Abstract
Adipose tissue-derived mesenchymal stromal/stem cells (ADMSCs) represent a novel therapeutic intervention for Type 1 Diabetes (T1D). The attractiveness of ADMSCs is characterized by their immunomodulatory activities, regenerative properties, and relative ease of access. ADMSC therapies in animal models and clinical trials have revealed decreased insulin dependence, increased β cell mass, and improved islet graft acceptance. Despite their potential, challenges in quality control, small-scale investigations, functional heterogeneity, and standardization limit the application of these therapies. This review synthesizes the current knowledge and recent outcomes of ADMSC therapies in treating T1D and highlights areas that need further investigation.
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Introduction
Type 1 Diabetes (T1D) is an immune-related disease caused by the autoimmune destruction of the insulin-producing β cells, resulting in lifelong insulin dependence. The onset of T1D is a complex interplay between an individual’s genetic predisposition and environmental factors that trigger the immune system, causing hyperglycemia and related complications upon β cell destruction1. The global incidence of T1D has been estimated to increase to 13.5-–17.4 million people by 20402,3. The steady increase in T1D prevalence indicates the need for novel T1D treatments.
T1D pathogenesis can be divided into three stages based on hyperglycemia’s presence (or absence) and associated symptoms4. Stage 1 is defined by normoglycaemia accompanied by two or more islet-directed autoantibodies. There is an observed influx of dendritic cells (DCs) into islets, potentially triggered by impaired islet architecture remodeling via apoptosis, cross-presentation of endogenous peptides, or superantigen-driven immune responses5. Autoreactive CD4+ T cells stimulate APCs (antigen-presenting cells) and help CD8+ T cells attack β cells by releasing TNF-α, IFN-γ, Fas/FASL, and perforin/granzyme (Fig. 1). Released cytokines also stimulate macrophages to damage β cells, yielding a positive feedback loop. This triggers NF-κB (Nuclear factor-κB) enhancer and activates β cells, which is primarily pro-apoptotic6. IFN-γ upregulates the expression of FAS receptors (CD95) on β cells, making them susceptible to IL-1β-induced apoptosis. IFN-γ also increases TNF-α and IL-1β secretion, along with reactive oxygen species (ROS), amplifying immune responses and exacerbating β cell stress7. In addition to oxidative stress, ER (Endoplasmic Reticulum) stress plays a critical role in β cell dysfunction and apoptosis in T1D. Increased cytokine exposure and sustained inflammatory signaling disrupt protein folding in the ER, accumulating misfolded proteins. This triggers the unfolded protein response (UPR), which, if unresolved, activates pro-apoptotic pathways involving CHOP (C/EBP homologous protein) and JNK (c-Jun N-terminal kinase), further promoting β cell demise. Additionally, prolonged ER stress impairs insulin biosynthesis and secretion, exacerbating metabolic dysfunction in early T1D pathogenesis7.
Fig. 1: Immunopathogenesis of T1D.
figure 1
T-lymphocyte-mediated insulitis, followed by the presence of one or more types of autoantibodies (AAbs) directed against insulin, glutamic acid decarboxylase (GAD), protein tyrosine phosphatase IA-2 or IA-2β, and zinc transporter 8 (ZnT8), is indicative of the immunological onset of T1D. Created in BioRender. Pociot, F. (2025) https://BioRender.com/c94c618.
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Stage 2 is defined by two or more autoantibodies, β cell dysfunction, and progressive elimination of the β cell mass4. The inflammatory microenvironment created in the islets causes an increase in vascular permeability and the infiltration of CD8+ T cells, CD20+ B cells, CD4+ T cells, and CD68+ macrophages8,9. Stage 3 marks the clinical diagnosis of T1D and is usually the initiation of insulin therapy4,5. The rate and extent of β cell destruction can vary among patients as can the age of onset and the number and type of antibodies present at diagnosis, pointing to its heterogenous nature in presentation4. The recent regulatory approval of a T1D immunotherapy designed to slow the immune-mediated destruction of pancreatic β cells underscores the fundamental immunological basis of type 1 diabetes while establishing a precedent for future immune-modulating therapeutic approaches to combat this condition.
