Journal
NATURE BIOTECHNOLOGY
Volume 40, Issue 7, Pages 1042-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41587-022-01219-z
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Funding
- HiLIFE and Biocenter Finland
- strategic grant consortium Excellence of Diabetes Research in Sweden, EXODIAB
- Academy of Finland [297466]
- MetaStem Center of Excellence grant [312437]
- Sigrid Juselius Foundation Grant
- Novo Nordisk Foundation
- Diabetes Wellness Finland
- Helsinki University Hospital Research Funds
- EMBO Long-Term Fellowship [ALT295-2019]
- Swedish Research Council
- Barndiabetesfonden
- Swedish Diabetes Foundation
- Family Erling-Persson Foundation
- Family Ernfors Foundation
- Diabetes Wellness Sweden
- Innovative Medicines Initiative 2 Joint Undertaking [115797, 945268]
- Union's Horizon 2020 research and innovation program
- European Federation of Pharmaceutical Industries and Associations, JDR
- Leona M. and Harry B. Helmsley Charitable Trust
- Academy of Finland (AKA) [297466, 297466] Funding Source: Academy of Finland (AKA)
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Transplanting pancreatic islet cells derived from human pluripotent stem cells has great potential for treating diabetes. This study generated functionally mature stem-cell-derived islets (SC-islets) using an optimized protocol and compared them comprehensively to primary adult islets. The results showed that SC-islets exhibited similar functional properties to adult islets in terms of insulin secretion, electrophysiology, signaling, and exocytosis. Additionally, single-cell transcriptomics revealed a continuous maturation trajectory of SC-islets in vitro and during engraftment in mice, closely resembling that of primary islets.
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.
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