Molecular mechanisms responsible for mesenchymal stem cell–dependent improvement of islet cell transplantation

Abstract

Islet cell transplantation holds great promise for restoring glycemic control in patients with type 1 diabetes. However, its long-term efficacy remains limited due to poor islet survival, immune rejection, and insufficient vascularization. Mesenchymal stem cells (MSCs) have emerged as potent biological adjuvants capable of addressing these challenges through a range of molecular mechanisms. MSCs secrete a variety of growth factors, immunoregulatory and pro-angiogenic molecules that enhance viability of islet cells, modulate the immune response, promote neo-angiogenesis and enhance islet engraftment. In addition, MSC-derived exosomes (MSC-Exos) have been identified as key mediators, delivering regulatory microRNAs and proteins that replicate many of the beneficial effects of MSCs in a cell-free format. MSC-Exos act as small RNA carriers and immunomodulators, promoting islet survival and functional integration. Understanding the molecular interplay between MSCs, their exosomes, and the islet microenvironment provides crucial insights for the development of advanced co-transplantation strategies. Accordingly, in this review article, we summarized current knowledge about molecular mechanisms that are responsible for MSC-dependent improvement of islet cell transplantation and we highlighted the translational potential of MSC and MSC-Exos-based approaches in improving islet graft outcomes for type 1 diabetes.

Introduction

Islet cell transplantation represents a promising therapeutic approach for the treatment of insulin-dependent diabetes mellitus, an autoimmune disease which results from the targeted destruction of insulin-producing β-cells within the pancreatic islets, leading to chronic hyperglycemia and long-term microvascular and macrovascular complications ¹ . The transplantation of isolated islets offers the potential to restore endogenous insulin production and maintain physiological glucose homeostasis ¹ . In patients with type 1 diabetes, clinical islet transplantation has been shown to enhance glycemic control, increase endogenous C-peptide production, and reduce dependence on exogenous insulin therapy. Beyond these metabolic improvements, islet transplantation also contributes to the stabilization of hemostatic parameters and the normalization of cerebral metabolic profiles, which are frequently disrupted in chronic diabetes. These systemic benefits are associated with preservation of brain structure and improved neurocognitive function, indicating that successful engraftment of functional islets can ameliorate both peripheral and central complications of type 1 diabetes, even in the context of ongoing immunosuppressive treatment ² . However, it has to be emphasized that the clinical success of islet transplantation remains limited by several biological and technical challenges that affect both the short-term engraftment and long-term function of the transplanted islets ³ . At the molecular level, the viability and function of transplanted islets are heavily influenced by their ability to re-establish a functional vasculature in the recipient tissue ³ . Native pancreatic islets are densely vascularized structures, receiving disproportionately high blood flow relative to their size. During the isolation process, islets are removed from their native vasculature, resulting in ischemic stress. Upon transplantation, rapid revascularization is crucial for delivering oxygen and nutrients, removing metabolic waste, and maintaining β-cell viability ⁴ . Molecular pathways such as vascular endothelial growth factor (VEGF) signaling, particularly through the VEGFR-2 receptor, play a central role in promoting angiogenesis around the graft ⁴ . The hypoxia-inducible factor 1 alpha (HIF-1α) pathway becomes up-regulated in response to hypoxia, further stimulating VEGF expression. However, prolonged or unresolved hypoxia can initiate apoptotic signaling cascades through mitochondrial dysfunction and increased expression of pro-apoptotic proteins like Bax, leading to caspase activation and β-cell death ⁴ .

Beyond ischemia and hypoxia-driven injury, the early phase of islet transplantation is characterized by a robust sterile inflammatory response that critically influences subsequent immune recognition and graft fate ³ . Tissue damage incurred during islet isolation, culture, and transplantation leads to the release of damage-associated molecular patterns (DAMPs), with high mobility group box 1 (HMGB1) identified as a central inflammatory alarmin in this context^3,4. HMGB1 is abundantly expressed in pancreatic islet cells and is rapidly translocated from the nucleus to the cytoplasm and released into the extracellular space following islet injury and hypoxia/reoxygenation stress, where it functions as a DAMP that potently activates innate immune signaling via Toll-like receptors (TLRs) and the receptor for advanced glycation end products (RAGE) on antigen-presenting cells ⁵ . This activation upregulates costimulatory molecules and increases production of proinflammatory cytokine, amplifying local inflammation and contributing to early graft failure and inflammatory loss of islet cells^2,4.

Accordingly, another important molecular barrier to successful islet engraftment is the host immune response ⁶ . Following transplantation, the allogeneic islets are recognized by the host immune system through both direct and indirect antigen presentation ⁶ . Donor antigen-presenting cells can directly stimulate recipient T lymphocytes, while host antigen-presenting cells process and present donor-derived peptides via major histocompatibility complex (MHC) class II molecules, initiating adaptive immune responses ⁶ . Cytotoxic CD8⁺ T cells contribute to graft destruction through perforin/granzyme pathways and Fas-Fas ligand-mediated apoptosis. In addition, pro-inflammatory cytokines such as interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ), released by activated immune cells, trigger intracellular stress responses in β-cells through the activation of nuclear factor kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) pathways ⁶ . These pathways up-regulate inducible nitric oxide synthase (iNOS) and other mediators of inflammation, further exacerbating cellular injury and apoptosis. In addition to adaptive immune mechanisms, the innate immune response contributes to early islet loss through a process known as the instant blood-mediated inflammatory reaction (IBMIR)^3,6. This phenomenon occurs immediately after the infusion of islets into the portal vein and is characterized by the rapid activation of coagulation and complement cascades^3,6. Tissue factor expressed on the surface of isolated islets triggers the extrinsic coagulation pathway, leading to thrombin generation, fibrin clot formation, and platelet activation. Concurrently, the complement system is activated, producing anaphylatoxins such as C3a and C5a that recruit neutrophils and monocytes to the site of transplantation^3,6. These innate immune cells release reactive oxygen species (ROS) and pro-inflammatory cytokines, resulting in oxidative stress and direct cytotoxicity to the islet graft. It has been estimated that up to 60% of transplanted islets may be lost within the first 24 h due to IBMIR-related damage^3,6. Oxidative stress is a central mediator of islet cell death during the peri-transplant period ⁷ . Pancreatic β-cells are inherently vulnerable to oxidative damage due to their relatively low expression of endogenous antioxidant enzymes, including superoxide dismutase, catalase, and glutathione peroxidase ⁷ . The ischemia-reperfusion injury encountered during the transplantation process leads to the generation of ROS that impair mitochondrial function, damage cellular membranes and DNA, and activate intrinsic apoptotic pathways ⁷ . Mitochondrial permeability transition and cytochrome c release into the cytosol initiate caspase-dependent cell death cascades, ultimately compromising islet survival and insulin-secretory function ⁷ .

Beyond the biological challenges, several logistical and technical limitations hinder the clinical application of islet transplantation^1,3. A critical issue is the limited availability of high-quality donor pancreases, compounded by variability in donor characteristics, ischemic times, and the efficiency of the isolation procedure. Moreover, multiple donors are often required to provide a sufficient islet mass for a single recipient, which increases the immunogenic complexity of the graft^1,3. The liver, accessed via intraportal infusion, remains the primary site for clinical islet implantation due to its convenience and vascularity ⁸ . However, the hepatic microenvironment presents several drawbacks, including susceptibility to IBMIR, exposure to high concentrations of immunosuppressive drugs, and a relatively hypoxic milieu ⁸ . These factors can impair revascularization, increase oxidative stress, and compromise the survival and function of the transplanted islets ⁸ . Alternative implantation sites, such as the omentum, subcutaneous space, or skeletal muscle, are under investigation but require significant optimization to support islet engraftment and immune protection ¹ .

Immunosuppressive therapy, while essential for preventing rejection, poses additional complications for islet survival ¹ . A variety of immunosuppressive and tolerance-inducing approaches have been tested, ranging from co-stimulatory blockade (such as CTLA4-Ig and anti-CD154-based therapies) to fusion protein strategies targeting interleukin pathways, which significantly prolonged islet graft survival and managed to induce long-term donor-specific tolerance ⁹ . In addition, agents such as tacrolimus and sirolimus exert direct cytotoxic effects on β-cells, impairing insulin secretion, mitochondrial metabolism, and β-cell proliferation. They also inhibit angiogenesis and contribute to oxidative stress^1,3. Accordingly, the development of targeted immunomodulatory strategies that preserve β-cell function without inducing systemic toxicity remains a major research priority ¹ .

