Acquisition of Dynamic Function in Human Stem Cell-Derived β Cells

Recent advances in human pluripotent stem cell (hPSC) differentiation protocols have generated insulin-producing cells resembling pancreatic beta cells. While these stem cell-derived beta (SC-beta) cells are capable of undergoing glucose-stimulated insulin secretion (GSIS), insulin secretion per cell remains low compared with islets and cells lack dynamic insulin release. Herein, we report a differentiation strategy focused on modulating transforming growth factor beta (TGF-beta) signaling, controlling cellular cluster size, and using an enriched serum-free media to generate SC-beta cells that express beta cell markers and undergo GSIS with first-and second-phase dynamic insulin secretion. Transplantation of these cells into mice greatly improves glucose tolerance. These results reveal that specific time frames for inhibiting and permitting TGF-beta signaling are required during SC-beta cell differentiation to achieve dynamic function. The capacity of these cells to undergo GSIS with dynamic insulin release makes them a promising cell source for diabetes cellular therapy.