After insulin replacement, the most common treatment strategies for T1D are immunotherapies10 and cell replacement therapies11. These treatment strategies have shifted how therapeutic development is viewed for T1D, redirecting the focus on targeting the cause over treating the symptom. This change arises from the need to target islet-specific immune pathways while avoiding toxicities associated with conventional treatments10. Thus, novel therapeutics have shifted towards utilizing the regenerative and immunomodulatory properties of stem/stromal cells, specifically mesenchymal stem cells (MSCs). MSCs, non-hematopoietic, multipotent stem cells can differentiate into numerous cell types, have tissue regenerative and immunomodulatory properties, conferring substantial therapeutic potential for T1D intervention12,13 which release various growth and inflammatory factors like vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), fibroblast growth factor (FGF) and prostaglandin E2 (PGE2), which contribute to the repair of injured tissues14. MSCs can be isolated from various sources (bone, cartilage, adipose, endothelium, and muscle) and can differentiate into multiple lineages12. Preclinical trials using MSCs to treat rheumatoid arthritis, T1D, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, autoimmune liver disease, and Sjogren’s syndrome have exhibited the cells’ immunosuppressive and regenerative potential in treating autoimmune diseases15. Their low immunogenicity and low tumorigenic effects16 add to their therapeutic applications, which have been significant challenges associated with islet transplantation, along with 60% islet loss occurring in most cases due to hypoxia and nutrition deficiencies17. They also play an essential role in lowering fasting blood sugar levels, hemoglobin A1c and C peptide levels, and treating microvascular complications associated with T1D14,15. Due to their abundance, ease of isolation, applicability, and autologous nature, ADMSCs have become a focus in the clinical setting14. For this review, “ADMSCs” will refer to all forms of Adipose tissue-derived mesenchymal stromal/stem cells unless identified explicitly as ADSCs (Adipose tissue-derived stromal/stem cells). Here, we discuss the therapeutic benefits, progress, and prospects of ADMSC therapy for T1D.
Adipose-derived mesenchymal stromal/stem cells (ADMSCs)
ADMSCs represent an attractive source of MSCs for therapeutic applications. Adipose tissue yields a high content of MSCs and is easily accessible relative to harvesting other MSC sources, making it particularly attractive for research18. They are isolated from different adipocyte tissue depots, like visceral, subcutaneous, and preperitoneal19. Subcutaneous and visceral ADMSCs exhibit distinct biological profiles despite similar surface markers. Subcutaneous ADMSCs display classical mesenchymal morphology with directed motility, efficient focal adhesion turnover, and increased ciliated cells. Conversely, viscerally isolated ADMSCs demonstrate enhanced differentiation potential toward osteogenic and adipogenic lineages, higher stemness gene expression (c-MYC, KLF4, NANOG, SOX2), and increased inflammatory cytokine secretion (IL-6, IL-8, TNFα), reflecting their physiological role in metabolic regulation and inflammatory signaling19. ADMSCs are predominantly isolated from white subcutaneous adipose tissue from surgical waste like lipoaspirates18. Isolation typically employs enzymatic digestion with collagenase (0.05–0.15%) for 30–90 min at 37 °C to break down the extracellular matrix, followed by centrifugation to collect the stromal vascular fraction, red blood cell lysis, and filtration through 70–250 μm nylon mesh to remove debris. The resulting cells are cultured on plastic surfaces, with non-adherent cells removed by washing. Adipose tissue represents an exceptionally rich MSC source, yielding 2 × 105−5 × 104 cells/gram compared to bone marrow’s 6-60 × 103 cells/ml, though yields vary with donor characteristics, tissue collection methods, and culture conditions20.
Stromal cells (adipocytes) retain the capacity for differentiation and self-renewal throughout an individual’s lifetime21. They also express α4 integrin that forms a heterodimer with CD29 to create very late activation antigen 4 (VLA-4) and mediate migration to inflammatory areas22. Further, ADMSCs have been shown to restore and preserve ß-cell mass effectively23, differentiate into insulin-producing cells (IPCs)24,25, and exert immunomodulatory effects (Fig. 2)26. ADMSCs have a higher differentiation potential into IPCs than bone marrow-derived MSCs (BMMSCs)27, more potent immunomodulatory effects, and higher cytokine secretion28. The International Society for Cell & Gene Therapy (ISCT) has defined the minimal criteria for characterizing ADMSCs: 1) adherence to plastic; 2) positive expression of CD73, CD90, CD105, CD13, CD29, and CD44 with negative expression of CD45, CD14, CD11b, CD79a, CD19, CD31, and CD235a; 3) ability to differentiate into pre-adipocytes, chondrocytes, and osteoblasts29. Beyond those included in the ISCT criteria, ADMSCs express other CD markers. Table 1 shows the positive cell markers expressed in ADMSCs and their biological and therapeutic functions.
Fig. 2: ADMSC applications in the treatment of T1D.
figure 2
ADMSCs modulate the immune system by shifting pro-inflammatory cells (M1 macrophages, Th1/Th17) to anti-inflammatory states (Tregs, M2 macrophages) while promoting insulin-producing β-cells regeneration via microRNAs. The dual effects of immunomodulation and regeneration aim to restore β-cell function and reduce autoimmune destruction. ADMSC, Adipose-Derived Mesenchymal Stem Cell; iPSCs, induced pluripotent stem cells; Th, T helper cell; Treg, regulatory T cell. Created in BioRender. Pociot, F. (2025) https://BioRender.com/o46i021.
