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

Nat Biotechnol. 2022 Jul;40(7):1042-1055. doi: 10.1038/s41587-022-01219-z. Epub 2022 Mar 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Glucose / metabolism
  • Humans
  • Insulin / metabolism
  • Islets of Langerhans Transplantation* / methods
  • Islets of Langerhans* / metabolism
  • Mice
  • Pluripotent Stem Cells* / metabolism

Substances

  • Insulin
  • Glucose