Introduction: Although diabetes results from the selective demise of insulin-producing beta cells, a cell-based therapy with a mixed cell population that works as a functional unit, will likely be most effective. Indeed, across species, islets are comprised of a mixture of endocrine cell types, often in different proportions and arrangements. However, the developmental mechanisms responsible, particularly in humans, remain poorly understood, hampering efforts to optimize the production of fully mature islets from stem cells.
Method: By fine-tuned differentiation conditions at early stage, we developed a strategy to generate islet organoids that are enriched for major islet cell types. 
Results: We observe “bud structures” developing from progenitor cells that progressively expand into islet organoids in a process that may resemble natural islet development and/or regeneration. Specifically, our characterization indicates that spontaenous clustering of a subset of progenitor cells may contribute to budding structure formation and facilitate subsequent endocrine cell commitment. Interestingly, during the endocrine induction in our islet organoid system, we initially observed a mixed organization of early endocrine cells that resembles a human islet-like architecture with cells seemingly randomly dispersed throughout the islet; while at the more matured stage, islet organoids adopted a mouse islet-like architecture with a core-mantle organization of beta cells in the center and alpha cells in the periphery. Along with islet cell remodeling, we also observed functional development (glucose regulated insulin secretion) within the heterogeneous population of these differentiated islet organoids.
Conclusion: Our islet budding model provides new opportunities to understand human islet development and could guide further optimization of islet manufacturing from stem cells. Our work to explore islet cell organization could also inform future attempts to engineer stem cell-derived islets with optimal cytoarchitecture and robust insulin production.