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Table 1 CD Markers Expressed in ADMSCS And Their Biological and Potential Therapeutic Functions
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Studies report that ADMSCs exhibit higher therapeutic capacity than other MSC sources30,31,32,33. When compared to BMMSCs, ADMSCs have been shown to exhibit higher proliferation rates34, adipogenic capacity30, and the ability to maintain morphology and cell activity up to the 15th passage29. A study by Yi et al. compared MSCs from different sources (adipose tissue, amniotic membrane, umbilical cord) and demonstrated that ADMSCs exhibit a more significant proportion of subpopulations associated with vascular regeneration, blood vessel development, and rates of angiogenesis35. Adipose tissue is highly vascularized to maintain body temperature and supply nutrients and oxygen, corresponding to its high angiogenic capabilities35. Additionally, a study by Liu et al. found that ADMSCs could help decrease body weight and adipose tissue in db/db mice. This result was not found by therapies using umbilical cord-derived mesenchymal stem cells (UCMSCs). Excess blood glucose can be stored as fat when not efficiently used or removed. While weight loss may signal improved glucose metabolism, it is not always reliable, as unintended weight loss can also occur in conditions like poorly managed diabetes. Although UCMSCs exhibited comparable regeneration of islet cells, they did not show any decrease in body weight or adipose tissue quantity36. Studies on BMMSCs have revealed compelling co-expression results of specific cell surface markers also present in ADMSCs. CD39 and CD73 work together in the catabolism of ATP, generating adenosine and phosphate from ATP/ADP. Adenosine is effective in the immunosuppression of T-cells via the adenosine A2A receptor. The suppression of T-cell proliferation has demonstrated solid anti-inflammatory effects, increased immunoregulation, and decreased tissue damage29. Since these CD markers are also present in ADMSCs, they may exhibit the same immunoregulatory effect, though no studies have been done in ADMSCs specifically.
The prevailing school of thought is that CD34 is negatively expressed in typical MSCs, which sets them apart from hematopoietic stem cells. However, CD34 can be positively expressed in ADMSCs37. However, this evidence for MSCs is based on cultured MSCs and not tissue-resident MSCs37. It has been shown that CD34 is variably expressed in ADMSCs cultured as a monolayer, and cells gradually lose expression across various passages. After 8-12 passages, most cultures have completely lost expression of CD3437,38. Although CD34 expression has been shown to enhance the proliferation and migration of progenitor cells, little is known regarding the biological function of CD34 in ADMSCs39. The functional role of CD34 in ADMSCs must be further researched to understand how its presence and absence affect the therapeutic effect of these cells. ADMSCs help suppress the overactive immune system and promote an anti-inflammatory response. Their immunotherapeutic properties allow them to target T1D development in the body by reducing the expression levels of proinflammatory cytokines, which attack the ß-cells. The immunomodulatory, regenerative, and trophic effects make them attractive for T1D therapy.
Immunomodulatory effect of ADMSCs
T1D is an autoimmune disease in which auto-reactive T cells are the primary attackers. Novel T1D treatments aim to target these lymphocytes. By evading CD8+ T cell activation, ADMSCs are less likely to be targeted and destroyed, allowing them to persist longer in allogeneic environments. ADMSC’s low MHC class I molecules and lack of MHC class II molecules do not effectively activate the CD4 + T cells, inhibiting T cell proliferation and reducing the overall alloimmune response40. Furthermore, their secretome has growth factors like i.e., granulocyte colony-stimulating factor (GCSF), granulocyte-macrophage colony-stimulating factor (GMCSF), nerve growth factor (NGF), keratinocyte growth factor (KGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), or insulin-like growth factor 1 (IGF-1), antiapoptotic, antioxidative, and anti-inflammatory signaling molecules30. Studies indicate that ADMSCs can inhibit the self-reacting T-cell expansion, development of dendritic cells, and β cell proliferation by influencing the pancreatic microenvironment through immune modulation41,42. Ock et al. found that ADMSC were more potent immunomodulators and efficient in forming colonies due to their proliferative potential compared to bone marrow and dermal tissue derived MSCs43. Their interaction with innate and adaptive immune cells results in the downregulation of proinflammatory cytokines like IL-1β, TNFα, and IL-6 and the upregulation of anti-inflammatory cytokines such as IL-10, PGE2, or indoleamine 2, 3-dioxygenase (IDO)44. In addition, a negative feedback mechanism exists between the activated T cells that produce IFNγ and the ADMSCs. IFNγ secretion primes the ADMSCs against T cell proliferation, allowing the ADMSCs to evade detection by the immune system. Concurrently, this priming enhances their ability to maintain self-renewal and differentiation into multiple cell lineages, promoting effective allogenic tissue repair and regeneration45,46. Li et al. showed that ADMSCs decreased fasting blood glucose in STZ-induced T1D animals, increasing insulin expression46. Rahavi et al. showed in vitro ADMSCs inhibit splenocyte proliferation in a dose-dependent manner and preserve pancreatic islets’ viability and insulin secretion capabilities in the presence of reactive splenocytes47. Table 2 summarizes their immunomodulatory effects.
Table 2 Immunomodulatory effects of ADMSCs in T1D
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Treg regulation of ADMSCs
Individuals with T1D have reduced CD4+CD25+ regulatory T cell (Tregs) functionality48. These cells are essential in regulating the immune system, maintaining homeostasis, and tolerating self-antigens in T1D patients (Fig. 2)48.