Mesenchymal stem cells or mesenchymal stromal cells (MSCs) are multipotent, self-renewable cells that exert profound immunomodulatory and trophic effects ¹⁰ . A growing body of evidence demonstrates that a large number of cellular preparations currently used in MSC-related experimental and clinical studies do not fulfill the rigorous functional criteria required to define true stem cells, particularly with respect to sustained self-renewal and reliable multilineage differentiation in vivo^11–13. Instead, these cells mediate their therapeutic effects predominantly through paracrine signaling, secretion of bioactive factors, and dynamic interactions with immune and tissue-resident cells that collectively regulate inflammation, promote endogenous repair, and maintain tissue homeostasis ¹² . In this context, the term “mesenchymal stromal cells” more accurately reflects their biological identity, encompassing their heterogeneous composition, context-dependent multipotency, and primary role as supportive and regulatory elements within tissue microenvironments rather than direct contributors to tissue replacement ¹¹ . As recently discussed by Caplan, continued use of the term “stem cell” has fostered conceptual ambiguity, inflated expectations regarding regenerative capacity, and impeded regulatory clarity, whereas adoption of the nomenclature “mesenchymal stromal cells” better aligns terminology with experimentally validated mechanisms of action and facilitates more precise scientific communication and clinical translation by emphasizing their function as medicinal signaling cells ¹² . MSCs are capable of suppressing both innate and adaptive immune responses through the secretion of soluble factors and direct cell-cell interactions ¹⁰ . They produce anti-inflammatory cytokines such as transforming growth factor-beta (TGF-β) and IL-10, and immunosuppressive molecules like indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2). These mediators inhibit T cell proliferation, reduce dendritic cell (DC) maturation, and promote the expansion of immunosuppressive regulatory T cells (Tregs), thereby fostering an immune-tolerant environment that protects the islet graft from rejection ¹⁰ . In addition to these effects, MSCs can locally modulate the immune milieu at the site of transplantation, reducing the recruitment and activation of effector immune cells and limiting inflammatory damage to the graft ¹⁴ . By creating a localized immunosuppressive niche, MSCs have the potential to decrease the dependence on systemic immunosuppressive drugs, which are associated with long-term toxicity and increased risk of infection or malignancy ¹⁰ . Furthermore, the immunomodulatory effects of MSCs are context-dependent and adapt dynamically to the local inflammatory milieu, enabling precise suppression of immune activation at the site of the graft ¹⁴ . This targeted regulation may permit reductions in systemic immunosuppressive dosing or the implementation of intermittent regimens, thereby limiting exposure to the deleterious side effects commonly associated with chronic immunosuppression^10,14. Such localized and adaptable immune control not only promotes graft survival and functional maintenance but also supports the development of transplantation protocols that are safer, more individualized, and optimized for patient-specific immune profiles^10,14. By integrating immunoprotection, modulation of inflammatory responses, and paracrine-mediated tissue support, MSC therapy represents a compelling approach to either replace or substantially reduce conventional systemic immunosuppression in the context of islet transplantation ¹⁴ . In addition to their immunomodulatory roles, MSCs promote angiogenesis by secreting pro-angiogenic factors such as VEGF, angiopoietin-1, and hepatocyte growth factor ¹⁵ . These molecules stimulate endothelial cell migration, proliferation, and tube formation, facilitating the rapid revascularization of the transplanted grafts, improving its oxygenation and nutrient supply. The presence of MSCs in the graft microenvironment has been associated with increased vascular density and enhanced long-term graft function in various preclinical models ¹⁵ . MSC also possess potent cytoprotective effects by mitigating oxidative stress and apoptosis ¹⁰ . They secrete a range of antioxidant enzymes and survival factors, including thioredoxin, insulin-like growth factor 1, and stromal cell-derived factor 1 (SDF-1) ¹⁰ . These molecules enhance the expression of anti-apoptotic proteins such as Bcl-2, inhibit caspase activation, and preserve mitochondrial integrity. Moreover, recent evidence suggests that MSCs can transfer functional mitochondria to damaged β-cells via tunneling nanotubes, restoring bioenergetic capacity and improving insulin secretion under stress conditions ¹⁰ .

Results obtained in a large number of experimental studies have consistently demonstrated that MSC-based therapy can delay or even prevent the onset of autoimmune diabetes, highlighting the broad immunomodulatory potential of these cells beyond their role in supporting islet transplantation^16–18. In nonobese diabetic (NOD) mice, administration of MSCs derived from resistant mouse strains prior to the clinical onset of disease significantly delayed the progression to overt hyperglycemia, reduced insulitis, and promoted a shift in immune responses toward regulatory phenotypes^16–18. By contrast, MSCs obtained from diabetic donors were less effective, emphasizing the critical importance of MSC source, functional integrity, and immunoregulatory capacity in mediating disease-modifying effects ¹⁶ . Mechanistically, in these preclinical models, MSCs home to key immune-regulatory sites, including pancreatic lymph nodes and the spleen, where they inhibit proliferation of autoreactive T cells, enhance the frequency and suppressive function of regulatory T cell populations, and limit activation of pathogenic effector T cells^16–18. In addition, MSCs reduce infiltration of pro-inflammatory immune cells, including CD8⁺ cytotoxic T cells and inflammatory macrophages, into the pancreatic islets, thereby attenuating β-cell destruction and preserving endogenous insulin production ¹⁸ . Beyond direct cellular interactions, MSCs also secrete soluble factors such as TGF-β, IL-10, PGE2, and IDO, which further suppress autoimmunity, modulate DC maturation, and maintain a tolerogenic microenvironment within the pancreatic tissue^16–18.

Beyond their immunomodulatory, angiogenic, and cytoprotective effects, MSCs contribute directly to pancreatic islet regeneration through multiple molecular mechanisms that influence β-cell survival, proliferation, and functional maturation. MSCs secrete a complex repertoire of growth factors, cytokines, and extracellular vesicles (EVs) enriched in microRNAs, which collectively activate pro-survival and proliferative signaling pathways in islet cells^19,20. Key soluble factors such as hepatocyte growth factor (HGF), insulin-like growth factor 1 (IGF-1), and fibroblast growth factor 2 (FGF-2) engage receptor tyrosine kinases on β-cells, stimulating the PI3K/Akt and MAPK/ERK pathways, thereby enhancing cell cycle progression, promoting DNA repair, and upregulating anti-apoptotic proteins including Bcl-2 and Bcl-xL^20,21. MSC-derived EVs deliver microRNAs such as miR-21, miR-146a, and miR-126, which modulate β-cell gene expression by suppressing pro-apoptotic mediators, attenuating oxidative stress, and enhancing insulin transcription and secretion ²⁰ . In addition, MSCs secrete SDF-1, which interacts with CXCR4 on progenitor and resident islet cells to promote chemotaxis, neogenesis, and local recruitment of endothelial and immune-supportive cells, creating a regenerative niche ²⁰ . MSCs also modulate key signaling pathways involved in β-cell dedifferentiation and functional maintenance, including Wnt/β-catenin, Notch, and TGF-β/Smad axes, thereby preserving β-cell identity and responsiveness to glucose stimuli ²⁰ . Furthermore, MSCs facilitate extracellular matrix remodeling by secreting matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), optimizing the islet microenvironment for survival and proliferation^19,20. Collectively, these mechanisms allow MSCs to not only protect existing β-cells from apoptosis and immune-mediated destruction but also stimulate regeneration and functional enhancement, creating a multi-layered support system that significantly improves islet engraftment and long-term function^19–21.

In line with these findings, the integration of MSCs into islet transplantation protocols was explored as novel multifaceted strategy which could address the key barriers limiting survival and function of transplanted islet cells (Table 1) ¹⁹ . Results obtained in several experimental studies demonstrated that, due to their immunoregulatory, angiomodulatory and cytoprotective properties, MSCs could be considered as potentially new therapeutic agents which may significantly improve the long-term outcomes of islet cell transplantation in clinical settings^20–22. MSCs have been shown to markedly enhance pancreatic islet viability, insulin secretory capacity, and vascularization when co-cultured with islets prior to transplantation, primarily through paracrine signaling, extracellular matrix remodeling, and direct cell–cell interactions^16–18. A substantial body of experimental evidence from diverse preclinical models demonstrates that MSC–islet co-transplantation significantly improves graft survival and long-term functional engraftment by promoting neovascularization, suppressing apoptosis, and modulating both innate and adaptive immune responses^16–18. MSCs derived from diverse tissue sources display low immunogenicity and exert their therapeutic effects largely through paracrine mechanisms, including the secretion of cytokines, growth factors, and extracellular vesicles that suppress innate and adaptive immune responses, attenuate inflammatory injury, and promote local immune tolerance ¹⁰ . These properties contribute to enhanced islet survival, preservation of insulin-secreting function, and improved revascularization following transplantation^16–18. In addition, MSC-mediated support facilitates tissue repair and microenvironmental remodeling at the graft site, thereby mitigating hypoxia and oxidative stress that commonly compromise early graft function ²³ . Notably, these beneficial effects include attenuation of early inflammatory events such as IBMIR and have been consistently observed across different transplantation sites and co-culture strategies, underscoring the robustness and translational potential of this therapeutic approach ²⁴ . Despite these advantages, significant challenges remain, including heterogeneity among MSC populations, variability in cell sources and manufacturing protocols, and incomplete understanding of optimal dosing and delivery strategies ²⁴ . Accordingly, in this review paper, we summarized current knowledge regarding MSC-based improvement of islet cell transplantation, emphasizing the underlying molecular mechanisms through which MSCs modulate detrimental immune response, facilitate the rapid vascularization and improve survival of the transplanted islet cells. We also critically examined how differences in MSC origin, preparation, and administration influence their capacity to modulate detrimental immune responses, accelerate graft revascularization, and enhance the survival and functional stability of transplanted islet cells. An extensive literature review was carried out in September 2025 across several databases (MEDLINE, EMBASE, and Google Scholar), from 1990 to the present. Key-words used in the selection were: “mesenchymal stem/stromal cells,” “islet cell transplantation,” “diabetes mellitus,” “immunomodulation,” “immunosuppression,” “neoangiogenesis,” “revascularization“, and “cell-based therapy.” All journals were considered and an initial search retrieved 67 articles. The abstracts of all these articles were subsequently reviewed by two of the authors (VV and CRH) independently to check their relevance to the subject of this manuscript. Articles were included if they provided original data or comprehensive analyses on MSC immunomodulatory, angiogenic, cytoprotective, or regenerative effects in the context of islet transplantation, and their findings are analyzed in this review. Studies focusing solely on unrelated topics or lacking mechanistic insights were excluded. To further enhance transparency and accessibility, we have summarized all final selected articles in a comprehensive table that includes the main methods, key results, and reference for each study (Table 2).

Table 1.

Key challenges in islet cell transplantation and therapeutic benefits of MSCs.

