remains limited to randomized but open-label pilot trials with modest effects on insulin secretion, and the surrogate markers used - HbA1c, C-peptide, and insulin requirements - have not been linked to definitive clinically meaningful endpoints, so adequately powered, blinded controlled trials with standardized protocols are still required.

SLE

SLE can be defined as a chronic inflammatory condition caused by an autoimmune response involving both the innate and adaptive immune systems, leading to damage in multiple organs and tissues, including the skin, kidneys, lungs, brain, blood vessels, and joints [ 147 ]. SLE is characterized by a dysregulated immune response that contributes to tissue injury through the production of inflammatory cytokines and aberrant T- and B-cell activation, with the subsequent production of autoantibodies that perpetuate damage across multiple organs [ 148 ]. A Th17/Treg imbalance is associated with the pathogenesis of SLE, contributing to an increased pro-inflammatory response [ 149 ]. Abnormal T-cell differentiation toward Th2 cells, together with their activation and associated cytokines, seems to play a vital role in the pathogenesis of SLE, ultimately contributing to B-cell hyperactivation [ 150 ].

Preclinical models of SLE have demonstrated the efficacy of MSC-based therapies in addressing lupus-associated complications such as lupus nephritis, with reductions in autoantibody levels and pro-inflammatory cytokines including IL-2, IL-12, IL-17, and IFN-γ [ 151 ]. In another study, MSCs showed recovery of Foxp3+ cells and downregulation of Th17 levels, accompanied by reductions in serum levels of anti-dsDNA antibodies and antinuclear antibodies (ANA) [ 152 ]. Preclinical results have also shown the therapeutic potential of MSC-EVs through their ability to inhibit pro-inflammatory responses and suppress autoimmune disease pathogenesis [ 153 ].

In patients with severe SLE refractory to conventional treatment, MSC-based therapies have been associated with clinical remission and improvement in organ dysfunction, together with an acceptable short-term safety profile in early-phase and frequently uncontrolled studies [ 154 ]. Clinical studies have reported lower proteinuria levels and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores in patients treated with MSC-based therapies compared with control groups [ 155 ]. Consistent with these observations, aggregate evidence restricted to randomized controlled trials, as synthesized in a recent systematic review and meta-analysis, indicates that MSC transplantation reduces disease activity and proteinuria relative to control interventions without increasing the incidence of adverse events; however, because only two randomized trials contributed to the disease-activity and renal analyses, these pooled estimates should be interpreted with caution and require confirmation in larger randomized trials [ 128 ]. In a small phase I clinical trial, allogeneic ADSCs administered to patients with refractory lupus nephritis were associated with reduced proteinuria and decreased disease activity, without serious adverse events; however, these findings should be regarded as preliminary evidence of therapeutic potential [ 156 ]. A case study by Liang et al. described the use of MSCs for diffuse alveolar hemorrhage, a rare but life-threatening complication of SLE, in a patient who did not respond to conventional pharmacological treatment; following MSC transplantation, the patient showed considerable clinical improvement, although single-case observations cannot establish therapeutic efficacy [ 157 ]. Taken together, however, clinical responses were not uniform, with some patients showing sustained improvement whereas others experienced relapse or no measurable response, and controlled studies with longer follow-up remain necessary [ 158 ].

Across the translational continuum, the SLE evidence remains dominated by preclinical and uncontrolled human observations. In preclinical models, MSC and MSC-EV administration consistently reduced autoantibody and pro-inflammatory cytokine levels, ameliorated lupus nephritis, and restored the Foxp3+/Th17 balance. In humans, early-phase uncontrolled studies reported clinical remission, improved organ function, and reductions in proteinuria and SLEDAI that must be interpreted cautiously given their uncontrolled designs. Randomized controlled evidence remains minimal, yet the pooled estimates restricted to randomized trials indicate reduced disease activity and proteinuria without an increased incidence of adverse events, although they rest on only two trials. Surrogate markers such as proteinuria, anti-dsDNA, and ANA have not been shown to translate into durable clinically meaningful benefit. The principal gaps are therefore the non-uniform clinical responses observed - with relapse or no measurable response in some patients - and the absence of adequately powered controlled trials with longer follow-up.

RA

RA is a chronic autoimmune disease affecting synovial joints, causing symptoms such as arthralgia, swelling, and limitation of movement, ultimately leading to articular cartilage destruction [ 159 ]. The interplay between the adaptive and innate immune systems plays a crucial role in RA pathogenesis. Abnormalities in the immune response lead to the production of autoantibodies, with rheumatoid factor (RF) being one of the most relevant [ 160 ]. T cells are also central players in RA pathogenesis, with an imbalance between TH1 and TH2 cells, TH17 overexpression, cytokine release by these cells, and impaired Treg function [ 161 ]. Synovial tissue in RA can be considered a tertiary lymphoid tissue, with a structure resembling secondary lymphoid tissues and containing sites for T- and B-cell differentiation. Within this tissue, abundant chemokines and pro-inflammatory factors promote inflammatory cell infiltration into the joints, contributing to pannus formation and synovial hyperplasia [ 162 ]. Fibroblast-like synoviocytes (FLSs) are specific fibroblasts located in the synovial membrane of the joints. Under the pro-inflammatory conditions present in RA, FLSs exhibit increased proliferation, reduced apoptosis, and increased expression of cytokines and chemokines, contributing to pannus formation [ 163 ].

Preclinical models of MSC-based therapies for RA have shown that MSCs can reduce the incidence and severity of the disease [ 136 ]. MSCs could immunomodulate the inflammatory response by inhibiting T-cell responses and promoting Treg cell induction, thereby contributing to decreased disease severity [ 164 ]. A study conducted by Liu et al. showed that MSCs inhibited the proliferation, invasive behavior, and inflammatory responses of FLSs, accompanied by reduced disease severity in a preclinical model of RA [ 165 ]. MSC-Exos exhibit therapeutic potential due to their ability to modulate immune responses, reduce pro-inflammatory cytokine production, and decrease synovial inflammation [ 166 ].

Clinical trials of MSC-based therapies for RA have generally shown an acceptable short-term safety profile in early-phase studies, with no serious adverse events reported [ 167 ]. However, these findings derive largely from small, heterogeneous, and frequently uncontrolled studies, and the efficacy of MSC-based therapy in RA has not been definitively established [ 168 , 169 ]. In 2010, Ra et al. started the first clinical study of MSC-based therapy for RA, reporting a favorable short-term safety profile and clinical improvements, including reductions in Visual Analog Scale (VAS) and Korean Western Ontario and McMaster Universities Osteoarthritis Index (KWOMAC) scores and discontinuation of corticosteroid therapy in two patients; as an early uncontrolled experience, however, these findings should be regarded as preliminary [ 114 ]. In a randomized, triple-blind, placebo-controlled phase 1/2 clinical trial, intra-articular administration of autologous BM-MSCs in RA patients with knee involvement showed improvements in pain and functional outcomes, including Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores and standing time, together with reductions in methotrexate and prednisolone use; however, most between-group differences did not reach statistical significance, warranting cautious interpretation [ 170 ]. Ghoryani et al. evaluated immunological, clinical, and laboratory outcomes in RA patients treated with autologous MSCs, reporting a decrease in peripheral Th17 cells and an increase in Tregs, together with reductions in DAS28-erythrocyte sedimentation rate (ESR) and VAS scores, RF levels, and overall disease severity; although these findings suggest immunomodulatory activity, they derive from a single study and require confirmation in larger controlled trials [ 171 ].