The reduction of the Treg ratio by disrupting the B7/CD28 pathway has been shown to accelerate the onset of T1D in NOD mice49. At the same time, the expansion of Tregs in pancreatic lymph nodes was correlated with disease resistance50. Several experimental therapies for T1D have demonstrated a better outcome when there was an increase in the frequency of Tregs, especially CD4+CD25+FOXp3+ Tregs51,52,53. It has been demonstrated in NOD mice that ADMSC transplantation can induce the expansion and proliferation of CD4+CD25+Foxp3+ Tregs and reduce the Th1 immune response53, which can help improve blood glucose levels in early-onset T1D. In an experiment exploring the ADMSC therapy in T1D, Bassi et al. demonstrated that mice treated with ADMSCs had higher CD4 + FOXp3+Helios+ cells and a lower frequency of IFN-γ and TNF α in pancreatic lymph nodes54. These results helped demonstrate an efficient long-term immune regulatory effect of ADMSCs in T1D treatment.
Anti-inflammatory response of ADMSCs
Cytokines play a crucial role in orchestrating complex interactions between pancreatic β cells and immune cells in the development of T1D55. ADMSCs secrete high levels of anti-inflammatory cytokines, including IL-1Ra, IL-4, IL-10, TGF-β, and IL-1356. They are shown to induce the proliferation of a subset of CD5+ regulatory B cells that secrete immunosuppressive IL-10, which suppresses Th1-type cytokines (IL-2 and IFNγ)57. ADMSC transplantation has also been reported to induce M2 macrophage polarization; proliferation of CD4+ and CD8 + T-cells; inhibition of monocyte-derived dendritic cells; B cell and natural killer cell differentiation and maturation; and reduction of macrophage and neutrophil infiltration into inflammation sites46.
Immune checkpoint blockades released by ADMSCs
MSCs express different types of immune checkpoint blockade inhibitors and their ligands, which allows them to influence cells of the adaptive and innate immune system, thus playing an important role in immunomodulation, as illustrated in Table 3.
Table 3 Immune Checkpoint Blockers released by ADMSCs
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While PD-1/PD-L1 inhibitors remain prominent in treating non-small cell lung cancer, as discussed by Li et al.58 and Paz-Ares et al.56 researchers are increasingly exploring additional immune checkpoint pathways. These include: avelumab for Merkel cell carcinoma59, TIM3 as an emerging cancer target60, ICOS/ICOS-L costimulatory pathway61, A2aR antagonists as next-generation checkpoint therapy62, TIGIT for melanoma treatment63, BTLA in NSCLC therapy58,64, TNFR265, IDO inhibitors66,67, and CD47 for NSCLC and metastatic cancers as shown by Lau et al., and Lian et al.68,69, Hazrati et al. Address MSCs’ therapeutic and immunomodulatory potential through immune checkpoint-related molecules, representing a comprehensive examination of how MSCs expressing these molecules could be leveraged for treating various cancers, with NSCLC, melanoma, and Merkel cell carcinoma being the primary disease targets. Recent studies have been successful in showing why pre-treated MSCs in inflammatory conditions (treated by TNFα and IFN-γ) lead to increased immune checkpoints, ligand expression on the MSC surface, and, thus, an overall increase in the cells’ immunomodulatory potential70,71,72. The impacts of the proinflammatory environments on the production of anti-inflammatory cytokines and their effects on the signaling pathways lead to an increased expression of immune checkpoint blockades and ligands on MSC surfaces73. Negative immunological checkpoint receptors like cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 are key in giving inhibitory signals for potentially autoreactive T cells74. A study by Kawadi-Horitani et al. demonstrated that the systemic application of ADMSCs with an anti-PD-L1 monoclonal antibody (mAB) reduced the incidence of developing T1D in male NOD mice from PD-1/PD-L1 blockade-induced T1D from 64% to 19%75. Their systemic injections partially protected the pancreas from β cell loss and preserved insulin content76. Their results were in line with what has been shown in a study exploring the T lymphocyte infiltration in pancreatic islets of a patient who developed T1D after being administered with immune checkpoint inhibitors77. They showed a substantial increase in T cell positive area and accumulated CXCL9 positive macrophages78 in pancreatic islets when injected with anti-PD-L1 mAb induced T1D without ADMSCs. A separate study showed that CD8-positive T cells secrete IFN-γ in response to PD-1 blockade, which activates infiltrated monocyte-derived macrophages to accelerate the progression of T1D53,79.
