Functional, metabolic and transcriptional maturation of stem cell derived beta cells

Diego Balboa; Tom Barsby; Väinö Lithovius; Jonna Saarimäki‐Vire; Muhmmad Omar‐Hmeadi; Oleg Dyachok; Hossam Montaser; Per-Eric Lund; Mingyu Yang; Hazem Ibrahim; Anna Näätänen; Vikash Chandra; Helena Vihinen; Eija Jokitalo; Jouni Kvist; Jarkko Ustinov; Anni I. Nieminen; Emilia Kuuluvainen; Ville Hietakangas; Pekka Katajisto; Joey Lau; Per‐Ola Carlsson; Sebastian Barg; Anders Tengholm; Timo Otonkoski

doi:10.1038/s41587-022-01219-z

Developmental BiologyNature BiotechnologyMar 3, 2022

Peer-reviewed journal article

Functional, metabolic and transcriptional maturation of stem cell derived beta cells

Diego Balboa iD, Tom Barsby iD, Väinö Lithovius iD, Jonna Saarimäki‐Vire iD, Muhmmad Omar‐Hmeadi iD, Oleg Dyachok iD, Hossam Montaser iD, Per-Eric Lund iD, Mingyu Yang iD, Hazem Ibrahim iD, Anna Näätänen, Vikash Chandra iD, Helena Vihinen iD, Eija Jokitalo iD, Jouni Kvist iD, Jarkko Ustinov, Anni I. Nieminen iD, Emilia Kuuluvainen iD, Ville Hietakangas iD, Pekka Katajisto iD, Joey Lau iD, Per‐Ola Carlsson iD, Sebastian Barg iD, Anders Tengholm iD, Timo Otonkoski iD

Abstract

Transplantation of pancreatic islet cells derived from human pluripotent stem cells is a promising treatment for diabetes. Despite progress in stem cell-derived islet (SC-islet) generation, detailed characterization of their functional properties has not been conducted. Here, we generated functionally mature SC-islets using an optimized protocol and comprehensively benchmarked them against primary adult islets. Biphasic glucose stimulated insulin secretion developed during in vitro maturation, associated with cytoarchitectural reorganization and increased alpha cells. Electrophysiology and exocytosis of SC-islets were comparable to 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 murine engraftment 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.

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