The RA evidence remains inconclusive despite the availability of a randomized, placebo-controlled trial: preclinical data show reduced disease severity, T-cell suppression, Treg induction, and inhibition of FLS proliferation and synovial inflammation, while human evidence derives largely from small, heterogeneous, often uncontrolled studies reporting reductions in DAS28-ESR, VAS, and RF with corticosteroid and methotrexate sparing. The single randomized, triple-blind, placebo-controlled trial of intra-articular BM-MSCs improved pain, WOMAC scores, and standing time, but most between-group differences were not statistically significant, and because surrogate markers such as DAS28-ESR and RF remain unlinked to durable clinically meaningful outcomes and the immunological improvements in refractory RA come from a single uncontrolled study, adequately powered controlled trials with standardized cell source, dose, and route are still required.

Current limitations, challenges, and future perspectives of MSC-based therapies

MSC-based therapies have shown therapeutic potential for autoimmune diseases, with promising results across preclinical and clinical studies (Table 1 ) aimed at translating the biological and immunomodulatory properties of MSCs into clinical applications, generally showing an acceptable short-term safety profile in early-phase and frequently uncontrolled studies. However, given the limited follow-up and methodological heterogeneity of these studies, the absence of serious adverse events should not be interpreted as definitive evidence of long-term safety. Nevertheless, although MSC-based therapies could represent a viable treatment for autoimmune diseases, their efficacy remains inconsistent across studies, potentially due to variations in MSC sources, cultivation techniques, and treatment protocols [ 125 ]. Additionally, key considerations for MSC-based therapies include MSC dosage, route of administration, treatment duration, and the immune status of the recipient, among others [ 47 ]. Furthermore, the lack of uniformity in MSC characterization represents an important limitation, highlighting the need for updated characterization guidelines and improved standardization to better account for MSC variability and enable more reliable comparisons across studies [ 172 ]. In this context, Stroncek et al. demonstrated functional and molecular differences among MSCs produced by different laboratories even when the same bone marrow starting material was used, with inter-laboratory manufacturing differences contributing more to MSC variability than the source material itself [ 173 ]. To address this limitation, the recent Delphi-driven consensus on MSC definition and clinical trial reporting aims to move beyond the 2006 minimal criteria, providing recommendations that address product heterogeneity and improve transparency and reproducibility in MSC-based clinical research [ 174 ]. Specific protocols should also be developed to optimize MSC production and survival following administration [ 175 ].

Another critical consideration concerns the immunogenicity of allogeneic MSCs. Although traditionally regarded as hypoimmunogenic or "immune privileged," MSCs are now more accurately described as "immune evasive, not immune privileged" [ 176 ]. Indeed, allogeneic MSCs remain susceptible to immune attack by the recipient, and their immunogenicity can be enhanced under pro-inflammatory conditions, potentially triggering allogeneic immune reactions that compromise long-term efficacy [ 177 ]. This is especially relevant for the chronic treatment of autoimmune diseases, in which repeated infusions are commonly required, and the heterogeneity of MSC-based products may further complicate the prediction of such immune responses, which could support the consideration of monitoring anti-HLA and donor-specific antibodies in clinical protocols [ 178 ].

Beyond the biological and manufacturing limitations discussed above, the clinical translation of MSC-based therapies has been further complicated by the commercialization of unproven stem cell-based interventions, a global problem that has proven resistant to regulatory efforts and has prompted calls for coordinated national and international responses [ 179 ]. These observations reinforce the need for strengthened regulatory vigilance and for conducting MSC-based research and therapy within the framework of controlled clinical trials.

Clinical evidence for MSC-EV- and MSC-Exo-based therapies remains limited and predominantly confined to the preclinical stage. However, several challenges remain in translating these promising preclinical findings into clinical applications, including scalable production, controlled biodistribution, release kinetics, cargo optimization, and a better understanding of their mechanisms of action [ 180 ]. Moreover, the clinical application of MSC-Exos faces additional challenges related to the lack of standardized isolation and purification protocols, batch-to-batch variability, storage conditions, and biosafety [ 181 ]. These barriers are now being addressed by dedicated consensus and regulatory initiatives, which have emphasized the need for harmonized quality and regulatory frameworks, standardized analytical approaches, and coordinated collaboration among regulatory authorities, industry, and academic investigators in order to accelerate the responsible clinical development of EV-based products [ 182 , 183 ]. In addition, in line with the MISEV2023 guidelines, rigorous functional characterization of EVs and the clear distinction between vesicle-mediated effects and those elicited by co-isolated soluble factors are required, given that attributing therapeutic activity to EVs alone demands appropriate control experiments [ 184 ].

Future research should therefore focus on overcoming these limitations and optimizing the translation of MSC- and MSC-EV-based therapies into more consistent, personalized, and clinically applicable therapeutic strategies. In this context, subsequent therapeutic approaches should also consider the potential influence of concomitant pharmacological treatments on MSC activity and clinical outcomes. Illustrating this complexity, a randomized study evaluating MSCs in combination with corticosteroids for acute GVHD was terminated early due to futility, raising the possibility that concomitant immunosuppressive treatments may influence MSC-mediated immunomodulation [ 185 ]. This experience highlights the importance of considering concomitant pharmacological treatments and other clinical parameters in these MSC-based therapeutic approaches, integrating MSCs within broader and longitudinal treatment strategies. The integration of stem cell-based therapies into personalized medicine represents an attractive perspective, aiming to tailor therapeutic strategies according to individual patient characteristics [ 186 ]. Accordingly, MSCs could be further explored not only as stand-alone therapies, but also as components of broader, multimodal, and individualized therapeutic strategies.

The progression of exosome-based therapies toward clinical translation has been encouraging, and further advances in this field could facilitate their incorporation into clinical practice [ 50 ].

Conclusions

MSCs and their secretome, particularly MSC-EVs and exosomes, represent potential therapeutic tools and promising investigational therapeutic approaches for immune-mediated disorders. Their immunomodulatory capacity-exerted through the regulation of innate and adaptive immune cell populations, modulation of pro- and anti-inflammatory cytokines, downregulation of pro-inflammatory responses, including Th1/Th17 responses, and promotion of regulatory phenotypes such as Tregs, Bregs, and M2 macrophages-provides a multifaceted biological mechanism capable of regulating inflammatory responses and promoting immune homeostasis. These properties have generated increasing interest in the potential application of MSC-based therapies for autoimmune diseases.

Preclinical and clinical evidence across MS, T1D, SLE, and RA supports the therapeutic potential of MSC- and MSC-EV-based interventions, together with an acceptable short-term safety profile in early-phase and frequently uncontrolled studies. Nevertheless, the absence of serious adverse events in these studies should not be interpreted as definitive evidence of long-term safety, and the available efficacy data should be regarded as preliminary evidence of therapeutic potential rather than established efficacy. Clinical studies have reported improvements across disease activity scores, biomarker profiles, and disease-specific functional outcomes; however, clinical translation remains constrained by manufacturing heterogeneity, variability in MSC dosage, route of administration, and treatment duration, as well as the need for standardized characterization, isolation, and production protocols.

The future of MSC-mediated immunomodulation will depend on overcoming these translational barriers while further exploring the integration of MSC-based therapies into multimodal and personalized treatment strategies. Understanding the crosstalk between MSCs and the host inflammatory microenvironment, including the potential influence of concomitant pharmacological therapies, may be critical for optimizing their therapeutic application. Integrating cell- and EV-based therapies within longitudinal and patient-tailored therapeutic frameworks positions MSC-mediated immunomodulation as a promising field for the continued development of regenerative and personalized medicine.

Disclosures

Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following:

Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.

Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.

Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Author Contributions

Concept and design: Eduardo Ciarrochi, Juan Bautista Ciarrochi

Acquisition, analysis, or interpretation of data: Eduardo Ciarrochi, Juan Bautista Ciarrochi

Critical review of the manuscript for important intellectual content: Eduardo Ciarrochi, Juan Bautista Ciarrochi

Supervision: Eduardo Ciarrochi

Drafting of the manuscript: Juan Bautista Ciarrochi

References

1. Translational potential of mesenchymal stem cells in regenerative therapies for human diseases: challenges and opportunities. Zhidu S, Ying T, Rui J, Chao Z. Stem Cell Res Ther. 2024;15:266. doi: 10.1186/s13287-024-03885-z.