Regenerative potential of ADMSCs
ADMSCs secrete bioactive growth factors, chemokines, and cytokines that help ameliorate metabolic abnormalities linked to T1D80. Possible mechanisms by which ADMSCs have been shown to improve hyperglycemia include islet β-cell regeneration, modulation of hepatic metabolism toward higher glucose utilization, reduction of inflammation, and amelioration of insulin resistance in peripheral tissues81. One key mechanism is their potential to differentiate into insulin-producing cells (IPCs), which has been demonstrated in vitro and in transplantation models (Fig. 2)81. However, these ADMSC-derived IPCs differ from primary β cells in their functionality. While they express key β cell markers such as PDX1, NKX6.1, and MAFA, their insulin secretion in response to glucose stimulation is often lower than that of native β cells. Compared to iPSC-derived β cells, ADMSC-derived IPCs exhibit lower insulin content and glucose responsiveness, highlighting the need for further optimization of differentiation protocols. Functional assessments of these IPCs have primarily been conducted in vitro through glucose-stimulated insulin secretion assays and in vivo transplantation studies in diabetic mouse models, showing partial glucose regulation and increased C-peptide levels. They also have the potential to facilitate endogenous β cell regeneration, preservation of residual β cell mass preservation, and improved islet graft acceptance82. Pre-clinical and clinical trials have shown effective β cell regeneration and preservation due to the paracrine release of trophic, immunomodulatory, and anti-inflammatory factors in the cells83,84. Furthermore, ADMSCs have been reported to promote β cell proliferation by enhancing the expression of pancreatic progenitor markers such as Ngn3 and NeuroD1, which are crucial for β cell neogenesis23. ADMSC-differentiated IPCs have been shown to induce insulin secretion and increase C-peptide, which is linked with alleviated hyperglycemia14. The regenerative and immunomodulatory properties of ADMSCs extend to β cell proliferation and restoration. The application of ADMSCs has shown increased activity of regulatory T cells and decreased autoreactive T cells, helping limit the autoimmune destruction of β cells41. Studies have also demonstrated increased pancreatic islet regeneration in T2D models85.
Genome engineering strategies have been explored to enhance ADMSC function for T1D therapy. Techniques such as viral and non-viral vectors and CRISPR/Cas9 have been employed to modify ADMSCs for improved immune evasion and therapeutic efficacy. Beyond the reported modifications involving IL-10 and CXCL4, additional studies have investigated overexpression of PDX1, NKX6.1, and MAFA to drive β cell-like differentiation and enhance insulin secretion86. However, the full potential of genome editing in ADMSCs remains underexplored. More studies are required to determine how genetic modifications impact ADMSC stability, differentiation potential, and long-term regenerative capacity. Notably, concerns remain regarding the unintended effects of genome editing on the epigenetic landscape of ADMSCs, which could influence their differentiation potential and safety profile. Addressing these challenges will be essential for optimizing genetically engineered ADMSCs for clinical applications.
Sen et al. demonstrated that delivering superoxide dismutase using ADMSCs as a gene delivery vehicle reduced inflammation, improved glucose tolerance, and enhanced homing in inflamed adipocyte pockets in vivo in mice86. These findings highlight the potential of ADMSCs as vehicles for targeted gene therapy in T1D. However, additional studies are needed to explore broader applications of genetic engineering in ADMSC-based therapies and assess long-term effects on cell function and stability.
Trophic activity of ADMSCs
The ability of ADMSCs to supply reparative cytokines and bioactive growth factors is superior in stimulating cell proliferation and differentiation87 compared to other MSCs. ADMSCs secrete growth factors like KDR, VEGF87, TGF-β, IL-8, HGF, KDR, and IGF-1. These factors promote angiogenesis, support the success of islet graft transplantation, and promote the production of IL-1Ra, IL-8, and HGF. The antiapoptotic and proangiogenic factors secreted by ADMSCs, such as VEGF88,89,90, IGF91,92, TGF-β86,93, and GM-F94, also add to their therapeutic benefits when used in islet transplantation for T1D14. However, culture conditions significantly affect ADMSC characteristics, including their growth capacity, surface marker expression, and therapeutic potential95. An increase in pancreatic duodenal homeobox (PDX-1) seen in multiple studies conducted in vitro in animal models23,30 is known to play a role in β cell differentiation by regulating normal pancreatic development and improving survival of graft transplants in STZ-induced diabetic mice96,97.
Understanding the effects of ADMSC on the bioenergetics of the target cells is also essential98, since cells affected by stress (e.g., diabetes condition) may have higher energetic demands, which can put cells under stress, impairing their repair and replication processes99. For instance, BMMSC treatment is shown to increase the bioenergetic capacity of the stressed cells through increased efficiency of oxidative phosphorylation and the TCA cycle100. It can be hypothesized that ADMSCs exhibit similar behaviors due to similar characteristics, but further research is necessary.
ADMSCs-derived extracellular vesicles (EVs)
Along with mediating intercellular communications, the molecular composition of EVs mirrors the effects of the parent cells, which makes them a valuable tool for diagnostic and therapeutic applications101. MSC-derived EVs contain bioactive cargos that provide therapeutic effects in Type 1 diabetes through dual mechanisms of immunomodulation and β-cell regeneration102. They carry functional miRNAs (miR-21, miR-106b-5p, miR-222-3p)103,104 and proteins like VEGFA that activate beneficial signaling pathways (PI3K/Akt/eNOS, GSK-3β)105 while inhibiting inflammatory ones (p38 MAPK, NF-κB)106. These molecular signals upregulate key pancreatic transcription factors (PDX1, PAX4, NeuroD) and survival proteins (Bcl-2, HIF-1α)107,108, collectively enhancing β-cell proliferation, insulin secretion, and islet survival—positioning MSC-EVs as promising therapeutic candidates for T1D treatment.
