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

Author:

Balboa DiegoORCID,Barsby Tom,Lithovius VäinöORCID,Saarimäki-Vire JonnaORCID,Omar-Hmeadi MuhmmadORCID,Dyachok Oleg,Montaser Hossam,Lund Per-Eric,Yang MingyuORCID,Ibrahim HazemORCID,Näätänen Anna,Chandra VikashORCID,Vihinen HelenaORCID,Jokitalo EijaORCID,Kvist Jouni,Ustinov Jarkko,Nieminen Anni I.ORCID,Kuuluvainen Emilia,Hietakangas Ville,Katajisto PekkaORCID,Lau JoeyORCID,Carlsson Per-Ola,Barg Sebastian,Tengholm AndersORCID,Otonkoski TimoORCID

Abstract

AbstractTransplantation 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.

Publisher

Springer Science and Business Media LLC

Subject

Biomedical Engineering,Molecular Medicine,Applied Microbiology and Biotechnology,Bioengineering,Biotechnology

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