Diabetes mellitus has emerged as a significant chronic disease worldwide that imposes substantial social and economic burdens. In 2021, around 537 million adults aged 20-79 were reported to have diabetes (1), including approximately 8.4 million with type 1 diabetes (T1D) (2). T1D, a chronic autoimmune disease, necessitates lifelong management via daily insulin injections or continuous infusion through a pump (3). Despite advancements, precise insulin dosage control remains challenging for some patients, leading to the risk of hypoglycemia and further complicating treatment (4). The FDA approval of Lantidra, the initial allogeneic pancreatic islet cell therapy product derived from deceased donors, marked a significant innovation in islet transplantation, offering new hope for T1D patients struggling with severe hypoglycemia despite intensive diabetes management (5, 6). This development not only signifies a breakthrough in transplantation technology but also provides an effective alternative treatment for adult T1D patients who cannot reach the desired glycated hemoglobin levels.

Islet transplantation, as an innovative treatment, offers T1D patients the potential to restore endogenous insulin production, reducing reliance on exogenous insulin and preventing long-term complications (7). This minimally invasive method has shown effectiveness beyond traditional treatments (8), with some centers reporting over 50% insulin independence after five years (9, 10). However, challenges remain, including donor cell scarcity, substantial cell loss post-transplantation due to immediate blood-mediated inflammatory reactions, hypoxia, and ischemia-reperfusion injury, as well as complications from immunosuppressants (11). Consequently, achieving optimal glucose control often necessitates multiple transplants.

Recent strides in regenerative medicine have identified mesenchymal stem cells (MSCs) as key players in overcoming these obstacles (12). Due to their multipotency, immunomodulatory properties, and low immunogenicity, MSCs derived from bone marrow, adipose tissue, and umbilical cord blood have demonstrated potential for enhancing islet graft survival, modulating immune responses, and promoting tissue repair and angiogenesis (13). This has been evidenced by their capacity to differentiate into different cell types, such as cells that produce insulin, and their secretion of a vast array of regenerative factors, making them promising candidates for co-transplantation with pancreatic islets (14). The immunomodulatory properties of MSCs, which are pivotal for modulating immune responses and fostering tissue repair, have been extensively documented, suggesting a significant reduction in transplant rejection risk (15, 16). Additionally, the therapeutic versatility of MSCs has been explored in various disease contexts, including cardiovascular diseases and liver injury, further supporting their broad potential in regenerative medicine.

Moreover, the exploration of MSC-derived exosomes represents an advancement in therapeutic strategies for pancreatic islet transplantation, highlighting a new direction in MSC-based treatments (17). These exosomes, as carriers of regenerative and immunomodulatory factors, present a novel approach to enhancing the microenvironment of transplanted islets, potentially reducing immunological rejection and supporting islet cell survival and function. This advancement in MSC-derived exosome research illustrates the ongoing innovation in treatment methodologies, aiming to address the complex challenges of islet transplantation in diabetes management.

The comparison between MSCs, induced pluripotent stem cells (iPSCs), and embryonic stem cells (ESCs) highlights their distinct roles in diabetes treatment. MSCs are favored for their immunomodulatory properties and minimal tumorigenic risk, presenting a safer option for clinical applications. Unlike MSCs, iPSCs and ESCs possess greater pluripotency, enabling the generation of a broader range of cell types. However, this approach is associated with increased ethical concerns for ESCs and increased tumorigenic potential for both iPSCs and ESCs (18, 19). Compared to their broader differentiation capabilities, the unique advantages of MSCs in regenerative medicine, particularly in mitigating autoimmune responses in diabetes, are the heightened risks associated with iPSCs and ESCs.

To enhance our understanding of MSC therapies, particularly in the realms of diabetes treatment and islet transplantation, advanced technologies such as artificial intelligence (AI) and single-cell RNA sequencing (scRNA-seq) offer groundbreaking approaches (20, 21). These innovations allow for the precise characterization of MSCs and in-depth analysis of their molecular behaviors, which is crucial for developing personalized, effective therapies. By incorporating findings from a recent study that utilized scRNA-seq to analyze immune heterogeneity in mouse models of islet transplantation, we obtained valuable insights into the immune mechanisms that may affect graft survival (22). The insights of this study into the transcriptomics of islet grafts underscore the potential of scRNA-seq for identifying key factors influencing the success of MSC therapies, highlighting the importance of these advanced methodologies in advancing personalized medicine and improving diabetes care strategies.

This review not only highlights the potential of MSCs in enhancing diabetes treatment through islet transplantation but also addresses persistent challenges such as MSC heterogeneity and the need for therapeutic optimization. This finding underscores the promise of advanced methodologies such as AI and scRNA-seq for overcoming these hurdles, suggesting that MSC therapy could offer more effective, personalized diabetes treatment solutions in the future.