Issue in islet cell transplantation	Underlying mechanisms/molecular pathways	Consequences for islet graft	MSC-mediated benefits	MSC mechanisms of action	Ref. no.
Ischemia and delayed revascularization	Loss of native vasculature during isolation; hypoxia; impaired VEGF–VEGFR-2 signaling; HIF-1α activation	Early graft dysfunction; β-cell hypoxia; apoptosis	Enhanced and accelerated revascularization	Secretion of VEGF, angiopoietin-1, HGF; stimulation of endothelial migration and tube formation; improved oxygen and nutrient delivery	D’Addio et al. 2 Verhoeff et al. 3 Fujita et al. 8 Meier et al. 9 Dominici et al. 11
Hypoxia-induced apoptosis	Prolonged HIF-1α activation; mitochondrial dysfunction; Bax up-regulation; caspase activation	β-cell death; reduced insulin secretion	Cytoprotection and improved cell survival	Up-regulation of anti-apoptotic proteins (Bcl-2); inhibition of caspases; preservation of mitochondrial integrity	Verhoeff et al. 3 Itoh et al. 5 Eguchi et al. 7 Meier et al. 9 Dominici et al. 11
Adaptive immune-mediated rejection	Allogeneic antigen presentation; CD8+ T-cell cytotoxicity; Fas/FasL and perforin/granzyme pathways	Progressive immune destruction of graft	Immunomodulation and immune tolerance	Secretion of TGF-β, IL-10, IDO, PGE2; suppression of T-cell proliferation; induction of Tregs	Bruni et al. 4 Eguchi et al. 7 Meier et al. 9 Harrell et al. 10
Pro-inflammatory cytokine toxicity	IL-1β, TNF-α, IFN-γ release; activation of NF-κB and JNK pathways; iNOS induction	Inflammatory stress; nitric oxide–mediated β-cell injury	Reduction of inflammatory signaling	Inhibition of DC maturation; cytokine profile shift toward anti-inflammatory milieu	Bruni et al. 4 Itoh et al. 5 Eguchi et al. 7 Meier et al. 9 Caplan 12
Instant blood-mediated inflammatory reaction (IBMIR)	Tissue factor expression; activation of coagulation and complement cascades; C3a/C5a generation	Up to ~60% early islet loss; oxidative and inflammatory damage	Attenuation of innate immune activation	Suppression of complement and leukocyte activation; reduced neutrophil and monocyte recruitment	D’Addio et al. 2 Bruni et al. 4 Kabakchieva et al. 6 Meier et al. 9 Dominici et al. 11
Oxidative stress and ischemia–reperfusion injury	Excess ROS production; low antioxidant defenses in β-cells; mitochondrial permeability transition	DNA, membrane, and mitochondrial damage; apoptosis	Antioxidant and anti-oxidative protection	Secretion of thioredoxin and other antioxidant enzymes; ROS scavenging; mitochondrial protection	Itoh et al. 5 Eguchi et al. 7 Harrell et al. 10 Caplan 12
Mitochondrial dysfunction	Cytochrome c release; impaired ATP production	Reduced insulin secretion and β-cell viability	Restoration of β-cell bioenergetics	Transfer of functional mitochondria via tunneling nanotubes; improved cellular metabolism	Czarnecka et al. 1 D’Addio et al. 2 Meier et al. 9 Dominici et al. 11
Toxicity of immunosuppressive drugs	Tacrolimus/sirolimus-induced β-cell dysfunction; inhibition of angiogenesis	Impaired graft survival and function	Reduced need for high-dose systemic immunosuppression	Local immune regulation by MSCs; preservation of β-cell function and angiogenic capacity	D’Addio et al. 2 Kabakchieva et al. 6 Meier et al. 9 Dominici et al. 11
Limited donor islet availability and graft efficiency	Need for multiple donors; variable islet quality	Increased immunogenicity; reduced clinical scalability	Improved functional efficiency of transplanted islets	Enhanced survival and function may reduce required islet mass per recipient	Czarnecka et al. 1 , D’Addio et al. 2 , Meier et al. 9 , Caplan 12

Abbreviations: MSC (mesenchymal stem cell), VEGF (vascular endothelial growth factor), VEGFR-2 (vascular endothelial growth factor receptor-2), HIF-1α (hypoxia-inducible factor-1 alpha), Bax (Bcl-2–associated X protein), Bcl-2 (B-cell lymphoma 2), CD8⁺ T cells (cluster of differentiation 8–positive cytotoxic T lymphocytes), Fas/FasL (Fas receptor/Fas ligand), IL-1β (interleukin-1 beta), TNF-α (tumor necrosis factor alpha), IFN-γ (interferon gamma), NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), JNK (c-Jun N-terminal kinase), iNOS (inducible nitric oxide synthase), TGF-β (transforming growth factor beta), IL-10 (interleukin-10), IDO (indoleamine 2,3-dioxygenase), PGE2 (prostaglandin E2), Tregs (regulatory T cells), DCs (dendritic cells), IBMIR (instant blood-mediated inflammatory reaction), C3a (complement component 3a), C5a (complement component 5a), ROS (reactive oxygen species), HGF (hepatocyte growth factor), ATP (adenosine triphosphate).

Table 2.

Summary of selected studies investigating the effects of MSCs and MSC-derived exosomes on islet transplantation.

Study category	Experimental model/study type	Tissue source of MSC/MSC-Exos	Key methods	Main findings relevant to islet transplantation	Ref.no
Islet transplantation—clinical background	Clinical studies, reviews	Not applicable	Analysis of clinical outcomes, metabolic and immunological parameters	Established the current status, challenges, and outcomes of allogeneic islet transplantation in T1D patients	Czarnecka et al. 1 D’Addio et al. 2 Verhoeff et al. 3 Bruni et al. 4
Islet injury and oxidative stress	Animal models, human samples	Not applicable	Measurement of HMGB1 release, oxidative stress markers, endothelial damage	Islet damage and oxidative stress strongly correlate with graft dysfunction and poor transplantation outcomes	Itoh et al. 5 Eguchi et al. 7
Immunological challenges in islet transplantation	Reviews, experimental studies	Not applicable	Immune profiling, alloimmune and autoimmune response analysis	Identified immune-mediated rejection and inflammation as key barriers to long-term graft survival	Kabakchieva et al. 6
Alternative transplantation sites and platforms	Animal models	Not applicable	Islet sheets, subcutaneous and liver-surface transplantation	Demonstrated improved engraftment and survival using alternative implantation sites and biomaterial platforms	Fujita et al. 8 Nakamura et al. 25 Yamashita et al. 26
Experimental optimization of islet transplantation	Animal models, best-practice guidelines	Not applicable	Standardized transplantation protocols and outcome measures	Provided methodological guidance to improve reproducibility and translational relevance	Meier et al. 9
MSC definition and nomenclature	Consensus statements, reviews	MSC identity	Phenotypic and functional criteria definition	Standardized MSC terminology and minimal defining criteria for research and clinical use	Dominici et al. 11 Caplan 12 Viswanathan et al. 13
MSC immunomodulatory mechanisms	In vitro and in vivo studies	Bone marrow, adipose, umbilical cord	Co-culture systems, immune cell assays	MSCs modulate innate and adaptive immune responses through cytokines and cell–cell interactions	Harrell etal. 10 Xv et al. 16 Carlsson et al. 18 Shrestha et al. 22
MSCs in diabetes and islet transplantation	Animal models, reviews	BM-MSCs, AD-MSCs, UC-MSCs	MSC–islet co-transplantation, metabolic assessment	MSCs improve glycemic control, reduce inflammation, and enhance islet graft survival	Barachini et al. 20 Mikłosz and Chabowski 21 Shrestha et al. 22 Mou et al. 23 Mei et al. 24
MSC–islet co-transplantation strategies	Animal models	Autologous and allogeneic MSCs	Co-transplantation, encapsulation, engineered constructs	Co-transplantation promotes revascularization, immune tolerance, and graft function	Koehler et al. 27 Unsal et al. 28 Ito et al. 29 Ben Nasr et al. 30 Duprez et al. 31
Angiogenic and vascular effects of MSCs	In vivo studies	MSCs (various sources)	Angiogenesis assays, endothelial interaction studies	MSCs enhance graft revascularization and endothelial protection	Mohamad Yusoff and Higashi 15 Ito et al. 29 Campa-Carranza et al. 32
MSC secretome and paracrine signaling	In vitro and in vivo studies	MSC-derived soluble factors	Conditioned media, proteomic analysis	MSC secretome supports islet viability and function independently of cell engraftment	Cooper et al. 33 Sionov and Ahdut-HaCohen 34
MSC-derived exosomes in islet transplantation	In vitro and animal models	MSC-derived exosomes	Exosome isolation, miRNA analysis, functional assays	Exosomes protect β-cells, reduce apoptosis, and improve islet survival and function	Chen et al. 35 Harrell et al. 36 Mattke et al. 37 Minhua et al. 38 Wen et al. 39
Donor-related variability of MSCs	In vitro studies, reviews	Age- and tissue-dependent MSCs	Secretome profiling, functional assays	MSC phenotype and therapeutic potency vary with donor age and tissue source	Turlo et al. 40 Galipeau and Sensébé 41 Zhou et al. 42
Translational and clinical considerations	Reviews, meta-analyses	MSC-based therapies	Safety, efficacy, and regulatory evaluation	Highlighted clinical challenges, ethical considerations, and safety issues of MSC therapies	de Klerk and Hebrok 19 Baldari et al. 43 Yu et al. 44 Volarevic et al. 45

Abbreviations: AD-MSCs (Adipose-Derived Mesenchymal Stromal Cells), BM-MSCs (Bone Marrow–Derived Mesenchymal Stromal Cells), MSC (Mesenchymal Stromal Cell), MSCs (Mesenchymal Stromal Cells), MSC-Exos (Mesenchymal Stromal cell–Derived Exosomes), T1D (Type 1 Diabetes), UC-MSCs (Umbilical Cord–Derived Mesenchymal Stromal Cells), and HMGB1 (High-Mobility Group Box 1 protein).

