Stem cells-derived islet transplantation toward clinical translation: Divergent strategies and convergent objectives

Figure 1 Schematic diagram of current stem cell-derived islet transplantation strategies. Xenotransplantation: Animal-derived islets (e.g., porcine) are isolated and directly infused into the patient. This strategy addresses donor organ shortage but faces significant challenges related to xenoimmunity, including hyperacute rejection and zoonotic infection risks, as well as ethical and regulatory hurdles. Allogeneic transplantation: Donor-derived islets from human cadavers are isolated and infused into the patient. While clinically established, this approach is severely limited by donor scarcity and requires lifelong systemic immunosuppression to prevent allograft rejection. Allogeneic stem cell transplantation: Human pluripotent stem cells [PSC; embryonic stem cells or induced PSCs (iPSCs)] are directed to differentiate into insulin-producing islet cells in vitro. Advanced protocols incorporate gene-editing techniques (e.g., CRISPR/Cas9) to reduce immunogenicity by disrupting human leukocyte antigen molecules or overexpressing immune checkpoint proteins (e.g., programmed death-ligand 1, CD47). The resulting “off-the-shelf” cell products enable standardized large-scale manufacturing but still typically require some level of immunosuppression, depending on the engineering strategy. Autologous stem cell transplantation: The patient’s own somatic cells (e.g., fibroblasts, peripheral blood mononuclear cells, or adipose-derived mesenchymal stem cells) are reprogrammed into iPSCs, which are then differentiated into islet cells and reinfused into the same patient. This personalized approach eliminates the need for immunosuppression and avoids allogeneic rejection, but is constrained by lengthy manufacturing timelines, high costs, and limited scalability. Created in BioRender (Supplementary material). SC: Stem cells; MSC: Mesenchymal stem cell; iPSC: Induced pluripotent stem cells; Tx: Transplantation; Allo: Allogeneic; Auto: Autologous; Xeno: Xenogeneic; 3D: Three-dimensional.

Figure 2 Roadmap for future development of stem cells-based diabetes therapy. This figure illustrates four key strategic directions aimed at advancing the clinical translation and efficacy of stem cell-derived islet (E-islet) transplantation. Gene editing strategies and related technologies to modify E-islets, reducing immunogenicity and enhancing immune compatibility. Microenvironment modulation creates a supportive niche, improving graft survival, vascularization, and long-term function. Establishment of standardized manufacturing process includes procedures, such as cell culture, differentiation, purification, and final formulation for clinical administration. Advanced cryopreservation techniques develop optimized freezing and rewarming protocols to ensure stable preservation, facilitate logistics, and improve the accessibility of islet products. Gene editing: Genetic modification of E-islets to reduce immunogenicity and enhance immune compatibility. Key approaches include CRISPR/Cas9-mediated gene editing, human leukocyte antigen-I knockout to evade CD8⁺ T cell recognition, and programmed death-ligand 1 overexpression to induce local immune tolerance. The goal is to create “immune-evasive” islet cells that survive without systemic immunosuppression. Microenvironment modulation: Creation of a supportive niche at the transplantation site to improve graft survival and function. Key approaches include anti-inflammatory agents, IgG silencing technology to prevent humoral rejection, biomaterial scaffolds, and mesenchymal stem cell co-transplantation to provide immunomodulatory and pro-angiogenic support. The goal is to protect islets during the critical early post-transplant period. Standardized production: Establishment of robust manufacturing processes for scalable clinical deployment. Key components include optimized cell culture, directed differentiation with QC checkpoints, purification, final formulation, and comprehensive quality testing. The goal is to enable “off-the-shelf” availability through reproducible and cost-effective manufacturing. Cryopreservation techniques: Development of optimized protocols for long-term storage and transportation of islet products. Key approaches include vitrification, optimized rewarming protocols, cell isolation and retrieval methods, and specialized injection solutions. The goal is to enable centralized manufacturing, global distribution, and on-demand availability. Created in BioRender (Supplementary material). HLA: Human leukocyte antigen; KO: Knockout; PD-L1: Programmed death-ligand 1; OE: Overexpression; TNF: Tumor necrosis factor; IL-1Ra: Interleukin-1 receptor antagonist; IgG: Immunoglobulin G.