2. Mesenchymal stem cell perspective: cell biology to clinical progress. Pittenger MF, Discher DE, Péault BM, Phinney DG, Hare JM, Caplan AI. NPJ Regen Med. 2019;4:22. doi: 10.1038/s41536-019-0083-6.

3. Mesenchymal stem cell immunomodulation: mechanisms and therapeutic potential. Song N, Scholtemeijer M, Shah K. Trends Pharmacol Sci. 2020;41:653–664. doi: 10.1016/j.tips.2020.06.009.

4. Immunomodulatory mechanisms of mesenchymal stem cells and their potential clinical applications. Huang Y, Wu Q, Tam PK. Int J Mol Sci. 2022;23:10023. doi: 10.3390/ijms231710023.

5. Mesenchymal stem cell-derived extracellular vesicles: novel frontiers in regenerative medicine. Keshtkar S, Azarpira N, Ghahremani MH. Stem Cell Res Ther. 2018;9:63. doi: 10.1186/s13287-018-0791-7.

6. Mechanisms of mesenchymal stem/stromal cell function. Spees JL, Lee RH, Gregory CA. Stem Cell Res Ther. 2016;7:125. doi: 10.1186/s13287-016-0363-7.

7. The secretion profile of mesenchymal stem cells and potential applications in treating human diseases. Han Y, Yang J, Fang J, et al. Signal Transduct Target Ther. 2022;7:92. doi: 10.1038/s41392-022-00932-0.

8. Human autoimmune diseases: a comprehensive update. Wang L, Wang FS, Gershwin ME. J Intern Med. 2015;278:369–395. doi: 10.1111/joim.12395.

9. Global landscape of autoimmune diseases across different lifespan: a three-decade perspective. Xiao XP, Wu MY, Li Y, Hu X, Qin BY. Medicine (Baltimore) 2026;105:0. doi: 10.1097/MD.0000000000047140.

10. Comparative United States autoimmune disease rates for 2010-2016 by sex, geographic region, and race. Roberts MH, Erdei E. Autoimmun Rev. 2020;19:102423. doi: 10.1016/j.autrev.2019.102423.

11. Estimation of prevalence of autoimmune diseases in the United States using electronic health record data. Abend AH, He I, Bahroos N, et al. J Clin Invest. 2024;135:0. doi: 10.1172/JCI178722.

12. An update on anti-inflammatory compounds: a review. Dhingra AK, Chopra B, Dass R, Mittal SK. Antiinflamm Antiallergy Agents Med Chem. 2015;14:81–97. doi: 10.2174/1871523014666150514102027.

13. Animal models of inflammation for screening of anti-inflammatory drugs: implications for the discovery and development of phytopharmaceuticals. Patil KR, Mahajan UB, Unger BS, et al. Int J Mol Sci. 2019;20:4367. doi: 10.3390/ijms20184367.

14. The use of patient-specific stem cells in different autoimmune diseases. Mohammedsaleh ZM. Saudi J Biol Sci. 2022;29:3338–3346. doi: 10.1016/j.sjbs.2022.02.009.

15. Challenges and advances in clinical applications of mesenchymal stromal cells. Zhou T, Yuan Z, Weng J, Pei D, Du X, He C, Lai P. J Hematol Oncol. 2021;14:24. doi: 10.1186/s13045-021-01037-x.

16. Mesenchymal stem cell-derived extracellular vesicles: challenges in clinical applications. Gowen A, Shahjin F, Chand S, Odegaard KE, Yelamanchili SV. Front Cell Dev Biol. 2020;8:149. doi: 10.3389/fcell.2020.00149.

17. Mesenchymal stem cells and immunomodulation: current status and future prospects. Gao F, Chiu SM, Motan DA, et al. Cell Death Dis. 2016;7:0. doi: 10.1038/cddis.2015.327.

18. Osteogenesis in transplants of bone marrow cells. Friedenstein AJ, Piatetzky-Shapiro II, Petrakova KV. https://pubmed.ncbi.nlm.nih.gov/5336210/ J Embryol Exp Morphol. 1966;16:381–390.

19. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Friedenstein AJ, Chailakhjan RK, Lalykina KS. Cell Tissue Kinet. 1970;3:393–403. doi: 10.1111/j.1365-2184.1970.tb00347.x.

20. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Lazarus HM, Haynesworth SE, Gerson SL, Rosenthal NS, Caplan AI. https://pubmed.ncbi.nlm.nih.gov/8528172/ Bone Marrow Transplant. 1995;16:557–564.

21. Mesenchymal stem cells in treating human diseases: molecular mechanisms and clinical studies. Han X, Liao R, Li X, et al. Signal Transduct Target Ther. 2025;10:262. doi: 10.1038/s41392-025-02313-9.

22. Immunoregulatory properties of clinical grade mesenchymal stromal cells: evidence, uncertainties, and clinical application. Ménard C, Tarte K. Stem Cell Res Ther. 2013;4:64. doi: 10.1186/scrt214.

23. Comparison of molecular profiles of human mesenchymal stem cells derived from bone marrow, umbilical cord blood, placenta and adipose tissue. Heo JS, Choi Y, Kim HS, Kim HO. Int J Mol Med. 2016;37:115–125. doi: 10.3892/ijmm.2015.2413.

24. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Dominici M, Le Blanc K, Mueller I, et al. Cytotherapy. 2006;8:315–317. doi: 10.1080/14653240600855905.

25. Defining minimal criteria for peer-reviewed reporting of mesenchymal stromal cell clinical trials for autoimmune diseases. Davies LC, Biard L, García-Olmo D, et al. Cytotherapy. 2025;27:1326–1337. doi: 10.1016/j.jcyt.2025.06.005.

26. International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials. Galipeau J, Krampera M, Barrett J, et al. Cytotherapy. 2016;18:151–159. doi: 10.1016/j.jcyt.2015.11.008.

27. Potency assays and biomarkers for cell-based advanced therapy medicinal products. Capelli C, Cuofano C, Pavoni C, et al. Front Immunol. 2023;14:1186224. doi: 10.3389/fimmu.2023.1186224.

28. Stem cell-based therapy for human diseases. Hoang DM, Pham PT, Bach TQ, et al. Signal Transduct Target Ther. 2022;7:272. doi: 10.1038/s41392-022-01134-4.

29. The MSC: an injury drugstore. Caplan AI, Correa D. Cell Stem Cell. 2011;9:11–15. doi: 10.1016/j.stem.2011.06.008.

30. Perinatal sources of mesenchymal stem cells: Wharton's jelly, amnion and chorion. Witkowska-Zimny M, Wrobel E. Cell Mol Biol Lett. 2011;16:493–514. doi: 10.2478/s11658-011-0019-7.

31. Adipose-derived stem cells for tissue repair and regeneration: ten years of research and a literature review. Mizuno H. J Nippon Med Sch. 2009;76:56–66. doi: 10.1272/jnms.76.56.

32. Comparative study of adipose-derived stem cells and bone marrow-derived stem cells in similar microenvironmental conditions. Guneta V, Tan NS, Chan SK, Tanavde V, Lim TC, Wong TC, Choong C. Exp Cell Res. 2016;348:155–164. doi: 10.1016/j.yexcr.2016.09.012.

33. Adipose tissue-derived stem cells in regenerative medicine. Frese L, Dijkman PE, Hoerstrup SP. Transfus Med Hemother. 2016;43:268–274. doi: 10.1159/000448180.