Bone marrow-derived MSC-EVs (BMMSC-EVs) and adipose-derived MSC-EVs (ADMSC-EVs) are the two most studied sources of MSC-derived EVs. While they share overlapping regenerative functions, they exhibit distinct molecular compositions and therapeutic effects. Studies comparing their regenerative capacity, immunomodulatory properties, and angiogenic potential have identified common signaling pathways, including VEGF109,110 and AKT-related pathways111,112. However, BMMSC-EVs tend to contain a broader range of protein types113, with higher levels of VEGFA, FGF-2, and PDGF-BB114, and they have been shown to enhance IL-10 secretion by 1.8-fold compared to ADMSC-EVs115, contributing to their potent immunosuppressive effects. In contrast, ADMSC-EVs exhibit higher levels of CD63 and phosphatidylserine116 and are enriched in hepatocyte growth factor (HGF), which supports tissue repair and anti-apoptotic functions. Their higher yield and accessibility make them attractive for scalable clinical applications.
Beyond EVs, MSCs release a wide array of bioactive molecules, collectively known as the MSC secretome, which plays a crucial role in their therapeutic potential. This secretome includes soluble proteins, cytokines, chemokines, growth factors, and metabolites that complement the effects of EVs. The MSC secretome contributes to β-cell regeneration by promoting proliferation, survival, and insulin secretion while modulating immune responses in T1D117. Among the key components, transforming growth factor-beta (TGF-β), IL-10, and prostaglandin E2 (PGE2) exert immunosuppressive effects, reducing autoreactive T-cell activation and fostering a tolerogenic microenvironment. Additionally, EV-contained cargo, such as miRNAs (e.g., miR-21, miR-146a, miR-155) and proteins (VEGFA, IGF-1, HGF), mediate islet protection, angiogenesis, and anti-inflammatory responses, ultimately enhancing β-cell function and islet survival118.
ADMSC-derived EVs exhibit the same immunoregulatory and multipotent properties as their parental cells, making them appealing as potential “mobile” drug delivery systems119. In 2018, Nojehdehi et al. demonstrated that in vivo intraperitoneal application of EVs derived from autologous ADMSCs ameliorated the autoimmune response in T1D mice120. Their study showed a significant increase in the levels of anti-inflammatory cytokines (TGF-β, IL-4, and IL-10) and a significant reduction in the production of pro-inflammatory cytokines (IL-17 and IFN-γ) without any significant changes in the stimulation index of tested mononuclear cells120. Another study conducted in 2021 by Gesmundo et al. demonstrated that ADMSC-derived EVs promoted β-cell proliferation and insulin secretion in INS-1E β cells and human pancreatic islets, even without cytokine exposure121. Similarly, Arzouni et al. reported improved glycemic control and islet function following administration of ADMSC-derived EVs in vivo, 28 days post-islet graft transplantation in mice122,123. Their findings also showed that these EVs improved insulin secretory function in both mouse and human islets in vitro124,125. By leveraging their unique cargo and immunomodulatory potential as summarized in Table 4, MSC-derived EVs—particularly those from ADMSCs and BMMSCs—offer a promising avenue for β-cell protection and regeneration in T1D treatment. However, further comparative studies are necessary to optimize their therapeutic potential for clinical applications.
Table 4 Immunomodulatory effects of ADMSC-EVs in T1D
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Route of administration of ADMSCs
The route of administration significantly influences the therapeutic potential of ADMSC treatment119. Intravenous injection (IV) is the most examined route126. However, it is associated with MSC entrapment in the lungs and in the reticuloendothelial system (RES) organs, such as the spleen, liver, bone marrow, thymus, and skin127,128,129. The human body’s defense mechanism in circulation and tissues, and the RES cells play an essential role in the clearance of substances130. Thus, IV administration is associated with less therapeutic efficacy126,130,131 and some organ-specific complications. Lung accumulation causes pulmonary and hemodynamic alterations in lung vessels130,132 that hamper the ability of MSCs to reach the pancreas101 and other target organs133. This entrapment is also a result of interactions between the MSC adhesion molecules and the ligands in the endothelium103, causing nonspecific accumulation. Another reason for the microembolization is that the average size of the injected MSCs is greater than that of the pulmonary capillaries134.
Hashemi et al. conducted a study that investigated the effects of intraperitoneal (IP) and IV infusion of ADMSCs and MSC-Conditioned Medium (CM) on the C57B1/6 male mice130. They measured the blood urinary glucose, body weight, and percentages of CD4 + CD25 + FOXP3 + T cells, IFN-γ, TGF-β, IL-4, IL-17, and IL-1. Their study showed significant (p < 0.05) amelioration of hyperglycemia at 6 weeks after injection and a significant increase in the number of insulin-positive islets in the CM–IP. Their results also indicated that IP-injected MSCs had a more significant impact on splenocyte suppression than IV-injected MSCs and higher levels of anti-inflammatory cytokines than the ADMSC–IV group, which could result from mesenteric circulation absorption130.
