Regenerative macrophages enhance stem cell-derived beta-cell function and engraftment

The generation of insulin-producing beta cells from human embryonic stem cells (SC-β 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. Since macrophages are essential for islet development, we hypothesized they could enhance SC-β-cell differentiation and function. We co-aggregated SC-macrophages which were either unpolarized (SC-MUnp), or polarized to inflammatory (SC-MInf) or regenerative (SC-MReg) states during stage 7 of SC-β-cell differentiation. SC-MRegs improved maturity marker expression, glucose-stimulated insulin secretion, and metabolic activity in SC-β cells. Transplantation of SC-β cells co-aggregated with SC-MRegs 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 significant advance in the production of SC-β cells as a regenerative cell therapy for type 1 diabetes.