Functional, metabolic and transcriptional maturation of human pancreatic islets derived from stem cells

TLDR

Transplantation of pancreatic islet cells derived from human pluripotent stem cells is a promising treatment for diabetes, yet detailed functional characterization of stem‑cell‑derived islets remains lacking. The study aims to generate functionally mature stem‑cell‑derived islets and benchmark them against primary adult islets. An optimized protocol was employed to produce SC‑islets, followed by comprehensive functional, electrophysiological, metabolic, and transcriptomic evaluation. SC‑islets displayed biphasic glucose‑stimulated insulin secretion, cytoarchitectural reorganization, alpha‑cell enrichment, and electrophysiological, signaling, and exocytotic properties similar to adult islets, achieved glucose‑responsive insulin secretion despite metabolic differences, and followed a maturation trajectory in single‑cell transcriptomics that culminated in a transcriptional landscape closely resembling primary islets, underscoring their advanced functionality and therapeutic promise.

Abstract

Abstract Transplantation of pancreatic islet cells derived from human pluripotent stem cells is a promising treatment for diabetes. Despite progress in the generation of stem-cell-derived islets (SC-islets), no detailed characterization of their functional properties has been conducted. Here, we generated functionally mature SC-islets using an optimized protocol and benchmarked them comprehensively against primary adult islets. Biphasic glucose-stimulated insulin secretion developed during in vitro maturation, associated with cytoarchitectural reorganization and the increasing presence of alpha cells. Electrophysiology, signaling and exocytosis of SC-islets were similar to those of adult islets. Glucose-responsive insulin secretion was achieved despite differences in glycolytic and mitochondrial glucose metabolism. Single-cell transcriptomics of SC-islets in vitro and throughout 6 months of engraftment in mice revealed a continuous maturation trajectory culminating in a transcriptional landscape closely resembling that of primary islets. Our thorough evaluation of SC-islet maturation highlights their advanced degree of functionality and supports their use in further efforts to understand and combat diabetes.