Diabetes mellitus remains a leading cause of morbidity worldwide, driven in type 1 diabetes by autoimmune destruction of pancreatic β-cells and in advanced type 2 diabetes by progressive β-cell dysfunction and failure. Diabetes affects around 830 million people globally, with the vast majority residing within low- and middle-income nations. Over the last few decades, the numbers of people who have diabetes and those with untreated diabetes have consistently increased. Although current pharmacologic therapies improve glycemic control, they do not restore functional β-cell mass. Consequently, strategies aimed at protecting, regenerating, or replacing insulin-producing cells have emerged as a major focus of regenerative medicine. Stem cell-based approaches offer the potential to generate renewable sources of glucose-responsive β-like cells, but challenges remain in achieving full functional maturation, immune protection, scalable manufacturing, and durable clinical engraftment. This review examines advances in engineering stem cell-derived insulin-producing cells for islet replacement therapy, with an emphasis on differentiation strategies, immunoprotective approaches, and the translational barriers that must be addressed for durable β-cell replacement.

Introduction: Adult pancreatic tissue contains cell populations with latent regenerative potential, but the processes governing their expansion and differentiation into endocrine lineages remain unclear. Methods: Adult human pancreatic cells obtained from donor tissue were isolated and expanded and analyzed for lineage potential using single-cell RNA sequencing, flow cytometry, and functional assays. A CD9 ⁺ PROCR ⁺ RGS16 ⁺ subpopulation, termed islet progenitor-like cells (IPCs), was evaluated for proliferative capacity and differentiation potential. Results: IPCs exhibited robust proliferative capacity and, upon differentiation, formed insulin- and glucagon-secreting organoids. Treatment of IPCs with the small molecule ISX9 induced expression of key transcription factors RFX6 and NEUROD1 through calcium-dependent chromatin remodeling mediated by NFAT recruitment of p300 and displacement of histone deacetylases (HDAC1-3). Pharmacologic inhibition of HDACs further enhanced IPC maturation and glucose-stimulated insulin secretion. Discussion: These findings define the molecular and epigenetic mechanisms driving the expansion and differentiation of adult IPCs into functional islet-like organoids, providing a foundation for future regenerative approaches using adult pancreatic tissue as a renewable source for endocrine cell replacement.

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Multipotent progenitor-like cells have been identified in the adult pancreas under various physiological and pathological conditions. Here, we identify and characterize a subset of adult pancreas-derived cells, termed islet pancridia cells (IPCs), that can be expanded in vitro and retain the potential for endocrine differentiation and islet cell function. Single-cell RNA sequencing of expanded pancridia revealed transcriptomic profiles resembling immature beta cells, enriched with markers of epithelial-mesenchymal transition. A CD9⁺, PROCR⁺ subpopulation of IPCs formed IPC clusters marked by restricted expression of RGS16, a known islet progenitor marker. In vivo, co-transplantation of expanded IPCs with a subtherapeutic dose of islets significantly improved graft function and partially restored native pancreatic endocrine activity in streptozotocin-induced diabetic mice. In vitro, treatment of RGS16⁺ IPC clusters with the small molecule ISX9 induced differentiation into islet organoids that co-expressed and secreted insulin and glucagon. ISX9-mediated differentiation was driven by calcineurin/NFAT-dependent recruitment of the histone acetyltransferase p300 and displacement of histone deacetylases (HDACs) at the RFX6 and NEUROD1 promoters. Pre-treatment with the HDAC inhibitor ITF2357 further enhanced islet cell differentiation by promoting chromatin remodeling and facilitating NFAT-targeted recruitment of p300. These findings uncover calcium-dependent and epigenetic mechanisms that regulate the differentiation of multipotent CD9⁺, PROCR⁺, RGS16⁺ IPCs into functional islet organoids and offer potential strategies for regenerating islet cell mass to treat diabetes.