Understanding and treating diabetes with islet stem cell models

Human pluripotent stem cell (hPSC)-derived islet cells provide a promising resource for diabetes research and cell therapies due to their unlimited supply. Recent studies have demonstrated feasibility of in vitro generation of glucose-responsive insulin-secreting pseudo-islets from hPSCs (SC-islets). These SC-islets consist of a heterogenous population of cells, including beta-like cells (SC-beta cells) which exhibit glucose-responsive insulin secretion and express genes characteristic of mature functional beta cells. However, functional differences between SC-beta cells and primary human beta cells still exist. My laboratory has taken two approaches to improve methodology for building an SC-islet model that better mimics in vivo conditions. First, we generated gene regulatory maps of SC-islets and primary human islets, using single cell RNA-seq and single nucleus ATAC-seq technology. Analysis of these maps revealed transcription factors that are not sufficiently active in SC-beta cells, providing a roadmap for improving SC-beta cell function. Second, we have worked toward developing an islet organoid model comprised of all cell types of the islet niche, including vascular endothelial cells and stromal cells. We further integrated this organoid model into a microfluidic platform in which the organoid is supported by a network of perfused human microvessels. This SC-islet organoid platform will serve as a model to study disease mechanisms of diabetes and to test therapeutics.