Therapeutic synergy of islet and MSC co-transplantation in experimental models of type 1 diabetes

Co-culture paradigms between MSCs and pancreatic islets have demonstrated that the mode of interaction critically determines islet viability and functional outcomes ²⁷ . Direct cell–cell contact enhances insulin secretory function more effectively than indirect contact, likely through adhesion-mediated signaling such as N-cadherin interactions, which preserve islet morphology and sustain glucose-stimulated insulin secretion during prolonged culture ²⁷ . Indirect co-culture systems, in which MSCs and islets are separated by semi-permeable membranes, still confer improvements in islet survival and function via paracrine mechanisms, although the full complement of functional benefits is observed primarily in direct contact systems. These observations indicate that MSCs support islet function through both contact-dependent and contact-independent pathways, highlighting the importance of cellular interactions in optimizing islet performance ²⁷ . Building on this mechanistic understanding, a growing body of evidence suggests that MSCs can enhance the efficacy of islet transplantation by supporting islet viability, promoting graft revascularization, and improving glycemic outcomes^20–22. To explore these synergistic effects, several preclinical studies have investigated the co-transplantation of MSCs with pancreatic islets in experimental models of type 1 diabetes^20,28,29.

By using a streptozotocin (STZ)-induced type 1 diabetes mellitus rat model, Unsal and colleagues demonstrated that simultaneous transplantation of pancreatic MSCs and islet cells markedly improved therapeutic efficacy compared with islet transplantation alone ²⁸ . The study included four experimental groups: (1) diabetic control (no transplant), (2) MSC-only transplant, (3) islet-only transplant, and (4) combined islet and MSC transplant. All animals were confirmed hyperglycemic after STZ induction and received transplants accordingly. After 30 days post-transplantation, blood glucose levels were significantly reduced in the islet-only and islet + MSC groups compared with controls. Notably, MSC + islet-treated mice exhibited superior glycemic control compared with islet-only treated diabetic animals, indicating that the co-transplantation of MSCs enhanced islet function and islet survival. In contrast, the MSC-only group showed no improvement in glucose regulation, reinforcing the necessity of islet cells for metabolic correction and suggesting MSCs act as supportive, rather than substitutive agents in the restoration of insulin production ²⁸ . Histological analysis provided further evidence supporting the functional data. Sections of pancreatic tissue from the islet + MSC group showed the highest mean number of residual islet cells, significantly exceeding that observed in the islet-only group. The control and MSC-only groups exhibited either complete absence or severe depletion of islet structures. These findings suggest that MSCs may have contributed to either better engraftment, reduced apoptosis, improved revascularization, or even stimulation of endogenous islet regeneration ²⁸ .

Similar findings were reported by Ben Nasr and colleagues who investigated the ability of bone-marrow-derived MSCs to improve survival of allogeneic islet grafts in a fully mismatched murine transplant model ³⁰ . Autologous, but not heterologous MSCs, strongly suppressed alloantigen-driven immune cell proliferation and skewed cytokine profiles toward a Th2 phenotype, characterized by increased IL-4 production, suggesting a shift away from pro-inflammatory responses. This immunomodulatory effect was dose-dependent and accompanied by MSC expression of regulatory mediators such as SDF-1α and TGF-β, which are known to contribute to immune regulation and nurturing of graft environments ³⁰ . Co-transplantation of islets with a single local dose of autologous MSCs under the kidney capsule significantly delayed allogeneic islet rejection compared with untreated controls and systemic MSC administration. Notably, approximately 30 % of mice receiving MSCs locally exhibited long-term graft function. In contrast, systemic infusion of autologous MSCs or local infusion of heterologous MSCs failed to confer this benefit, indicating that the protective effects of MSCs depended on both cell origin and route of delivery ³⁰ . Histological evaluation demonstrated that locally co-transplanted MSCs preserved islet architecture and insulin expression while reducing dense infiltration of CD4⁺ and CD8⁺ T cells within the graft, suggesting that MSCs created a localized niche favorable for graft survival. Further characterization of the immune response in treated recipients revealed that local MSC delivery was associated with reduced alloantigen-specific proliferation and a relative increase in IL-4-producing cells, alongside lower frequencies of IL-17 and IFN-γ-producing effector Th17 and Th1 cells ³⁰ . In addition, local MSC administration was associated with an expansion of IL-10–secreting immunosuppressive Tregs in the spleen, in the absence of detectable systemic immunosuppression, indicating that the immunoregulatory activity of MSCs was largely confined to the graft microenvironment. These findings support the concept that locally administered autologous MSCs can establish an immunoprivileged site at the transplant location, limiting detrimental immune attack while avoiding broader systemic immune suppression ³⁰ .

These findings are further supported by study conducted by Ito and colleagues demonstrating that co-transplantation of MSCs with pancreatic islets enhanced graft revascularization and preserved islet function, thereby improving the overall outcomes of islet transplantation ²⁹ . The authors conducted a series of experiments using both syngeneic Lewis rats and immunodeficient NOD-SCID mice to examine the effects of co-transplanted MSCs on glycemic control, graft survival, and vascularization ²⁹ . STZ-induced diabetic Lewis rats received 500 or 300 syngeneic islets, either alone or co-transplanted with 1 × 10⁷ BM-MSCs into the portal vein. At the 500-islet dose, all animals (8 of 8) receiving islets + MSCs achieved normoglycemia, whereas only 3 of 10 rats transplanted with islets alone became normoglycemic. Similarly, with a lower dose of 300 islets, co-transplantation with MSCs resulted in diabetes reversal in 5 of 9 rats, compared with only 1 of 10 in the islet-alone group. This demonstrated that MSCs significantly improved the functional efficiency of the islet grafts, allowing for therapeutic efficacy with a reduced islet mass. Intravenous glucose tolerance testing at day 56 post-transplantation further confirmed improved glucose handling in the co-transplant group compared with controls ²⁹ . To evaluate the underlying mechanisms, particularly graft vascularization, the researchers utilized a subrenal capsule model in NOD-SCID mice. Islets, with or without MSCs, were transplanted under the kidney capsule and analyzed histologically after 7 days ²⁹ . Immunostaining revealed that islet grafts co-transplanted with MSCs had a significantly higher density of capillary segments per β-cell than islets transplanted alone, suggesting enhanced revascularization. In the rat liver transplants, islets co-transplanted with MSCs maintained better structural integrity and displayed more prominent vascular features, whereas islet-alone grafts showed greater fragmentation and poorer integration into host tissue. To explore whether MSCs directly contributed to vascularization, Ito and colleagues tracked MSC localization and expression of angiogenic markers. Labeled MSCs were found in close proximity to the islet grafts, and some expressed VEGF. A subset of MSCs also co-expressed von Willebrand factor (vWF), an endothelial cell marker, indicating either endothelial differentiation or close interaction with host vasculature ²⁹ . These findings suggested that MSCs supported graft vascularization through both paracrine secretion of VEGF and potential integration into forming capillaries. In this study, Ito and colleagues demonstrated that MSC co-transplantation significantly improved glycemic outcomes, enhanced islet viability, and accelerated graft vascularization ²⁹ . These effects were particularly relevant during the critical post-transplantation window when islets were vulnerable to hypoxia and immune attack. Despite these promising outcomes, the study raised questions for future investigation. These include determining the optimal MSC-to-islet ratio, evaluating the long-term persistence and safety of MSCs within the graft, and assessing the feasibility of intraportal co-transplantation in larger animal models or clinical settings. Although the renal capsule model was useful for vascular analysis, clinical translation would require adaptation to the intraportal route commonly used in human islet transplantation ²⁹ .

Composite MSC-islet constructs and bioengineered delivery systems as innovative platforms for islet cell transplantation

Results obtained in several recently published studies demonstrated that combining islets with MSC and utilizing advanced delivery platforms, such as recombinant peptide (RCP) scaffolds and engineered cell sheets, may significantly enhance islet graft survival, vascularization, and function in transplantation models, offering promising strategies for improving clinical outcomes in diabetes treatment^25,26,31,32.

Campa-Carranza and colleagues designed a novel Neovascularized Implantable Cell Homing and Encapsulation (NICHE) platform in order to improve MSC-dependent support of allogeneic islet transplantation ³² . Structurally, the NICHE was composed of two main compartments housed within a porous, biocompatible scaffold ³² . The outer compartment served as a vascularization chamber, designed to support and guide the ingrowth of host vasculature. This compartment was filled with a collagen-based hydrogel in combination with MSCs. The central, inner compartment functioned as a cell reservoir, intended to house pancreatic islets. This region was accessible to immune and endothelial cells due to the device’s engineered porosity but retained structural separation from the surrounding tissue to protect transplanted cells from mechanical stress and from the attack of recipients’ immune cells ³² . Campa-Carranza and colleagues demonstrated that MSCs, when preloaded into the NICHE’s central cell reservoir, efficiently supported early graft survival by enhancing vascular integration, modulating innate and adaptive immune responses, and creating a more favorable cytokine and transcriptional landscape ³² .

It is well known that the diabetic environment hinder tissue regeneration and promote a more intense foreign body response ³² . Accordingly, diabetic rats exhibited significantly thicker fibrotic capsules around NICHE devices compared with non-diabetic controls. Interestingly, male diabetic animals displayed more pronounced fibrosis than females, suggesting a sex-dependent differential response to biomaterial implantation under hyperglycemic conditions ³² . These findings align with broader evidence that sex influences tissue integration and transplantation outcomes through hormonal, genetic, and immunological mechanisms ⁴⁶ . Sex hormones modulate innate and adaptive immunity, shaping cytokine profiles, T cell activity, and the balance between pro-inflammatory and regulatory pathways, which can directly affect fibrosis and tissue remodeling. Sex chromosome-linked gene expression further contributes to differential immune responses, and intrinsic differences in drug metabolism may alter the efficacy of immunomodulatory therapies. In the context of diabetes, interactions between hyperglycemia-induced oxidative stress and sex-specific immune regulation may exacerbate fibrotic responses in males relative to females ⁴⁶ .