Khatri et al. studied the MSCs in direct and indirect contact with pancreatic islets and evaluated the protective aspect of MSC administration through the intrapancreatic and IV routes135. In vitro, examination of STZ-damaged MIN6-cells showed superior protection to the cells from STZ through the AKT/ERK pathways involved in mitogenic signaling in the presence of MSCs. They also showed that the IPR route of administration in vivo resulted in a higher proliferation in pancreatic islets and balance in the Th1/Th2 response. In line with other experiments128,136,138,138, they demonstrated in vitro an upregulation of EGF and IL-10 and a downregulation of IL-1β and TNF-α; thus, the ADMSC secretome impeded the proapoptotic microenvironment. Additionally, Schröder et al. demonstrated that histone deacetylase inhibitors can enhance the differentiation potential of mesenchymal stem cells toward pancreatic endocrine lineages, with the broad-spectrum inhibitor LBH589 significantly upregulating key transcription factors Isl1 and Pax6 while reducing uncontrolled proliferation139. Another team also demonstrated that direct intra-arterial administration of ADMSCs into the pancreas could maintain glycemic regulation in an STZ-induced preclinical diabetic rat model140 better than when the same therapy was given via an IV route.
In an in vivo study, Yaochite et al. evaluated the long-term therapeutic efficacy and biodistribution of ADMSCs administered through intrasplenic and intrapancreatic routes141. They found that the intrasplenic route reversed hyperglycemia in 70% of diabetic mice, compared to 42% with the intrapancreatic route141. The intrapancreatic route was chosen to deliver ADMSCs directly to the pancreas. The intrasplenic route aimed to deliver therapeutics to the pancreas137 via the splenic artery and promote the modulation of splenocytes to reduce the immunogenic response to the β cells. This principle also aligns with a study that showed NOD mice treated with irradiated splenocytes that exhibited normoglycemia also exhibited the reappearance of pancreatic islets without invasive insulitis142, thus highlighting the role of the splenocytes in promoting β cell proliferation. Histological analysis of the pancreas 70 days after ADMSC administration showed that the β cell mass and insulin production from the intrasplenic route were significantly higher than the intrapancreatic route. There were also increased TGF-β levels in the pancreas in the group administered the ADMSCs through the intrasplenic route.
Clinical trials using ADMSCs
The success of ADMSCs in treating T1D in preclinical research has led to their application in the clinical setting, where their therapeutic potential is further investigated. ADMSCs’ regenerative properties have been tested for treating a range of conditions, including rheumatoid arthritis (NCT01663116, NCT03691909), tissue damage (NCT02298023, NCT02784964), and skin wounds (NCT02394873, NCT02092870), along with many others.
There are 409 registered clinical trials analyzing the potential of ADMSC-based therapies (search: adipose-derived stem cells https://clinicaltrials.gov/, accessed on 24 July 2024). Of these, only four studies are for T1D (results have been posted from three). These trials analyze the safety and efficacy of both autologous and allogeneic ADMSC treatment, administered IV, for decreasing insulin dependence in patients with T1D (Table 5). ADMSCs were collected from healthy adults in all trials, and IVs were injected into the patient’s arm. In NCT03920397, an oral dose of cholecalciferol 2000UI/day was also administered, leading to partial clinical remission in all patients receiving the combined treatment. This study defined partial clinical remission by an IDAA1c index < 9. Gabbay et al. studied combined treatments with cholecalciferol and insulin, finding patients in the combined treatment group to have higher levels of CCL2 serum and regulatory T cells. The increase in these levels may correspond to the delayed destruction of β cells. With ADMSCs, an oral vitamin dose has led to C peptide stability, preservation of T-cells, reduced insulin dependence, and lower HbA1c levels in patients143.
Table 5 Clinical Trials of ADMSCs
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The ISCT has provided minimal criteria for defining ADMSCs, leading to variation in proliferation rates, cell quality, immunomodulatory effects, cellular composition, and CD marker expression144,145,146,147. This variability is a challenge for clinical application due to inconsistencies between studies. To accelerate the use of ADMSCs in the clinic, a set of quality control criteria must be implemented to define them, along with standardized assays and culturing methods147,148,149.
The use of MSCs in a clinical setting is also associated with ethical concerns. An article examining MSC-related complications like pulmonary embolism and tumor formation stressed the need to focus on the safety issues and complications associated with the clinical translation of MSCs150. This also extends to considerations for recruiting appropriate subjects, avoiding misconceptions regarding MSC therapeutic potency, and facilitating informed decisions regarding consent forms151.
Future prospects
ADMSCs have immense therapeutic potential152, but minimal protocol standardization and clinical understanding limit their applications. Before these treatments can be granted routine therapeutic approval, further research with more subjects and larger time frames must be completed, along with standardized ADMSC procedures. Moreover, several aspects require further investigation to optimize their therapeutic potential.