In islet transplantation for diabetes treatment, MSCs play a vital role by safeguarding islet cells and improving the outcomes of both allo- and xenotransplantation (29–31). The broad array of secreted molecules, including growth factors and immunomodulatory agents, contributes to enhancing transplantation efficacy and survival (32). During regeneration, these secretory factors facilitate tissue remodeling and promote cellular homeostasis. This multifaceted action of MSCs addresses key challenges in islet transplantation, including reducing graft rejection and improving graft performance, thus enhancing the efficacy of diabetes treatments (33, 34). Moreover, the potential of MSCs for novel therapeutic strategies marks an advancement in diabetes management, suggesting that MSCs are important elements in both regenerative medicine and autoimmune therapy. The role of MSCs in enhancing outcomes in diabetes patients through islet transplantation is critical, as they emphasize the broad therapeutic potential of these cells and open new paths for diabetes care advancements.

The exploration of the use of MSCs in diabetes treatment, particularly through islet transplantation, highlights their potential for advancing therapeutic strategies. MSCs are at the forefront of regenerative medicine and autoimmune therapy, offering innovative approaches to improve patient outcomes in diabetes care. Their broad therapeutic capabilities and potential for new pathways in diabetes management underscore their role in the field.

The integration of MSCs into pancreatic islet transplantation protocols has been the focus of numerous studies, revealing substantial improvements in transplantation outcomes (34). These cells have demonstrated the capacity to enhance both the engraftment and survival rates of transplanted islets as well as their long-term functionality, which is important for successful transplantation. MSCs exert beneficial effects through immunomodulatory effects, mitigating immune-mediated rejection and autoimmune attacks. Additionally, MSCs promote a supportive microenvironment for islets by stimulating angiogenesis and tissue repair, addressing the challenges of islet transplantation and advancing diabetes treatment modalities.

The integration of MSC therapy into clinical practice presents scientific and ethical challenges, including complexities and potential risks such as immunogenicity and tumorigenicity. Examining these obstacles and emphasizing the importance of rigorous selection, ethical sourcing practices, and adherence to regulatory guidelines will ensure safety and efficacy. This highlights the necessity of continuous research, ethical deliberation, and regulatory updates to optimize MSC therapies for diverse conditions, particularly diabetes treatment through islet transplantation.

Despite the promising potential of MSCs in regenerative medicine and diabetes treatment, MSCs face significant challenges that hinder their clinical translation. These include their inherent heterogeneity, which complicates the consistency of therapeutic outcomes, and concerns about immunogenicity that may elicit immune responses in recipients (42). Additionally, the potential for MSCs to contribute to tumorigenesis remains a critical area of investigation (43). It is important to critically evaluate these challenges, drawing upon data from past clinical trials and current research, to provide a comprehensive understanding of the limitations and barriers facing the use of MSCs in islet transplantation. This underscores the complexity of translating MSC therapy from bench to bedside and emphasizes the need for continued research to overcome these obstacles.

The ethical implications of MSC sourcing involve considerations such as donor consent, particularly for MSCs derived from human tissues (44). Ethical sourcing ensures that donors are fully informed and agree to the use of their cells for research or therapeutic purposes. Regulatory policies for MSC therapies, governed by agencies such as the FDA and the European Medicines Agency, focus on ensuring the safety, efficacy, and quality of MSC-based products (45). These regulations necessitate rigorous clinical trials and manufacturing standards to prevent risks such as immunogenicity and tumorigenicity, aiming to safeguard patient health while fostering innovation in MSC therapy development.

The progression of MSCs from early preclinical studies to clinical applications illustrates both their potential and the complexities involved in MSC therapy. Despite advancements, challenges affect their clinical success (42). In diabetes treatment, especially islet transplantation, the variability and adaptability of MSCs require careful clinical evaluation. The variability of MSCs due to their different sources, preparation methods, and delivery techniques poses significant challenges to their standardization and consistency in therapies (46, 47). To minimize heterogeneity and improve the predictability of outcomes, it is important to explore strategies and potential guidelines, such as stringent cell characterization, uniform culture conditions, and standardized delivery methods (48). Emphasizing the need for comprehensive quality control and clinical protocol standardization will offer insights into advancing MSC therapies toward more reliable and effective clinical applications, thus enhancing their utility in regenerative medicine and beyond. Innovations such as AI (49) and scRNA-seq (50) are promising methods for addressing these obstacles, indicating that MSC therapy might become a standard, personalized treatment option for diabetes in the future (Figure 1).

This review underscores the significant impact of MSCs on islet transplantation for diabetes treatment. This finding highlights the role of MSCs in enhancing islet graft survival, modulating immune responses, and promoting angiogenesis and tissue repair, indicating their potential for use in diabetes management. Challenges such as MSC heterogeneity and the need for optimization in therapeutic applications are acknowledged, with advanced technologies such as AI and scRNA-seq offering promising solutions. The synergy between MSCs and islet transplantation is emphasized as a forward-looking approach to personalized, MSC-based interventions, setting a new direction in therapeutic strategies against diabetes.

LM: Funding acquisition, Writing – original draft, Writing – review & editing. TW: Writing – review & editing. XW: Conceptualization, Funding acquisition, Writing – original draft, Writing – review & editing. ZP: Conceptualization, Writing – original draft, Writing – review & editing.