Vascularization was also markedly impaired in the diabetic microenvironment, as evidenced by reduced vessel density and surface area ³² . MSCs-enriched NICHE had a profound impact on vascularization within the implant. At 4 weeks post-implantation, MSC-bearing devices exhibited a significant increase in both vessel density and vessel area compared with controls, with notable sex differences: females developed more numerous small-caliber vessels, whereas males developed fewer but larger-caliber vessels. Importantly, these vessels were functional, with evidence of blood perfusion and selective permeability ³² . Markers of vascular maturity, such as VE-cadherin and endothelial nitric oxide synthase (eNOS), were elevated in the MSC-treated animals, peaking around week four to five, supporting the hypothesis about MSC-dependent generation of pre-vascularization window which importantly contributed to the optimal islet transplantation. Transplantation of syngeneic islets into the pre-vascularized MSC-enhanced NICHE resulted in significantly improved islet engraftment. At 28 days post-transplantation, the MSC: islet co-transplantation group retained nearly 64% of the initially loaded islet volume compared with just 27% in the islets-only group ³² .

Campa-Carranza and colleagues also demonstrated that MSCs enhanced islet viability through the modulation of local immune response ³² . During the early post-transplant phase (days 3–7), MSCs significantly altered the phenotype of innate immune cells within pancreatic islets, skewing macrophages toward a more anti-inflammatory phenotype and reducing the presence of neutrophils and natural killer (NK) cells ³² . By day 14, the adaptive immune system began to dominate. CD8⁺ T cells were especially prominent in male animals, with MSCs reducing their accumulation only partially ³² . In females, however, MSC co-delivery led to a greater increase in immunosuppressive FoxP3+ Tregs, correlating with improved islet cell survival and preservation of glucagon-producing α-cells. Spatial proximity analysis confirmed that Tregs were more closely associated with islets in MSC-treated groups, particularly in females ³² . Cytokine profiling further supported these immunological findings. MSCs led to the elevations in immunosuppressive TGF-β and pro-angiogenic VEGF. Moreover, pro-inflammatory mediators like MCP-1, IL-6, and IFN-γ were reduced in MSC groups, particularly in males, suggesting a reprogramming of the local immune milieu toward a more tolerogenic state ³² . Analysis of draining lymph nodes (dLN) revealed that the immune-modulatory effects of MSCs extended beyond the implant itself. In male islets-only recipients, dLNs exhibited increased CD8+ T cells and macrophage infiltration by day 7, patterns that were attenuated in MSC co-transplant groups. However, the systemic compartment, as represented by the spleen, remained largely unaffected, indicating that the immune response was primarily localized during the early post-transplant period. Importantly, 2 weeks post-transplantation, T cell-mediated immune rejection begins to emerge despite MSC presence, suggesting that while MSCs delay rejection and improve engraftment, they were not sufficient as a stand-alone therapy for long-term immune protection in allogeneic settings ³² .

In order to delineate transcriptional signatures, Campa-Carranza performed spatial transcriptomics on NICHE implants at day 7, categorizing the tissue into three meta-domains: the islet cluster, peri-islet cluster, and vascularized tissue cluster ³² . Islets showed enriched expression of endocrine-related genes (Ins2, Gcg, Iapp, Cltrn), while the peri-islet regions up-regulated immune signaling genes such as Il12b, Irf1, and Tgfb1. The vascularized areas were enriched in extracellular matrix remodeling and angiogenic genes (Col1a1, Igf1, Cxcl12). Notably, sex-specific and MSC-related differences were evident at the transcriptional level, as well. In females, MSC co-transplantation led to the up-regulation of genes associated with immunomodulation and vessel maturation (Nt5e (CD73) and Angpt2), while in males, MSCs down-regulated the expression of Ccl2 gene which is responsible for the monocyte recruitment ³² . These results further supported the hypothesis that the efficacy of MSC: islet co-transplantation was influenced by sex-specific host factors. From differences in fibrotic response and vessel architecture to divergent immune cell infiltration and cytokine profiles, male and female animals showed distinct responses to both the NICHE environment and MSC treatment. These findings underscore the need to incorporate sex as a biological variable in the design of future preclinical and clinical studies of islet transplantation and MSC-based therapies ³² .

Building upon the concept of engineered microenvironments to enhance MSC function and islet engraftment, Nakamura and colleagues introduced an innovative cell transplantation platform (CellSaic) which were designed to overcome major limitations of traditional cell aggregates such as spheroids, which frequently suffer from central necrosis due to restricted diffusion of oxygen and nutrients ²⁵ . The CellSaic system was based on RCP petaloid micro-pieces derived from a human collagen I α1 sequence, produced in yeast to eliminate animal-derived risks. When MSCs were cultured with these petaloid-shaped RCP fragments under low-attachment conditions, they adhered to the fragments and self-organized into a three-dimensional mosaic-like structure, maintaining interstitial spaces that supported superior diffusion and vascular ingrowth ²⁵ .

In subcutaneous implantation experiments which were conducted in immunodeficient NOD/SCID mice, MSC-CellSaic constructs showed significantly improved viability and angiogenesis over traditional MSC spheroids ²⁵ . Among different RCP fragment geometries (petaloid, chapped, plain), the petaloid structure produced the most favorable outcomes, likely due to its optimized surface roughness and cellular adherence properties. These results highlight the importance of not only scaffold presence but also microtopographic design in influencing graft performance ²⁵ . Functionally, the CellSaic system was evaluated in a streptozotocin-induced diabetic mouse model using co-transplantation of rat pancreatic islets with either MSC-CellSaic constructs, MSCs in suspension, or islets alone. Mice receiving islets alone remained hyperglycemic, while those transplanted with MSCs in suspension showed moderate improvement. In contrast, animals receiving MSC-CellSaic+islets exhibited significantly improved blood glucose control, with lower non-fasting glucose levels from day 7 through day 28. An intraperitoneal glucose tolerance test at day 28 confirmed enhanced glucose handling in the CellSaic group compared with both other groups ²⁵ . Histological analysis of graft sites corroborated these findings. The MSC-CellSaic+islet group had more intact islet structures, higher insulin-positive area, and greater vascularization compared with the other groups, where grafts were poorly developed or nearly undetectable. Furthermore, the study observed a “snowball effect,” where adjacent CellSaic units could fuse into larger constructs through MSC proliferation and scaffold bridging. This fusion was further enhanced by periodic addition of new RCP fragments, indicating the modularity and scalability of the platform. These findings demonstrated that scaffold-based approaches, particularly those integrating engineered geometry and viable support cells, may significantly enhance outcomes in cellular therapies. CellSaic provided both structural and functional support for MSC survival, enhanced MSC-driven angiogenesis, and significantly improved the engraftment and function of co-transplanted islets (Fig. 1). The upcoming studies should confirmed long-term efficacy of MSC-CellSaic + islet transplantation approach in large animal models, paving the way for its possible implementation in clinical settings ²⁵ .

Figure 1.

Schematic representation of the recombinant peptide petaloid scaffold platform applied to pancreatic islet transplantation with MSCs. Petaloid scaffold pieces provide a biocompatible matrix for co-culturing MSCs (oval dark blue) and pancreatic islets (represented as light green oval structures, enabling close interaction and retention of transplanted cells. MSCs release trophic and angiogenic factors that promote vascular ingrowth, improve nutrient and oxygen delivery, and enhance islet survival and insulin secretion. In addition, MSC-derived immunomodulatory signals protect the graft from immune-mediated rejection. The combined system results in enhanced vascularization, reduced immune attack, and improved islet graft function. The petaloid scaffold components are depicted as light-blue triangular structures, MSCs are shown as light-blue oval cells with dark-blue nuclei, pancreatic islets are illustrated as light-green oval structures, and newly formed blood vessels are represented as red tubular formations. The figure was prepared by using CorelDraw.

Similar to these results were findings reported by Yamashita and colleagues who used a pig model of type 1 diabetes mellitus generated by total pancreatectomy to investigate the feasibility and efficacy of subcutaneous transplantation of adipose tissue-derived MSCs (AT-MSC)-islet sheets ²⁶ . Their rationale was motivated by the limitations of intraportal islet transplantation (early graft loss, portal venous thrombosis) and the relative advantages of a subcutaneous site that allows easier access, graft removal, and lower invasiveness. AT-MSCs were isolated from inguinal subcutaneous adipose tissue of young pigs ²⁶ . The density of 2.0 × 10⁶ AT-MSCs was selected for subsequent islet/AT-MSCs sheet construction since these sheets displayed the greatest thickness, reduced anaerobic metabolism (lower lactate/glucose ratios), the lowest expression of hypoxia-inducible factor 1α (HIF-1α), while still maintaining high expression of pro-angiogenic VEGFA and IL-6. Pancreatic islets were seeded onto these AT-MSC sheets (10,000 islet equivalents (IEQs) were distributed across each AT-MSCs sheet), followed by a 24-h coculture on temperature-responsive dishes prior to transplantation). Histological analysis and immunostaining confirmed that islets adhered well to the AT-MSCS sheets. Functional in vitro assays revealed enhanced viability, cytokine secretion, and glucose responsiveness of islet/AT-MSCs sheets compared with islets alone. Viability of islet cells was significantly higher, secretion of pro-angiogenic IL8 was much greater, the glucose stimulation index (ratio of insulin secretion at high versus low glucose) was superior while pro-inflammatory IL16 was lower in the islet/AT-MSCs sheet constructs than in pure islets ²⁶ .

Subcutaneously transplanted islet/AT-MSCs sheets were implanted into two pancreatectomized pigs at waist and buttock regions ²⁶ . Persistent hyperglycemia was observed, insulin secretion was undetectable and ketone bodies significantly rose (on day 3 and day 7) in pancreatectomized pigs prior to the transplantation of islet/AT-MSCs sheets. After transplantation, both pigs displayed hypoglycemia during the first week, necessitating glucose administration for stabilization. Subsequently, both experimental animals attained normoglycemia without further requirement for exogenous glucose. Insulin secretion rose sharply immediately after islet/AT-MSC transplantation, plateaued thereafter, and remained stable. Intravenous glucose tolerance test, conducted on day 10 posttransplantation, showed prompt rises in blood glucose following glucose bolus, followed by insulin responses and glucose normalization by about 10 min postinjection, indicating functional responsiveness of the grafted islets to glucose challenge ²⁶ . In addition, histological examination of the extracted grafts confirm the presence of insulin-positive cells in the graft site. After graftectomy (the grafts were removed on day 14), experimental animals reverted to hyperglycemia and insulin secretion became undetectable, confirming that the normalization depended on the functional properties of islet/AT-MSCs grafts ²⁶ . These results demonstrated that subcutaneous transplantation of islet/AT-MSC cell sheets can result in normalized blood glucose levels within approximately 2 weeks, with functional insulin secretion in response to glucose challenge. Without additional immunosuppressive therapy, AT-MSC sheets managed to improve islet survival, enhance glucose responsiveness, and provide a scaffold that potentially supports vascularization and reduces inflammatory cytokine responses. Despite these encouraging results, the study had several limitations, including a short observation period (14 days post-transplantation until graftectomy), a limited sample size involving only two experimental pigs, and partial disintegration of the islet/AT-MSC cell sheet structure following transplantation. These issues highlight the need for further investigations with extended study duration, larger cohorts, and improved graft stability in similarly designed experiments ²⁶ .

