Exendin-4 enhances insulin-positive phenotype of human pluripotent stem cell-derived β cells during transplantation

An emerging technique for the treatment of type 1 diabetes, which is characterized by hyperglycemia resulting from the loss of insulin-secreting β cells, involves transplantation of human pluripotent stem cell (hPSC)-derived β cells. This transplantation procedure can induce normoglycemia, yet the efficiency of cell survival and function post transplantation remain opportunities for improvement. Here, we investigated treatment with Exendin-4, a GLP-1 receptor agonist, throughout the post-transplantation period to improve the survival and function of transplanted cells. hPSC-derived β cell clusters were transplanted on microporous PLG scaffolds into the peritoneal fat, with Exendin-4 delivery resulting in a more rapid restoration of normoglycemia relative to control. We interrogated multiple avenues by which Exendin-4 enhanced transplantation, and observed a higher rate of cell survival, increased expression of maturation markers and greater metabolic outputs than untreated cells. Collectively, Exendin-4 delivered alongside hPSC-derived β cell transplantation decreased time to improved blood glucose levels and enhanced β cell number, differentiation, and maturation.