Regenerative macrophages enhance stem cell–derived β cell function and engraftment

The generation of insulin-producing, stem cell–derived β cells (SC-β cells) from human embryonic or induced pluripotent stem cells holds promise for treating type 1 diabetes. Transplantation of SC-β cells is already in clinical testing, but generating mature cells with insulin-secreting properties similar to endogenous cells has been challenging. Given that macrophages are essential for islet development, we hypothesized that they could enhance SC-β cell differentiation and function. We coaggregated autologous SC-macrophages that were either unpolarized (SC-M Unp ) or polarized to inflammatory (SC-M Inf ) or regenerative (SC-M Reg ) states during stage 7 of SC-β cell differentiation. SC-M Regs improved maturity marker expression, glucose-stimulated insulin secretion, and metabolic activity in SC-β cells. Transplantation of SC-β cells coaggregated with SC-M Regs into diabetic mice normalized glycemia significantly faster than transplantation of SC-β cells alone. The finding that addition of macrophages during SC-β differentiation accelerates functional maturation represents a notable advance in the production of SC-β cells as a regenerative cell therapy for type 1 diabetes.