Duprez and colleagues investigated the feasibility of generating composite grafts comprising MSCs and pancreatic islets to ensure sustained spatial association of MSCs with the islets throughout and following transplantation, thereby mitigating the limitations associated with systemic MSC administration, which frequently results in their migration to non-target tissues ³¹ . To develop these composite MSC-islet grafts, the researchers co-cultured human islets with varying quantities of human MSCs and observed rapid and dose-dependent adhesion of MSCs to the islet surfaces. Confocal microscopy revealed that MSCs not only adhered to the islet surface but also infiltrated the interior of the islets. Maximum surface coverage was achieved within 48 h, with stability maintained for up to 96 h. Functional testing of these composite islets showed that insulin secretion in response to glucose stimulation was preserved. In dynamic perifusion assays, composite islets and control islets displayed similar glucose-stimulated insulin secretion profiles, with no significant difference in stimulation index ³¹ . Moreover, insulin output per unit DNA (corrected for MSC DNA) remained unchanged, indicating that the MSC coating did not impair islet function. In order to assess the immunomodulatory properties of MSCs in the context of islet transplantation, the authors conducted mixed lymphocyte–islet reactions using human pbMNCs. The addition of MSCs, even at low ratios, significantly suppressed T cell proliferation in response to islet antigens, demonstrating a strong immunosuppressive effect likely mediated by paracrine factors ³¹ . This suggests that MSC–islet composites could help mitigate host immune responses at the graft site. Importantly, Duprez and colleagues also examined the innate immune compatibility of these composites using a human blood loop model, simulating the early intravascular exposure that occurs during intraportal transplantation. Both composite and control islets activated coagulation (as indicated by thrombin-antithrombin complex levels) and complement (C3a) to a similar extent. Platelet and granulocyte consumption and lymphocyte activation were also comparable, indicating that the addition of MSCs did not exacerbate the instant blood-mediated inflammatory reaction typically observed in intraportal islet transplantation ³¹ . These in vitro findings were further validated by in vivo experiments conducted in immunodeficient mice ³¹ . Human MSC-islet grafts remained viable and insulin-positive 2 weeks after their transplantation under the kidney capsule of immunodeficient animals. However, a critical observation emerged from experiments conducted in immunocompetent mice using murine MSC–islet composites. After 28 days, histological analysis of the grafts revealed ectopic bone formation at the transplant site, indicative of osteogenic differentiation of MSCs. This was not observed in immunodeficient mice receiving human MSC–islet grafts, suggesting species- or context-specific differentiation risks. This finding raises important concerns about the potential for unintended MSC differentiation in vivo, especially in non-target tissue environments. The risk of undesired differentiation, such as ectopic bone formation, underscores the need for careful consideration of MSC source, differentiation state, and long-term in vivo behavior in clinical translation ³¹ .

Remaining obstacles and challenges for safe therapeutic use of MSCs in clinical settings

Although MSCs have been widely studied as supportive adjuncts to pancreatic islet transplantation, their effects are not universally beneficial under all stress conditions encountered during the transplantation process^20,23. Early post-transplantation graft loss remains substantial, with a large proportion of transplanted islets failing to engraft due to challenging stressors such as hypoxia, oxidative stress, and impaired vasculogenesis inherent to the islet graft microenvironment. Immediately following isolation and infusion, islets experience prolonged periods of hypoxia before revascularization can occur, because the native dense vasculature is disrupted during procurement and re-establishment of blood supply is both delayed and often incomplete. This hypoxic milieu contributes to rapid cell death and functional decline in β-cells, which are intrinsically susceptible to oxidative imbalances due to low endogenous antioxidant capacity^20,23. In clinical settings, a significant fraction of intraportally transplanted islets fail to establish stable engraftment, a phenomenon linked to hypoxia and oxidative insult post-transplantation ²⁴ . Studies focusing on MSC co-culture and co-transplantation have documented heterogeneous outcomes under oxidative and inflammatory stress^20,24. In vitro co-culture of islets with MSCs subjected to pro-inflammatory cytokines demonstrated that MSCs could preserve insulin secretory responses even though they did not significantly improve overall islet viability under strong cytokine stress, indicating that protective effects may be limited under conditions of severe oxidative or inflammatory challenge^24,35,47. Moreover, some MSC-mediated molecular interactions appear to be context-dependent, as certain secreted factors can exert conflicting influences. Interestingly, some proteins secreted by MSCs have been reported to include both protective and potentially detrimental effects on islet endothelial cells under oxidative conditions^35,47.

The intrinsic heterogeneity of MSC populations also contributes to inconsistent outcomes, because MSCs derived from different donors or tissues vary in their secretome profiles, antioxidant capacity, and angiogenic potential^10,43. In addition, the severe oxidative and hypoxic microenvironment experienced by islets soon after transplantation can impede MSC survival and function, reducing their ability to exert beneficial effects ⁴⁷ . Preconditioning strategies aimed at enhancing MSC resistance to oxidative stress and improving their angiogenic output are being investigated precisely because unmodified MSCs may not fully counteract graft hypoxia and oxidative damage in all contexts ⁴³ . These findings underscore that while MSCs have considerable potential to support islet survival and function, their efficacy may be constrained by the severity of oxidative and hypoxic stressors, variable angiogenic responses, and donor-dependent MSC heterogeneity, highlighting the need for optimized MSC preparation, preconditioning, and delivery strategies to overcome these limitations ⁴³ .

Clinical studies investigating MSCs have produced heterogeneous and sometimes contradictory results with respect to immunomodulatory efficacy and long-term clinical benefit^14,20,22. While numerous trials report favorable safety profiles and signals of therapeutic activity in inflammatory, autoimmune, and degenerative conditions, others demonstrate limited or no efficacy, even within similar disease indications. This variability highlights an important challenge in the clinical translation of MSC-based therapies and underscores the need to critically acknowledge and address the sources of inconsistency across studies^14,20,22.

One major contributor to these divergent outcomes is the intrinsic heterogeneity of MSC preparations. MSCs can be isolated from a wide range of tissues, and accumulating evidence demonstrates that their biological properties, functional behavior, and therapeutic potential are strongly influenced by their tissue of origin^24,47,43. Commonly used sources include adult bone marrow, adipose tissue, perinatal tissues such as umbilical cord and placenta, and induced pluripotent stem cell–derived MSCs (iPSC-MSCs). Although all these populations meet minimal phenotypic criteria for MSCs, comparative studies consistently demonstrate source-dependent differences in immunomodulatory capacity, angiogenic potential, proliferation kinetics, secretome composition, and scalability. These differences have important implications for clinical translation, affecting the reproducibility, efficacy, and predictability of MSC-based therapies^24,47,43.

Bone marrow–derived MSCs (BM-MSCs) remain the most extensively characterized and clinically studied source^24,47,43. They exhibit well-documented immunosuppressive activity, including suppression of allogeneic T cell proliferation and modulation of innate immune responses, and produce a wide range of immunoregulatory cytokines. Adipose tissue–derived MSCs (AT-MSCs) typically provide higher yields and enhanced proliferative capacity compared with BM-MSCs, and in some studies demonstrate even stronger immunomodulatory effects, mediated by elevated secretion of cytokines and lipid mediators such as IL-6 and prostaglandin E2 ²⁴ , ⁴⁷ . Umbilical cord–derived MSCs (UC-MSCs) and placenta-derived MSCs offer additional advantages including non-invasive procurement, high proliferative potential, low immunogenicity, and robust paracrine anti-inflammatory effects^35,47. Notably, in paired comparisons, placenta-derived MSCs have been reported to exert stronger immunomodulatory activity than UC-MSCs, reflecting source-specific differences in cytokine secretion and immunoregulatory function. iPSC-MSCs represent a promising alternative due to their potential for scalable, donor-independent production and capacity to recapitulate many functional features of primary MSCs. However, their immunomodulatory and angiogenic properties can vary depending on differentiation protocols and epigenetic background, requiring careful characterization for clinical use^20,35,47.

Angiogenic capacity is another source-dependent feature with important therapeutic implications ¹⁵ . Comparative studies show that BM-MSCs and placenta-derived MSCs frequently display higher expression of angiogenesis-related genes and superior ability to support endothelial cell proliferation, migration, and tube formation in vitro relative to AT-MSCs and UC-MSCs^14,15. Differences in angiogenic potential are thought to reflect the tissue microenvironment of origin and influence MSC-mediated vascularization and tissue repair after transplantation^14,15.

These source-dependent differences have practical implications for clinical translation. Perinatal MSC sources, such as UC and placenta, offer scalable and non-invasive access, rapid expansion, and improved batch-to-batch consistency, facilitating clinical manufacturing^24,47,43. Adult sources, including BM and AT, offer distinct functional advantages, particularly in terms of immunomodulation, but could be more affected by donor age, invasive harvest procedures, and inter-donor variability^24,47,43.