Different ADMSC collection methods and patient characteristics lead to varied results across cells, even when treated with similar procedures153. Not only for clinical applications but in pre-clinical research, variation in cell origins, culturing conditions, and obtainment procedures increase the difficulty of comparing across research outcomes or applying results to a clinical setting153. Thus, a standardized ADMSC collection, culture, and isolation protocol must be established before their application in the clinic. Further, understanding how donor characteristics (age, genetics, comorbidities, and general health) affect the function of collected cells is imperative to determine donor criteria154. Also, understanding how patient-specific factors influence ADMSC therapy outcomes is crucial for personalizing treatment approaches. Lipogems® is trying to redefine the use of adipose tissue by harnessing its regenerative powers with a new approach. Lipogems® obtains micro-fragmented adipose tissue through a minimally invasive procedure, yielding tissue with highly regenerative MSCs. After the tissue has been washed, it is emulsified, yielding adipose clusters between 0.3 and 0.8 mm that can be implanted into the body155. This technique has been clinically available since 2010 and suggests a possible route to continue studying the potential of ADMSCs to treat T1D. Although Lipogems® has been mainly used in cosmetic and orthopedic procedures, it is important to understand how their collection process may help improve ADMSC therapy availability.
Numerous studies suggest that altering the culture conditions of MSCs can enhance their therapeutic potential156,157,158. Cultivating MSCs in 3D cultures is reported to boost their immunomodulatory function159 and EV production160. Hazrati et al. showed that a multicellular spheroid 3D culture increases the angiogenic potential of the MSCs by inducing the production of CXCL12, HGF, VEGF, and FGF-2, improves MSC survival due to a higher binding rate than single-celled suspensions, and decreases expression of pro-inflammatory cytokines91,161. Patel et al. found that a lower seeding density of MSCs led to higher EV yield143. Hypoxia priming of MSCs is beneficial to their therapeutic use155. Studies show that using hypoxia158,162,163 and inflammatory conditions164 as a preconditioning tool can enhance MSC pro-survival markers and increase the release of growth factors and chemo-attractants involved in cell proliferation158,165. Specific studies analyzing these results in ADMSCs are imperative to understanding how these cells respond to the pre-treatments. These pre-treated ADMSCs in T1D therapeutics may increase their efficacy and decrease dosage requirements164. Thus, standardization and optimizing the ex vivo expansion and preparation of ADMSCs can significantly impact their therapeutic efficacy146,147.
While ADMSCs offer promising regenerative and immunomodulatory effects, concerns remain regarding their potential role in tumorigenesis. Their ability to secrete high growth factors, including VEGF, FGF, and HGF, which promote angiogenesis and cell proliferation, has raised concerns about their possible involvement in supporting tumor growth or therapy resistance. Some studies suggest that MSCs can contribute to tumor progression by interacting with the tumor microenvironment, enhancing cancer cell survival, and promoting metastasis in certain conditions57,166. For instance, MSCs have been shown to facilitate epithelial-to-mesenchymal transition (EMT) in some cancers, associated with increased invasiveness and resistance to therapy167. Although ADMSC-based therapies have not been directly linked to tumor formation in clinical trials, further long-term studies are necessary to ensure their safety. Future research should focus on identifying markers that distinguish pro-regenerative from pro-tumorigenic MSCs and evaluating strategies to mitigate any potential risks associated with ADMSC therapy. CD markers and secretory signatures might help establish more robust characterization criteria for ADMSCs. For instance, understanding CD34’s biological function might better guide researchers in understanding how passage numbers affect therapeutic potential165. Furthermore, identifying and selecting ADMSCs with specific surface markers that indicate their functional status might help their immunomodulatory and regenerative properties.
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Acknowledgements
R.Y. is supported by the Lundbeck Foundation grant R303-2018-3148.
Author information
Authors and Affiliations
Translational Type 1 Diabetes Research, Department of Clinical and Translational Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
Vanshika Sood, Hannah Ricioli, George Chigozie Njoku, Flemming Pociot & Reza Yarani
Department of Science & Health, DIS Study Abroad in Scandinavia, Copenhagen, Denmark
Vanshika Sood, Susana Dietrich & Reza Yarani
Department of Neuroscience, Washington and Lee University, Lexington, VA, USA
Vanshika Sood
Department of Biology, Stanford University, Stanford, CA, USA
Hannah Ricioli
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA
George Chigozie Njoku
Interventional Radiology Innovation at Stanford (IRIS), Department of Radiology, School of Medicine, Stanford University, Stanford, CA, USA
Rosita Primavera, Avnesh S. Thakor & Reza Yarani
Contributions
V.S. and R.Y. conceptualized, conceived, and planned the review. V.S. and H.R. reviewed the literature and wrote the manuscript’s first draft. G.C.N., visualization, writing, review, and editing. R.P., review and editing. S.D., review and editing. A.S.T., review and editing. F.P., review, and editing. R.Y., project administration, supervision, writing, review and editing, visualization.
Corresponding author
Correspondence to Reza Yarani.
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Competing interests
AST is a cofounder and holds stock options for Teal Health and is on the Scientific Advisory Board, received grants, or is a consultant for RespondHealth Inc, Cellular Vehicles Inc, Nephrogen Inc, ReThink64 Inc, AlloTRx Inc, Inari Inc, and Genentech Inc. The other authors declare no competing interests.
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