Studies on functionality of pancreatic islet-like clusters derived from human pluripotent stem cells

Abstract

Insulin secretion is elaborately modulated in pancreatic $\beta$ cells within 3D islets. Using human pluripotent stem cells to develop islet-like structures with insulin-producing $\beta$ cells for the treatment of diabetes is challenging. In this study, we demonstrate that pancreatic islet-like clusters derived from human embryonic stem cells (hESCs) have competences for glucose-responsive insulin secretion and therapeutic effects. Pancreatic hormone-expressing endocrine cells (ECs) were differentiated from hESCs using a step-wise protocol based on developmental stages. The hESC-derived ECs expressed pancreatic hormones such as insulin, somatostatin, and pancreatic polypeptide. Notably, dissociated ECs autonomously aggregated to form 3D clusters of consistent sizes. These EC clusters (ECCs) enhanced insulin secretion against glucose stimulus and potassium channel inhibition in vitro. Furthermore, $\beta$ cell-deficient mice transplanted with ECCs survived for more than 40 d while retaining a normal blood glucose level to some extent. In addition, ECCs could be generated from human pluripotent stem cells. These results suggest that hPSC-derived, islet-like clusters may be alternative therapeutic cell sources for treating diabetes.