34. The therapeutic potential of bone marrow mesenchymal stem cells in premature ovarian failure. He Y, Chen D, Yang L, Hou Q, Ma H, Xu X. Stem Cell Res Ther. 2018;9:263. doi: 10.1186/s13287-018-1008-9.

35. The therapeutic potential of bone marrow-derived stromal cells. Mezey E. J Cell Biochem. 2011;112:2683–2687. doi: 10.1002/jcb.23216.

36. A comparison of the use of adipose-derived and bone marrow-derived stem cells for peripheral nerve regeneration in vitro and in vivo. Zhou LN, Wang JC, Zilundu PL, et al. Stem Cell Res Ther. 2020;11:153. doi: 10.1186/s13287-020-01661-3.

37. Discarded Wharton jelly of the human umbilical cord: a viable source for mesenchymal stromal cells. Watson N, Divers R, Kedar R, Mehindru A, Mehindru A, Borlongan MC, Borlongan CV. Cytotherapy. 2015;17:18–24. doi: 10.1016/j.jcyt.2014.08.009.

38. Comparative characterization of cells from the various compartments of the human umbilical cord shows that the Wharton's jelly compartment provides the best source of clinically utilizable mesenchymal stem cells. Subramanian A, Fong CY, Biswas A, Bongso A. PLoS One. 2015;10:0. doi: 10.1371/journal.pone.0127992.

39. Biological characteristics of umbilical cord mesenchymal stem cells and its therapeutic potential for hematological disorders. Shang Y, Guan H, Zhou F. Front Cell Dev Biol. 2021;9:570179. doi: 10.3389/fcell.2021.570179.

40. Allogeneic vs. autologous mesenchymal stem/stromal cells in their medication practice. Li C, Zhao H, Cheng L, Wang B. Cell Biosci. 2021;11:187. doi: 10.1186/s13578-021-00698-y.

41. Mesenchymal stem/stromal cell-based therapy: mechanism, systemic safety and biodistribution for precision clinical applications. Zhuang WZ, Lin YH, Su LJ, et al. J Biomed Sci. 2021;28:28. doi: 10.1186/s12929-021-00725-7.

42. Anti-donor immune responses elicited by allogeneic mesenchymal stem cells and their extracellular vesicles: are we still learning? Lohan P, Treacy O, Griffin MD, Ritter T, Ryan AE. Front Immunol. 2017;8:1626. doi: 10.3389/fimmu.2017.01626.

43. Alloreactive immune response associated to human mesenchymal stromal cells treatment: a systematic review. Sanabria-de la Torre R, Quiñones-Vico MI, Fernández-González A, Sánchez-Díaz M, Montero-Vílchez T, Sierra-Sánchez Á, Arias-Santiago S. J Clin Med. 2021;10:2991. doi: 10.3390/jcm10132991.

44. Concise review: MSC-derived exosomes for cell-free therapy. Phinney DG, Pittenger MF. Stem Cells. 2017;35:851–858. doi: 10.1002/stem.2575.

45. Exosomes derived from mesenchymal stem cells modulate miR-126 to ameliorate hyperglycemia-induced retinal inflammation via targeting HMGB1. Zhang W, Wang Y, Kong Y. Invest Ophthalmol Vis Sci. 2019;60:294–303. doi: 10.1167/iovs.18-25617.

46. Mesenchymal stem cell secretome for regenerative medicine: where do we stand? Trigo CM, Rodrigues JS, Camões SP, Solá S, Miranda JP. J Adv Res. 2025;70:103–124. doi: 10.1016/j.jare.2024.05.004.

47. Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases. Shi Y, Wang Y, Li Q, Liu K, Hou J, Shao C, Wang Y. Nat Rev Nephrol. 2018;14:493–507. doi: 10.1038/s41581-018-0023-5.

48. Proteomic analysis of the secretome of human bone marrow-derived mesenchymal stem cells primed by pro-inflammatory cytokines. Maffioli E, Nonnis S, Angioni R, et al. J Proteomics. 2017;166:115–126. doi: 10.1016/j.jprot.2017.07.012.

49. Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches. Welsh JA, Goberdhan DC, O'Driscoll L, et al. J Extracell Vesicles. 2024;13:0. doi: 10.1002/jev2.12404.

50. Clinical applications of stem cell-derived exosomes. Tan F, Li X, Wang Z, Li J, Shahzad K, Zheng J. Signal Transduct Target Ther. 2024;9:17. doi: 10.1038/s41392-023-01704-0.

51. The therapeutic potential of mesenchymal stem cell-derived exosomes in treatment of neurodegenerative diseases. Gorabi AM, Kiaie N, Barreto GE, Read MI, Tafti HA, Sahebkar A. Mol Neurobiol. 2019;56:8157–8167. doi: 10.1007/s12035-019-01663-0.

52. Targeted therapy for inflammatory diseases with mesenchymal stem cells and their derived exosomes: from basic to clinics. Wang S, Lei B, Zhang E, et al. Int J Nanomedicine. 2022;17:1757–1781. doi: 10.2147/IJN.S355366.

53. Mesenchymal stem cell-derived extracellular vesicles for renal repair. Nargesi AA, Lerman LO, Eirin A. Curr Gene Ther. 2017;17:29–42. doi: 10.2174/1566523217666170412110724.

54. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Li T, Yan Y, Wang B, et al. Stem Cells Dev. 2013;22:845–854. doi: 10.1089/scd.2012.0395.

55. Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Yu B, Kim HW, Gong M, et al. Int J Cardiol. 2015;182:349–360. doi: 10.1016/j.ijcard.2014.12.043.

56. Human bone marrow- and adipose-mesenchymal stem cells secrete exosomes enriched in distinctive miRNA and tRNA species. Baglio SR, Rooijers K, Koppers-Lalic D, et al. Stem Cell Res Ther. 2015;6:127. doi: 10.1186/s13287-015-0116-z.

57. Recent advances in the role of mesenchymal stem cells as modulators in autoinflammatory diseases. Chen B, Chen Z, He M, Zhang L, Yang L, Wei L. Front Immunol. 2024;15:1525380. doi: 10.3389/fimmu.2024.1525380.

58. Stem cell-derived exosomes: a comprehensive review of biomedical applications, challenges, and future directions. Zhang J, Tian X, Li Y, et al. Int J Nanomedicine. 2025;20:10857–10905. doi: 10.2147/IJN.S527137.

59. Immunomodulation by mesenchymal stem cells and clinical experience. Le Blanc K, Ringdén O. J Intern Med. 2007;262:509–525. doi: 10.1111/j.1365-2796.2007.01844.x.

60. Immunogenicity of mesenchymal stromal/stem cells. Chen W, Lv L, Chen N, Cui E. Scand J Immunol. 2023;97:0. doi: 10.1111/sji.13267.

61. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Meirelles Lda S, Fontes AM, Covas DT, Caplan AI. Cytokine Growth Factor Rev. 2009;20:419–427. doi: 10.1016/j.cytogfr.2009.10.002.

62. Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism. Djouad F, Charbonnier LM, Bouffi C, et al. Stem Cells. 2007;25:2025–2032. doi: 10.1634/stemcells.2006-0548.

63. The role of secreted factors in stem cells-mediated immune regulation. Lin L, Du L. Cell Immunol. 2018;326:24–32. doi: 10.1016/j.cellimm.2017.07.010.

64. The cross-talk between mesenchymal stem cells and immune cells in tissue repair and regeneration. Harrell CR, Djonov V, Volarevic V. Int J Mol Sci. 2021;22:2472. doi: 10.3390/ijms22052472.

65. The interplay between mesenchymal stem cells and the immune microenvironment in rotator cuff tendon-to-bone healing: current progress and future directions. Li D, Zou Y, Zhao Y. Front Immunol. 2025;16:1661340. doi: 10.3389/fimmu.2025.1661340.

66. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Wang Y, Chen X, Cao W, Shi Y. Nat Immunol. 2014;15:1009–1016. doi: 10.1038/ni.3002.

67. Mesenchymal stem cells: a double-edged sword in regulating immune responses. Li W, Ren G, Huang Y, et al. Cell Death Differ. 2012;19:1505–1513. doi: 10.1038/cdd.2012.26.

68. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Ren G, Zhang L, Zhao X, et al. Cell Stem Cell. 2008;2:141–150. doi: 10.1016/j.stem.2007.11.014.

69. The systemic cellular immune response against allogeneic mesenchymal stem cells is influenced by inflammation, differentiation and MHC compatibility: in vivo study in the horse. Cequier A, Vázquez FJ, Vitoria A, et al. Front Vet Sci. 2024;11:1391872. doi: 10.3389/fvets.2024.1391872.

70. Reciprocal regulation of mesenchymal stem cells and immune responses. Wang Y, Fang J, Liu B, Shao C, Shi Y. Cell Stem Cell. 2022;29:1515–1530. doi: 10.1016/j.stem.2022.10.001.

71. Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice. Sudres M, Norol F, Trenado A, et al. J Immunol. 2006;176:7761–7767. doi: 10.4049/jimmunol.176.12.7761.

72. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Zappia E, Casazza S, Pedemonte E, et al. Blood. 2005;106:1755–1761. doi: 10.1182/blood-2005-04-1496.

73. The role of MSCs and CAR-MSCs in cellular immunotherapy. Yan L, Li J, Zhang C. Cell Commun Signal. 2023;21:187. doi: 10.1186/s12964-023-01191-4.

74. T cells in health and disease. Sun L, Su Y, Jiao A, Wang X, Zhang B. Signal Transduct Target Ther. 2023;8:235. doi: 10.1038/s41392-023-01471-y.

75. Immunobiology of mesenchymal stem cells. Ma S, Xie N, Li W, Yuan B, Shi Y, Wang Y. Cell Death Differ. 2014;21:216–225. doi: 10.1038/cdd.2013.158.

76. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells. Selmani Z, Naji A, Zidi I, et al. Stem Cells. 2008;26:212–222. doi: 10.1634/stemcells.2007-0554.

77. Immunomodulatory properties of mesenchymal stem cells: cytokines and factors. Soleymaninejadian E, Pramanik K, Samadian E. Am J Reprod Immunol. 2012;67:1–8. doi: 10.1111/j.1600-0897.2011.01069.x.

78. Cytokines differently define the immunomodulation of mesenchymal stem cells from the periodontal ligament. Behm C, Blufstein A, Gahn J, Nemec M, Moritz A, Rausch-Fan X, Andrukhov O. Cells. 2020;9:1222. doi: 10.3390/cells9051222.

79. A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells. Chabannes D, Hill M, Merieau E, et al. Blood. 2007;110:3691–3694. doi: 10.1182/blood-2007-02-075481.

80. Leukemia inhibitory factor inhibits T helper 17 cell differentiation and confers treatment effects of neural progenitor cell therapy in autoimmune disease. Cao W, Yang Y, Wang Z, et al. Immunity. 2011;35:273–284. doi: 10.1016/j.immuni.2011.06.011.

81. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Augello A, Tasso R, Negrini SM, Amateis A, Indiveri F, Cancedda R, Pennesi G. Eur J Immunol. 2005;35:1482–1490. doi: 10.1002/eji.200425405.

82. Evidence for the involvement of galectin-3 in mesenchymal stem cell suppression of allogeneic T-cell proliferation. Sioud M, Mobergslien A, Boudabous A, Fløisand Y. Scand J Immunol. 2010;71:267–274. doi: 10.1111/j.1365-3083.2010.02378.x.

83. Adipose derived mesenchymal stem cell exosomes loaded with miR-10a promote the differentiation of Th17 and Treg from naive CD4(+) T cell. Bolandi Z, Mokhberian N, Eftekhary M, Sharifi K, Soudi S, Ghanbarian H, Hashemi SM. Life Sci. 2020;259:118218. doi: 10.1016/j.lfs.2020.118218.

84. In vitro treatment of murine splenocytes with extracellular vesicles derived from mesenchymal stem cells altered the mRNA levels of the master regulator genes of T helper cell subsets. Yeganeh A, Fathollahi A, Hashemi SM, Yeganeh F. Mol Biol Rep. 2023;50:3309–3316. doi: 10.1007/s11033-023-08247-1.

85. Importance of B cells (Review) Liu Z, Dai H, Cui X, Liu Y, Dong Z. Int J Mol Med. 2026;57:2. doi: 10.3892/ijmm.2025.5673.

86. Human mesenchymal stem cells modulate B-cell functions. Corcione A, Benvenuto F, Ferretti E, et al. Blood. 2006;107:367–372. doi: 10.1182/blood-2005-07-2657.

87. Interferon-γ-dependent inhibition of B cell activation by bone marrow-derived mesenchymal stem cells in a murine model of systemic lupus erythematosus. Schena F, Gambini C, Gregorio A, et al. Arthritis Rheum. 2010;62:2776–2786. doi: 10.1002/art.27560.

88. Human mesenchymal stem cell-treated regulatory CD23+CD43+ B cells alleviate intestinal inflammation. Chen X, Cai C, Xu D, et al. Theranostics. 2019;9:4633–4647. doi: 10.7150/thno.32260.

89. Differential and transferable modulatory effects of mesenchymal stromal cell-derived extracellular vesicles on T, B and NK cell functions. Di Trapani M, Bassi G, Midolo M, et al. Sci Rep. 2016;6:24120. doi: 10.1038/srep24120.

90. Mesenchymal stromal cell-derived exosomes affect mRNA expression and function of B-lymphocytes. Khare D, Or R, Resnick I, Barkatz C, Almogi-Hazan O, Avni B. Front Immunol. 2018;9:3053. doi: 10.3389/fimmu.2018.03053.

91. Natural killer cell memory in infection, inflammation and cancer. Cerwenka A, Lanier LL. Nat Rev Immunol. 2016;16:112–123. doi: 10.1038/nri.2015.9.

92. Interactions between human mesenchymal stem cells and natural killer cells. Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M. Stem Cells. 2006;24:74–85. doi: 10.1634/stemcells.2004-0359.

93. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, Moretta L. Blood. 2008;111:1327–1333. doi: 10.1182/blood-2007-02-074997.

94. Molecular mechanisms responsible for therapeutic potential of mesenchymal stem cell-derived secretome. Harrell CR, Fellabaum C, Jovicic N, Djonov V, Arsenijevic N, Volarevic V. Cells. 2019;8:467. doi: 10.3390/cells8050467.

95. ADSC secretome constrains NK cell activity by attenuating IL-2-mediated JAK-STAT and AKT signaling pathway via upregulation of CIS and DUSP4. Ko E, Yoon T, Lee Y, Kim J, Park YB. Stem Cell Res Ther. 2023;14:329. doi: 10.1186/s13287-023-03516-z.

96. Tissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets. Guan F, Wang R, Yi Z, et al. Signal Transduct Target Ther. 2025;10:93. doi: 10.1038/s41392-025-02124-y.

97. M1/M2 macrophages and their overlaps - myth or reality? Strizova Z, Benesova I, Bartolini R, Novysedlak R, Cecrdlova E, Foley LK, Striz I. Clin Sci (Lond) 2023;137:1067–1093. doi: 10.1042/CS20220531.

98. The importance of HLA assessment in "off-the-shelf" allogeneic mesenchymal stem cells based-therapies. Kot M, Baj-Krzyworzeka M, Szatanek R, Musiał-Wysocka A, Suda-Szczurek M, Majka M. Int J Mol Sci. 2019;20:5680. doi: 10.3390/ijms20225680.

99. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Németh K, Leelahavanichkul A, Yuen PS, et al. Nat Med. 2009;15:42–49. doi: 10.1038/nm.1905.

100. Human Mesenchymal stem cells program macrophage plasticity by altering their metabolic status via a PGE(2)-dependent mechanism. Vasandan AB, Jahnavi S, Shashank C, Prasad P, Kumar A, Prasanna SJ. Sci Rep. 2016;6:38308. doi: 10.1038/srep38308.

101. Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation. François M, Romieu-Mourez R, Li M, Galipeau J. Mol Ther. 2012;20:187–195. doi: 10.1038/mt.2011.189.

102. Mesenchymal stem cell-derived interleukin 1 receptor antagonist promotes macrophage polarization and inhibits B cell differentiation. Luz-Crawford P, Djouad F, Toupet K, et al. Stem Cells. 2016;34:483–492. doi: 10.1002/stem.2254.

103. CCR2 positive exosome released by mesenchymal stem cells suppresses macrophage functions and alleviates ischemia/reperfusion-induced renal injury. Shen B, Liu J, Zhang F, et al. Stem Cells Int. 2016;2016:1240301. doi: 10.1155/2016/1240301.

104. Atorvastatin-pretreated mesenchymal stem cell-derived extracellular vesicles promote cardiac repair after myocardial infarction via shifting macrophage polarization by targeting microRNA-139-3p/Stat1 pathway. Ning Y, Huang P, Chen G, et al. BMC Med. 2023;21:96. doi: 10.1186/s12916-023-02778-x.

105. Development and function of dendritic cell subsets. Mildner A, Jung S. Immunity. 2014;40:642–656. doi: 10.1016/j.immuni.2014.04.016.

106. Mesenchymal stromal cell-like cells set the balance of stimulatory and inhibitory signals in monocyte-derived dendritic cells. Bacskai I, Mázló A, Kis-Tóth K, et al. Stem Cells Dev. 2015;24:1805–1816. doi: 10.1089/scd.2014.0509.

107. Human umbilical cord blood-derived stromal cells suppress xenogeneic immune cell response in vitro. Hao L, Zhang C, Chen XH, et al. Croat Med J. 2009;50:351–360. doi: 10.3325/cmj.2009.50.351.

108. Emerging role and mechanism of mesenchymal stem cells-derived extracellular vesicles in rheumatic disease. Wang Z, Yang C, Yan S, et al. J Inflamm Res. 2024;17:6827–6846. doi: 10.2147/JIR.S488201.

109. Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients. Favaro E, Carpanetto A, Caorsi C, et al. Diabetologia. 2016;59:325–333. doi: 10.1007/s00125-015-3808-0.

110. Editorial: Regulation of inflammation in chronic disease. Zhong J, Shi G. Front Immunol. 2019;10:737. doi: 10.3389/fimmu.2019.00737.

111. Resolution of inflammation: what controls its onset? Sugimoto MA, Sousa LP, Pinho V, Perretti M, Teixeira MM. Front Immunol. 2016;7:160. doi: 10.3389/fimmu.2016.00160.

112. Editorial: Inflammation and chronic disease. Orlando FA, Mainous AG 3rd. Front Med (Lausanne) 2024;11:1434533. doi: 10.3389/fmed.2024.1434533.

113. Safety of intravenous mesenchymal stem cell therapy: a meta-analysis of randomized controlled trials. Habiba UE, Greene DL, Ahmad K, et al. Regener Med Rep. 2025;2:83–99.

114. Stem cell treatment for patients with autoimmune disease by systemic infusion of culture-expanded autologous adipose tissue derived mesenchymal stem cells. Ra JC, Kang SK, Shin IS, et al. J Transl Med. 2011;9:181. doi: 10.1186/1479-5876-9-181.

115. Mesenchymal stem cell-based immunomodulation: properties and clinical application. Wang M, Yuan Q, Xie L. Stem Cells Int. 2018;2018:3057624. doi: 10.1155/2018/3057624.

116. Review of multiple sclerosis: epidemiology, etiology, pathophysiology, and treatment. Haki M, Al-Biati HA, Al-Tameemi ZS, Ali IS, Al-Hussaniy HA. Medicine (Baltimore) 2024;103:0. doi: 10.1097/MD.0000000000037297.

117. A comprehensive review on neuroimmunology: insights from multiple sclerosis to future therapeutic developments. Eva L, Pleș H, Covache-Busuioc RA, et al. Biomedicines. 2023;11:2489. doi: 10.3390/biomedicines11092489.

118. Neurodegeneration in multiple sclerosis and neuromyelitis optica. Kawachi I, Lassmann H. J Neurol Neurosurg Psychiatry. 2017;88:137–145. doi: 10.1136/jnnp-2016-313300.

119. Mesenchymal stem cell therapy in multiple sclerosis: a systematic review and meta-analysis. Islam MA, Alam SS, Kundu S, Ahmed S, Sultana S, Patar A, Hossan T. J Clin Med. 2023;12:6311. doi: 10.3390/jcm12196311.

120. Amelioration of experimental autoimmune encephalomyelitis through transplantation of placental derived mesenchymal stem cells. Jiang H, Zhang Y, Tian K, Wang B, Han S. Sci Rep. 2017;7:41837. doi: 10.1038/srep41837.

121. Hepatocyte growth factor mediates mesenchymal stem cell-induced recovery in multiple sclerosis models. Bai L, Lennon DP, Caplan AI, et al. Nat Neurosci. 2012;15:862–870. doi: 10.1038/nn.3109.

122. Murine adipose-derived mesenchymal stromal cell vesicles: in vitro clues for neuroprotective and neuroregenerative approaches. Farinazzo A, Turano E, Marconi S, Bistaffa E, Bazzoli E, Bonetti B. Cytotherapy. 2015;17:571–578. doi: 10.1016/j.jcyt.2015.01.005.

123. Insights into exosome transport through the blood-brain barrier and the potential therapeutical applications in brain diseases. Abdelsalam M, Ahmed M, Osaid Z, Hamoudi R, Harati R. Pharmaceuticals (Basel) 2023;16:571. doi: 10.3390/ph16040571.

124. Immunomodulatory role of mesenchymal stem cell therapy in multiple sclerosis: a systematic review. Amin MN, Hashish R, Agha Tabari K, Swami SS, Kasagga A, Assefa AK, Yu AK. Cureus. 2025;17:0. doi: 10.7759/cureus.86988.

125. Efficacy and safety of mesenchymal stem cell transplantation in the treatment of autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, and ankylosing spondylitis): a systematic review and meta-analysis of randomized controlled trial. Zeng L, Yu G, Yang K, Xiang W, Li J, Chen H. Stem Cells Int. 2022;2022:9463314. doi: 10.1155/2022/9463314.

126. Autologous mesenchymal stem cell transplantation in multiple sclerosis: a meta-analysis. Zhou Y, Zhang X, Xue H, Liu L, Zhu J, Jin T. Stem Cells Int. 2019;2019:8536785. doi: 10.1155/2019/8536785.

127. Efficacy and safety of stem cell transplantation for multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials. Nawar AA, Farid AM, Wally R, et al. Sci Rep. 2024;14:12545. doi: 10.1038/s41598-024-62726-4.

128. Efficacy and safety of mesenchymal stromal cell transplantation in the treatment of autoimmune and rheumatic immune diseases: a systematic review and meta-analysis of randomized controlled trials. Zeng L, Liu C, Wu Y, et al. Stem Cell Res Ther. 2025;16:65. doi: 10.1186/s13287-025-04184-x.

129. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Connick P, Kolappan M, Crawley C, et al. Lancet Neurol. 2012;11:150–156. doi: 10.1016/S1474-4422(11)70305-2.

130. Beneficial effects of autologous mesenchymal stem cell transplantation in active progressive multiple sclerosis. Petrou P, Kassis I, Levin N, et al. Brain. 2020;143:3574–3588. doi: 10.1093/brain/awaa333.

131. Epidemiology of type 1 diabetes. Maahs DM, West NA, Lawrence JM, Mayer-Davis EJ. Endocrinol Metab Clin North Am. 2010;39:481–497. doi: 10.1016/j.ecl.2010.05.011.

132. Prevalence and incidence of type 1 diabetes in the world: a systematic review and meta-analysis. Mobasseri M, Shirmohammadi M, Amiri T, Vahed N, Hosseini Fard H, Ghojazadeh M. Health Promot Perspect. 2020;10:98–115. doi: 10.34172/hpp.2020.18.

133. The pathophysiology, presentation and classification of type 1 diabetes. Aamodt KI, Powers AC. Diabetes Obes Metab. 2025;27:15–27. doi: 10.1111/dom.16628.

134. Analysis of islet inflammation in human type 1 diabetes. Willcox A, Richardson SJ, Bone AJ, Foulis AK, Morgan NG. Clin Exp Immunol. 2009;155:173–181. doi: 10.1111/j.1365-2249.2008.03860.x.

135. The multifaceted role of B lymphocytes in type 1 diabetes. Khalefa SA, Ben Nasr M, Usuelli V, Yerra P, Lunati ME, Fiorina P. Semin Immunol. 2026;82:102034. doi: 10.1016/j.smim.2026.102034.

136. Mesenchymal stem cells in the treatment of inflammatory and autoimmune diseases in experimental animal models. Klinker MW, Wei CH. World J Stem Cells. 2015;7:556–567. doi: 10.4252/wjsc.v7.i3.556.

137. Immune regulatory properties of allogeneic adipose-derived mesenchymal stem cells in the treatment of experimental autoimmune diabetes. Bassi ÊJ, Moraes-Vieira PM, Moreira-Sá CS, et al. Diabetes. 2012;61:2534–2545. doi: 10.2337/db11-0844.

138. Exosomes derived from mesenchymal stem cells in diabetes and diabetic complications. Jiao YR, Chen KX, Tang X, Tang YL, Yang HL, Yin YL, Li CJ. Cell Death Dis. 2024;15:271. doi: 10.1038/s41419-024-06659-w.

139. The role of mesenchymal stem cells in the treatment of type 1 diabetes. Jayasinghe M, Prathiraja O, Perera PB, et al. Cureus. 2022;14:0. doi: 10.7759/cureus.27337.

140. Mesenchymal stem cell-based therapy for type 1 & 2 diabetes mellitus patients: a systematic review and meta-analysis of randomized controlled trials. Kashbour M, Abdelmalik A, Yassin MN, et al. Diabetol Metab Syndr. 2025;17:189. doi: 10.1186/s13098-025-01619-6.

141. Long term effects of the implantation of Wharton's jelly-derived mesenchymal stem cells from the umbilical cord for newly-onset type 1 diabetes mellitus. Hu J, Yu X, Wang Z, et al. Endocr J. 2013;60:347–357. doi: 10.1507/endocrj.ej12-0343.

142. Prevention of chronic diabetic complications in type 1 diabetes by co-transplantation of umbilical cord mesenchymal stromal cells and autologous bone marrow: a pilot randomized controlled open-label clinical study with 8-year follow-up. Wu Z, Xu X, Cai J, et al. Cytotherapy. 2022;24:421–427. doi: 10.1016/j.jcyt.2021.09.015.

143. Umbilical cord mesenchymal stromal cell with autologous bone marrow cell transplantation in established type 1 diabetes: a pilot randomized controlled open-label clinical study to assess safety and impact on insulin secretion. Cai J, Wu Z, Xu X, et al. Diabetes Care. 2016;39:149–157. doi: 10.2337/dc15-0171.

144. Current status of stem cell therapy for type 1 diabetes: a critique and a prospective consideration. Ghoneim MA, Gabr MM, El-Halawani SM, Refaie AF. Stem Cell Res Ther. 2024;15:23. doi: 10.1186/s13287-024-03636-0.

145. Stem cell-based clinical trials for diabetes mellitus. de Klerk E, Hebrok M. Front Endocrinol (Lausanne) 2021;12:631463. doi: 10.3389/fendo.2021.631463.

146. Meta-analysis shows that mesenchymal stem cell therapy can be a possible treatment for diabetes. Habiba UE, Khan N, Greene DL, Ahmad K, Shamim S, Umer A. Front Endocrinol (Lausanne) 2024;15:1380443. doi: 10.3389/fendo.2024.1380443.

147. Systemic lupus erythematosus: updated insights on the pathogenesis, diagnosis, prevention and therapeutics. Dai X, Fan Y, Zhao X. Signal Transduct Target Ther. 2025;10:102. doi: 10.1038/s41392-025-02168-0.

148. The pathogenesis of systemic lupus erythematosus-an update. Choi J, Kim ST, Craft J. Curr Opin Immunol. 2012;24:651–657. doi: 10.1016/j.coi.2012.10.004.

149. Altered Th17/Treg ratio in peripheral blood of systemic lupus erythematosus but not primary antiphospholipid syndrome. Álvarez-Rodríguez L, Martínez-Taboada V, Calvo-Alén J, Beares I, Villa I, López-Hoyos M. Front Immunol. 2019;10:391. doi: 10.3389/fimmu.2019.00391.

150. Updated insight into the role of Th2-associated immunity in systemic lupus erythematosus. Wang H, Li C, Ren G, et al. Autoimmun Rev. 2023;22:103213. doi: 10.1016/j.autrev.2022.103213.

151. Efficacy of mesenchymal stem cells in animal models of lupus nephritis: a meta-analysis. Zhou T, Liao C, Li HY, Lin W, Lin S, Zhong H. Stem Cell Res Ther. 2020;11:48. doi: 10.1186/s13287-019-1538-9.

152. Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans. Sun L, Akiyama K, Zhang H, et al. Stem Cells. 2009;27:1421–1432. doi: 10.1002/stem.68.

153. Therapeutic development of mesenchymal stem cells or their extracellular vesicles to inhibit autoimmune-mediated inflammatory processes in systemic lupus erythematosus. Sharma J, Hampton JM, Valiente GR, et al. Front Immunol. 2017;8:526. doi: 10.3389/fimmu.2017.00526.

154. Allogeneic mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus: 4 years of experience. Wang D, Zhang H, Liang J, et al. Cell Transplant. 2013;22:2267–2277. doi: 10.3727/096368911X582769c.

155. Clinical efficacy and safety of mesenchymal stem cells for systemic lupus erythematosus. Zhou T, Li HY, Liao C, Lin W, Lin S. Stem Cells Int. 2020;2020:6518508. doi: 10.1155/2020/6518508.

156. Allogeneic adipose-derived mesenchymal stromal cell transplantation for refractory lupus nephritis: Results of a phase I clinical trial. Ranjbar A, Hassanzadeh H, Jahandoust F, et al. Curr Res Transl Med. 2022;70:103324. doi: 10.1016/j.retram.2021.103324.

157. Mesenchymal stem cell transplantation for diffuse alveolar hemorrhage in SLE. Liang J, Gu F, Wang H, et al. Nat Rev Rheumatol. 2010;6:486–489. doi: 10.1038/nrrheum.2010.80.

158. Umbilical cord mesenchymal stem cell transplantation in active and refractory systemic lupus erythematosus: a multicenter clinical study. Wang D, Li J, Zhang Y, et al. Arthritis Res Ther. 2014;16:0. doi: 10.1186/ar4520.

159. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J. Bone Res. 2018;6:15. doi: 10.1038/s41413-018-0016-9.

160. The etiology of rheumatoid arthritis. Scherer HU, Häupl T, Burmester GR. J Autoimmun. 2020;110:102400. doi: 10.1016/j.jaut.2019.102400.

161. T cell dysregulation in rheumatoid arthritis: from genetic susceptibility to established disease. Chin A, Small A, Wong SW, Wechalekar MD. Curr Rheumatol Rep. 2025;27:14. doi: 10.1007/s11926-025-01180-1.

162. B cells in rheumatoid arthritis: pathogenic mechanisms and treatment prospects. Wu F, Gao J, Kang J, Wang X, Niu Q, Liu J, Zhang L. Front Immunol. 2021;12:750753. doi: 10.3389/fimmu.2021.750753.

163. Transformation of fibroblast-like synoviocytes in rheumatoid arthritis; from a friend to foe. Mousavi MJ, Karami J, Aslani S, et al. Auto Immun Highlights. 2021;12:3. doi: 10.1186/s13317-020-00145-x.

164. Adoptive transfer of human gingiva-derived mesenchymal stem cells ameliorates collagen-induced arthritis via suppression of Th1 and Th17 cells and enhancement of regulatory T cell differentiation. Chen M, Su W, Lin X, et al. Arthritis Rheum. 2013;65:1181–1193. doi: 10.1002/art.37894.

165. Therapeutic potential of human umbilical cord mesenchymal stem cells in the treatment of rheumatoid arthritis. Liu Y, Mu R, Wang S, et al. Arthritis Res Ther. 2010;12:0. doi: 10.1186/ar3187.

166. Mesenchymal stem cell therapy in osteoarthritis and rheumatoid arthritis: a systematic review of exosomal microRNAs. Hejazian SS, Hejazian SM, Mostafavi Montazeri SS, Abediazar S, Zununi Vahed S, Barzegari A. Biologics. 2025;19:747–785. doi: 10.2147/BTT.S571417.

167. Mesenchymal stem cell-based therapy for rheumatoid arthritis. Sarsenova M, Issabekova A, Abisheva S, Rutskaya-Moroshan K, Ogay V, Saparov A. Int J Mol Sci. 2021;22:11592. doi: 10.3390/ijms222111592.

168. Safety and efficacy of mesenchymal stem cells therapy in the treatment of rheumatoid arthritis disease: a systematic review and meta-analysis of clinical trials. Mesa LE, López JG, López Quiceno L, Barrios Arroyave F, Halpert K, Camacho JC. PLoS One. 2023;18:0. doi: 10.1371/journal.pone.0284828.

169. A comprehensive review on the role of mesenchymal stromal/stem cells in the management of rheumatoid arthritis. Pignatti E, Maccaferri M, Pisciotta A, Carnevale G, Salvarani C. Expert Rev Clin Immunol. 2024;20:463–484. doi: 10.1080/1744666X.2023.2299729.

170. Intra-articular knee implantation of autologous bone marrow-derived mesenchymal stromal cells in rheumatoid arthritis patients with knee involvement: Results of a randomized, triple-blind, placebo-controlled phase 1/2 clinical trial. Shadmanfar S, Labibzadeh N, Emadedin M, et al. Cytotherapy. 2018;20:499–506. doi: 10.1016/j.jcyt.2017.12.009.

171. Amelioration of clinical symptoms of patients with refractory rheumatoid arthritis following treatment with autologous bone marrow-derived mesenchymal stem cells: a successful clinical trial in Iran. Ghoryani M, Shariati-Sarabi Z, Tavakkol-Afshari J, Ghasemi A, Poursamimi J, Mohammadi M. Biomed Pharmacother. 2019;109:1834–1840. doi: 10.1016/j.biopha.2018.11.056.

172. Therapeutic use of mesenchymal stromal cells: the need for inclusive characterization guidelines to accommodate all tissue sources and species. Wright A, Arthaud-Day ML, Weiss ML. Front Cell Dev Biol. 2021;9:632717. doi: 10.3389/fcell.2021.632717.

173. Human mesenchymal stromal cell (MSC) characteristics vary among laboratories when manufactured from the same source material: a report by the Cellular Therapy Team of the Biomedical Excellence for Safer Transfusion (BEST) Collaborative. Stroncek DF, Jin P, McKenna DH, et al. Front Cell Dev Biol. 2020;8:458. doi: 10.3389/fcell.2020.00458.

174. Delphi-driven consensus definition for mesenchymal stromal cells and clinical reporting guidelines for mesenchymal stromal cell-based therapeutics. Renesme L, Cobey KD, Lalu MM, et al. Cytotherapy. 2025;27:146–168. doi: 10.1016/j.jcyt.2024.10.008.

175. Introduction to stem cell therapy. Biehl JK, Russell B. J Cardiovasc Nurs. 2009;24:98–103. doi: 10.1097/JCN.0b013e318197a6a5.

176. Mesenchymal stem cells: immune evasive, not immune privileged. Ankrum JA, Ong JF, Karp JM. Nat Biotechnol. 2014;32:252–260. doi: 10.1038/nbt.2816.

177. Unveiling the immunogenicity of allogeneic mesenchymal stromal cells: challenges and strategies for enhanced therapeutic efficacy. Li Y, Jin M, Guo D, et al. Biomed Pharmacother. 2024;180:117537. doi: 10.1016/j.biopha.2024.117537.

178. The issue of heterogeneity of MSC-based advanced therapy medicinal products-a review. Česnik AB, Švajger U. Front Cell Dev Biol. 2024;12:1400347. doi: 10.3389/fcell.2024.1400347.

179. Marketing of unproven stem cell-based interventions: a call to action. Sipp D, Caulfield T, Kaye J, et al. Sci Transl Med. 2017;9:0. doi: 10.1126/scitranslmed.aag0426.

180. Therapeutic potential of mesenchymal stem cell-derived exosomes for regenerative medicine applications. Roszkowski S. Clin Exp Med. 2024;24:46. doi: 10.1007/s10238-023-01282-z.

181. Applications, challenges and prospects of mesenchymal stem cell exosomes in regenerative medicine. Rezabakhsh A, Sokullu E, Rahbarghazi R. Stem Cell Res Ther. 2021;12:521. doi: 10.1186/s13287-021-02596-z.

182. From lab to industry: advancing the translational potential of extracellular vesicles through the ISEV Translation, Regulation and Advocacy Committee (ISEV-TRA) Gurriaran-Rodriguez U, Bussolati B, Gimona M, et al. J Extracell Vesicles. 2026;15:0. doi: 10.1002/jev2.70220.

183. Navigating the global regulatory landscape for exosome-based therapeutics: challenges, strategies, and future directions. Verma N, Arora S. Pharmaceutics. 2025;17:990. doi: 10.3390/pharmaceutics17080990.

184. MISEV2023: shaping the future of EV research by enhancing rigour, reproducibility and transparency. Samuels M, Giamas G. Cancer Gene Ther. 2024;31:649–651. doi: 10.1038/s41417-024-00759-7.

185. Early cessation of a randomised study in acute graft versus host disease: upfront mesenchymal stromal cells with corticosteroids versus corticosteroids alone. Purtill D, Cirillo M, Fogarty J, et al. Bone Marrow Transplant. 2020;55:2199–2201. doi: 10.1038/s41409-020-0955-9.

186. Revolutionizing medicine: recent developments and future prospects in stem-cell therapy. Hussen BM, Taheri M, Yashooa RK, Abdullah GH, Abdullah SR, Kheder RK, Mustafa SA. Int J Surg. 2024;110:8002–8024. doi: 10.1097/JS9.0000000000002109.