Pancreas-derived MSCs or MSCs isolated from the peripancreatic microenvironment appear to retain tissue-specific properties that may enhance compatibility with pancreatic islets, representing potentially highly relevant source for islet co-transplantation ³ , ⁴⁸ . Experimental studies indicate that these cells express high levels of immunomodulatory and pro-angiogenic factors that may support immunosuppression, extracellular matrix remodeling, and neo-angiogenesis^33,48. Pancreas-derived MSCs have been shown to suppress T lymphocyte proliferation, modulate inflammatory cytokine production, and promote endothelial cell migration and tube formation, all of which are critical for supporting islet engraftment in transplantation, where early inflammatory damage and poor revascularization are major causes of graft loss^33,48. In addition, these tissue-specific MSCs may provide local niche signals that help preserve beta-cell viability and maintain insulin secretory capacity, offering potential advantages over non-pancreatic MSCs in supporting long-term graft function. While the availability of pancreatic tissue and the limited number of studies currently constrain broader clinical application, pancreas-derived MSCs offer unique tissue-specific properties that may enhance islet graft survival, support beta-cell function, and provide a targeted approach for improving outcomes in islet transplantation^33,48.

Furthermore, it is important to recognize that donor-related factors such as age, sex, health status, and underlying disease can significantly influence MSC phenotype and functional potency ⁴⁰ . MSCs obtained from older or diseased donors often display reduced proliferative capacity, altered cytokine secretion, and diminished immunoregulatory activity compared with cells derived from younger, healthy donors ⁴⁰ .

Manufacturing-related variables further contribute to inconsistencies in clinical outcomes. Isolation techniques, culture conditions, expansion media, oxygen tension, serum supplementation, and seeding density differ widely among laboratories and clinical manufacturing facilities^41,42. These parameters can profoundly affect MSC viability, immunophenotype, gene expression, and functional behavior. Moreover, prolonged in vitro expansion and higher passage numbers are associated with replicative senescence, genomic instability, and loss of functional potency, which may compromise therapeutic efficacy if not adequately controlled^41,42. Differences in cryopreservation, thawing procedures, and post-thaw recovery conditions also influence MSC function and may transiently impair immunomodulatory activity at the time of administration. Another critical limitation in current MSC clinical development is the lack of standardized, mechanism-based potency assays^41,42. Traditional characterization criteria, such as adherence to plastic, surface marker expression, and trilineage differentiation capacity, do not reliably predict in vivo immunomodulatory function or clinical efficacy. As a result, MSC products meeting minimal release criteria may differ substantially in their biological activity. The absence of validated potency assays aligned with disease-specific mechanisms of action hampers meaningful comparison across studies and contributes to variability in therapeutic outcomes^41,42. Collectively, these biological and manufacturing-related factors likely underlie the conflicting results observed in MSC clinical trials. Addressing these challenges requires urgent efforts toward standardization and reproducibility in MSC manufacturing and characterization. Harmonization of tissue sourcing, donor selection criteria, culture and expansion protocols, passage limits, and cryopreservation methods, along with the development of robust, predictive potency assays, will be essential to ensure product consistency. Such standardization is critical for improving the reliability of clinical trial outcomes, enabling cross-study comparisons, and ultimately achieving more predictable and reproducible therapeutic benefits from MSC-based therapies^41,42.

A comprehensive evaluation of safety considerations and long-term outcomes is essential when discussing the translational potential of MSCs^44,45. While numerous clinical and preclinical studies have documented short-term improvements in tissue repair, inflammation modulation, and functional outcomes following MSC administration, data on long-term persistence and sustained efficacy remain limited ⁴⁵ . The fate of infused MSCs in vivo is not fully understood, and evidence suggests that these cells often exert their effects through transient “hit and run” mechanisms rather than long-term engraftment. This transient presence may inherently limit long-term risks, but also underscores the need for extended follow-up to monitor potential delayed adverse events^44,45.

One important safety consideration is the risk of ectopic differentiation, where MSCs might differentiate into unwanted cell types in off-target tissues ⁴⁵ . Although clinical autopsy studies in humans have not shown overt ectopic tissue formation or malignant transformation from donor MSCs, the possibility could not be entirely excluded, particularly with ex vivo expanded cells that have undergone prolonged culture ⁴⁵ . Extended in vitro expansion increases the likelihood of genetic and chromosomal abnormalities, which could theoretically enhance tumorigenic potential or lead to unpredictable behavior after transplantation ⁴⁵ . While MSCs are generally considered to have lower tumorigenicity than pluripotent stem cells, their interactions with the host microenvironment, including tumor sites, could influence tumor progression or immune escape in susceptible individuals. Fibrosis and profibrogenic responses represent another potential risk of MSC therapy. MSCs are capable of differentiating into myofibroblast-like cells under certain conditions, and an imbalance between tissue repair and fibrotic processes could contribute to scar formation or organ dysfunction in chronic injury settings ⁴⁵ . Reports from clinical trials and animal models have also identified thromboembolism, particularly after intravenous administration of MSCs, emphasizing the importance of careful dosing, delivery method optimization, and patient selection to mitigate this complication. In addition, long-term outcomes beyond 1 to 2 years are sparsely reported for most indications, making it difficult to fully characterize the durability of therapeutic effects and the incidence of delayed adverse events ⁴⁵ . Comprehensive long-term follow-up in larger cohorts is therefore critical to determine whether MSC therapy confers truly durable clinical benefits and to identify any late-emerging safety concerns. Strategies to mitigate potential risks in translational contexts include minimizing ex vivo expansion to reduce the accumulation of genetic aberrations, rigorous quality control and potency assays during manufacturing, careful monitoring of patients post-therapy, and consideration of cell-free approaches such as MSC-derived exosomes (MSC-Exos) that may retain paracrine benefits with reduced safety risks ³⁶ .

Therapeutic potential of MSC-Exos in islet transplantation

Pancreatic islet survival and function are critically influenced by the local microenvironment, and MSCs have been shown to exert robust supportive effects on insulin-producing Langerhans islets through multiple paracrine and secretome-mediated mechanisms ³⁴ . MSCs secrete a broad repertoire of bioactive factors that collectively attenuate pro-inflammatory signaling, suppress immune-mediated β-cell damage, and enhance revascularization and tissue repair. MSC-sourced secretome fosters the preservation of islet architecture and β-cell viability, promotes insulin secretory capacity, and improves outcomes in preclinical models of islet transplantation, highlighting the therapeutic potential of harnessing MSC-derived secreted factors to optimize islet function in diabetes ³⁴ . Building on this foundation, MSC-Exos have emerged as promising acellular therapeutic agents capable of recapitulating many of the beneficial effects of MSCs, while avoiding several side effects associated with MSC-based therapy ³⁶ . MSC-Exos are nanosized extracellular vesicles (30–150 nm in diameter), enriched with bioactive molecules (growth factors, immunoregulatory proteins, lipids, and nucleic acids) ⁴⁹ . These vesicles act as key mediators of intercellular communication and have been shown to exert immunomodulatory, anti-inflammatory, pro-angiogenic, and tissue-regenerative effects ⁴⁹ . MSC-Exos can emulate key biological activities of MSCs but without the safety concerns associated with living cells, such as ectopic differentiation or tumorigenicity, and they are generally considered to have lower immunogenicity and enhanced stability, allowing for easier storage, transport, and administration ³⁶ . Compared with whole MSCs, exosomes are less likely to be sequestered in the pulmonary vasculature after systemic delivery, and they do not proliferate in vivo, potentially reducing risks of adverse events inherent to cell transplantation^36,37. Despite these conceptual advantages, the evidence base for MSC-Exos-based therapies is still evolving, and direct comparisons with MSC-cell based therapy in controlled clinical settings are limited^36,37. Some preclinical studies show that Exos derived from different MSC sources can modulate inflammation and support tissue regeneration with efficacy comparable with their cellular counterparts, but therapeutic outcomes may vary depending on the source of the parent cells and the methods used for vesicle isolation and characterization^36,37. MSC-Exos lack the capacity for self-renewal and differentiation that living MSCs possess, which may limit their utility in settings where cell replacement or direct structural contribution is needed, although they remain potent mediators of paracrine signaling ³⁷ . Production scalability, consistent isolation and purification methods, and robust characterization are also challenges, as current techniques yield limited quantities of vesicles with variable composition and biological activity^36,37.

In the context of islet cell transplantation for the treatment of diabetes mellitus, MSC-Exos offer a novel strategy to enhance graft survival, reduce immune-mediated rejection, and support functional integration of transplanted islets^37,38. One of the critical challenges in islet transplantation is the hostile microenvironment into which the islets are introduced, characterized by hypoxia, inflammation, and immune activation^3,6. MSC-Exos can counteract these deleterious factors through the delivery of regulatory miRNAs, cytokines, and growth factors^37,38. MSC-Exos’ cargo containing miR-21, miR-146a, and miR-155 could modulate macrophage polarization, suppress pro-inflammatory cytokine production and promote an anti-inflammatory milieu conducive to graft acceptance^36,38. In addition, MSC-Exos can inhibit T cell activation and proliferation, reduce DC maturation, and increase the proportion of immunosuppressive Tregs, collectively shifting the immune response toward tolerance rather than rejection^36,49. In parallel with their immunoregulatory properties, MSC-Exos could also contribute to graft revascularization, through the delivery of pro-angiogenic VEGF, angiopoietin-1 (Ang-1), and miR-126, which stimulate endothelial cell proliferation, migration, and tube formation^38,50. By facilitating the rapid establishment of a functional microvascular network around the islet graft, MSC-Exos can significantly reduce hypoxia-induced cell death and improve the metabolic function of the islets^38,50. Novel MSC-Exos-based therapeutic agent, Exosome Derived Multiple Allogeneic Proteins Paracrine Signaling (Exo-dMAPPs) could further enhance the therapeutic potential of MSC-Exos-based strategies for improvement of islet cell engraftment and outcomes^36,51. By combining the immunomodulatory and pro-angiogenic effects of MSC-Exos with a diverse repertoire of allogeneic proteins involved in paracrine signaling, Exo-dMAPPs may create a highly supportive microenvironment for transplanted islets ³⁶ . These engineered vesicles could attenuate local inflammation, promote immune tolerance, and stimulate rapid vascularization around the graft, thereby improving islet survival, functional integration, and long-term glycemic control ⁵¹ .

In line with these observations are results obtained by Wen and colleagues who demonstrated that MSC-Exos could act as small RNA delivery vehicles and immunomodulatory agents to enhance islet survival and suppress graft rejection ³⁹ . Exosomes derived from human bone marrow–derived MSCs (hBM-MSC-Exos) which were previously transfected with plasmid constructs encoding small interfering (si)Fas and anti–miR-375 sequences, successfully modulated Fas and miR-375-driven signaling pathways in recipient pancreatic β cells ³⁹ . The silencing of Fas reduced the sensitivity of islet cells to death receptor–mediated apoptosis, while modulation of miR-375 relieved microRNA-mediated suppression of survival pathways within islet cells. Accordingly, BM-MSC-Exos-treated islets exhibited higher viability, lower apoptotic indices, and better insulin secretion performance under exposure to inflammatory cytokines compared with control, BM-MSC-Exos-untreated islets. Beyond islet protection, Wen and coworkers. demonstrated that hBM-MSC-Exos could actively modulate host immune response. BM-MSC-Exos inhibited proliferation of activated lymphocytes in vitro and favored expansion of immunosuppressive Tregs, shifting the immune balance toward tolerance ³⁹ . To extend these in vitro findings, Wen et al. used a humanized NOD-SCID gamma (NSG) mouse model in which human islets were transplanted along with peripheral blood mononuclear cells (pbMNCs) to simulate immune challenge ³⁹ . Transplanted human islets in NSG mice receiving the engineered hBM-MSC-Exos showed down-regulation of Fas and miR-375 expression, corroborating successful delivery and functional effect in the graft milieu. In addition, hBM-MSC-Exos-treated mice displayed reduced graft rejection markers and a more tolerogenic immune milieu. Specifically, pbMNC proliferation was curtailed, and Treg populations in graft-associated lymphoid compartments were increased. This dual immunoregulatory effect likely contributed to prolongation of islet graft survival and protection against immune-mediated destruction ³⁹ .

These findings demonstrated that hBM-MSC-Exos may act as bifunctional agents which precisely deliver cytoprotective small RNAs to islet grafts, silencing deleterious gene expression and efficiently modulate host immunologic responses through the attenuation of effector cell proliferation and through the enhancement of Treg-dependent immunosuppression ³⁹ . The synergy of these two mechanisms plausibly leads to improved islet graft viability, function, and reduced rejection risk ³⁹ . However, despite of these promising results, several limitations of this study have to be noted. Wen and colleagues did not explore the dose–response curves or limiting thresholds of BM-MSC-Exos-mediated delivery and follow-up period in the humanized model was relatively limited, so the long-term persistence of protective, immune suppression-dependent effects remains unproven. In addition, humanized NSG + pbMNC model cannot fully recapitulate the complexity of a fully immunocompetent recipients. Therefore, long-term studies, conducted in large immunocompetent animals are needed to evaluate durability, safety, immune tolerance, and functional success of hBM-MSC-Exos in the support of islet transplantation ²⁷ . Ensuring batch to batch consistency, purity, potency, and safety, as well as long-term biocompatibility and stability of MSC-Exos, will be critical for their regulatory approval and clinical adoption. Continued research is also needed to determine whether engineered or cargo enhanced MSC-Exos can overcome limitations in therapeutic efficacy without introducing new safety concerns. Taken together, these aspects underscore the potential of MSC Exos as complementary or alternative strategies to MSC cell-based therapy, but they also highlight the need for rigorous comparative studies and standardized methodologies to realize their full clinical potential ³⁶ .

Conclusion

Mesenchymal stem cells have emerged as valuable biological adjuncts to improve the outcomes of islet cell transplantation through multiple molecular mechanisms, including immunomodulation, anti-apoptotic signaling, promotion of angiogenesis, and suppression of detrimental immune responses (Fig. 2). By modulating both innate and adaptive immunity, protecting β-cells from oxidative stress, and enhancing revascularization, MSCs significantly support graft survival and functional integration (Table 3). Their capacity to home to injured tissues and influence the local microenvironment via paracrine signaling further enhances their therapeutic potential. MSC-Exos have attracted attention as a cell-free alternative, capable of preserving islet viability, stimulating angiogenesis, and regulating immune responses without risks associated with cell-based therapy. Despite encouraging results, challenges remain in fully understanding the molecular pathways involved. Continued research is required to optimize dosing, delivery, and production protocols, highlighting the promise of MSC- and MSC-Exo-based approaches to advance islet transplantation as a durable therapy for type 1 diabetes.

Figure 2.

Therapeutic roles of MSCs and MSC-Exos in islet cell transplantation. MSCs and MSC-derived exosomes (MSC-Exos) play crucial therapeutic roles in islet cell transplantation. MSCs act as potent biological adjuvants, improving islet graft survival and function through multiple mechanisms, including immunomodulation, suppression of immune responses, anti-apoptotic signaling, and promotion of angiogenesis. They secrete growth factors, pro-angiogenic molecules, and immunoregulatory mediators that enhance islet viability, support engraftment, and promote neo-angiogenesis. The figure was prepared by using CorelDraw.

Table 3.

Mechanisms of action, biological effects, and translational considerations of MSCs and MSC-Exos in islet transplantation.

Category	Mechanisms/properties	Key molecules/factors	Effects on islet grafts	Source/derivatives	Clinical/translational considerations	Ref. no.
Immunomodulation	Suppression of innate and adaptive immune responses; modulation of inflammatory milieu	TGF-β, IL-10, IDO, PGE2	Inhibits T cell proliferation, reduces DC maturation, promotes Tregs, protects graft from rejection	BM-MSCs, AT-MSCs, UC-MSCs, Placenta-MSCs, iPSC-MSCs	Reduces need for systemic immunosuppression; context-dependent and adaptive effects allow targeted immune control; may permit intermittent dosing	Eguchi et al. 7
Cytoprotection	Anti-apoptotic effects; oxidative stress reduction; mitochondrial support	IGF-1, Thioredoxin, SDF-1, Bcl-2, Bcl-xL	Protects β-cells from apoptosis, maintains mitochondrial integrity, restores insulin secretion	BM-MSCs, Pancreas-derived MSCs, MSC-Exos	Supports graft viability under inflammatory stress; MSC-Exos may provide cell-free cytoprotection with lower safety risks	Eguchi et al. 7
Angiogenesis/Vascularization	Promotion of neovascularization; endothelial cell migration and proliferation	VEGF, Angiopoietin-1, HGF, miR-126	Enhances graft oxygenation, nutrient supply, and long-term function	BM-MSCs, Placenta-MSCs, MSC-Exos	Accelerates revascularization; source-dependent variation in angiogenic capacity; critical for early graft survival	Fujita et al. 8
β-cell Regeneration	Promotion of proliferation, survival, and functional maturation of β-cells	HGF, IGF-1, FGF-2, SDF-1, miR-21, miR-146a, miR-126	Activates pro-survival pathways (PI3K/Akt, MAPK/ERK), enhances insulin transcription, preserves β-cell identity	MSCs, MSC-derived EVs	Supports endogenous regeneration and functional enhancement of transplanted islets	Eguchi et al. 7
Disease Modulation	Delay or prevention of autoimmune diabetes onset	TGF-β, IL-10, IDO, PGE2, Treg induction	Reduces insulitis, limits β-cell destruction, shifts immune response to regulatory phenotype	BM-MSCs, AT-MSCs, UC-MSCs	Demonstrates preventive immunomodulatory potential; strengthens rationale for MSC use in islet transplantation	[preclinical models]
MSC-Exos	cell-free delivery of immunomodulatory, pro-angiogenic, and regenerative factors	miRNAs (miR-21, miR-146a, miR-126, anti-miR-375), VEGF, HGF, TGF-β	Suppresses T cell activation, enhances Tregs, promotes revascularization, improves graft survival	BM-MSC-Exos, engineered Exo-dMAPPs	Lower risk of tumorigenicity and ectopic differentiation; stable, scalable, and suitable for off-the-shelf therapies	de Klerk and Hebrok 19 Barachini et al. 20 Mikłosz and Chabowski 21 Shrestha et al. 22 Mou et al. 23 Mei et al. 24
Source-Dependent Properties	Functional differences depending on tissue origin	Cytokine profiles, angiogenic gene expression, proliferation kinetics	Immunomodulatory strength, angiogenic potential, β-cell support	BM, AT, UC, Placenta, iPSC, Pancreas-derived MSCs	Source selection affects clinical efficacy, scalability, and reproducibility; pancreas-derived MSCs may offer tissue-specific advantages	Koehler et al. 27
Safety/Translational Considerations	Minimizing risks and variability	Quality control, standardized potency assays, minimal ex vivo expansion	Reduces risk of ectopic differentiation, tumorigenicity, thromboembolism	All MSC types and derivatives	Critical for reproducible clinical outcomes; MSC-Exos may mitigate some risks associated with living cell therapy	[safety]

Abbreviations: MSCs (mesenchymal stromal cells), MSC-Exos (MSC-derived exosomes), miRNAs (microRNAs), VEGF (vascular endothelial growth factor), HGF (hepatocyte growth factor), Ang-1 (angiopoietin-1), IDO (indoleamine 2,3-dioxygenase), PGE2 (prostaglandin E2), DC (dendritic cell), TGF-β (Transforming Growth Factor-Beta), IL-10 (interleukin-10), Tregs (regulatory T cells), IGF-1 (insulin-like growth factor 1), FGF-2 (fibroblast growth factor 2), SDF-1 (stromal cell-derived factor 1), Exo-dMAPPs (exosome-derived multiple allogeneic proteins paracrine signaling), hBM-MSC-Exos (human bone marrow–derived mesenchymal stromal cell exosomes), siRNAs (small interfering RNAs), siFas (small interfering Fas RNA), anti-miR (anti-microRNA), anti-miR-375 (anti-microRNA-375).