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

Nature Biotechnology, Journal Year: 2022, Volume and Issue: 40(7), P. 1042 - 1055

Published: March 3, 2022

Abstract Transplantation of pancreatic islet cells derived from human pluripotent stem is a promising treatment for diabetes. Despite progress in the generation stem-cell-derived islets (SC-islets), no detailed characterization 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 vitro maturation, associated with cytoarchitectural reorganization increasing presence alpha cells. Electrophysiology, signaling exocytosis were similar to those Glucose-responsive was achieved despite differences glycolytic mitochondrial glucose metabolism. Single-cell transcriptomics throughout 6 months engraftment mice revealed continuous maturation trajectory culminating transcriptional landscape closely resembling that Our thorough evaluation SC-islet highlights advanced degree functionality supports use further efforts understand combat

Language: Английский

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Multi-lineage Human iPSC-Derived Platforms for Disease Modeling and Drug Discovery

Cell stem cell, Journal Year: 2020, Volume and Issue: 26(3), P. 309 - 329

Published: March 1, 2020

Language: Английский

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Generation of insulin-producing pancreatic β cells from multiple human stem cell lines

Nature Protocols, Journal Year: 2021, Volume and Issue: 16(9), P. 4109 - 4143

Published: Aug. 4, 2021

Language: Английский

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Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes

Cell stem cell, Journal Year: 2023, Volume and Issue: 30(5), P. 530 - 548

Published: May 1, 2023

The generation of islet-like endocrine clusters from human pluripotent stem cells (hPSCs) has the potential to provide an unlimited source insulin-producing β for treatment diabetes. In order this cell therapy become widely adopted, highly functional and well-characterized cell-derived islets (SC-islets) need be manufactured at scale. Furthermore, successful SC-islet replacement strategies should prevent significant loss immediately following transplantation avoid long-term immune rejection. This review highlights most recent advances in characterization SC-islets as well ensure graft viability safety after transplantation.

Language: Английский

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Single-cell transcriptomic and spatial landscapes of the developing human pancreas

Cell Metabolism, Journal Year: 2022, Volume and Issue: 35(1), P. 184 - 199.e5

Published: Dec. 12, 2022

Current differentiation protocols have not been successful in reproducibly generating fully functional human beta cells vitro, partly due to incomplete understanding of pancreas development. Here, we present detailed transcriptomic analysis the various cell types developing pancreas, including their spatial gene patterns. We integrated single-cell RNA sequencing with transcriptomics at multiple developmental time points and revealed distinct temporal-spatial cascades. Cell trajectory inference identified endocrine progenitor populations branch-specific genes as progenitors differentiate toward alpha or cells. Spatial trajectories indicated that Schwann are spatially co-located progenitors, cell-cell connectivity predicted they may interact via L1CAM-EPHB2 signaling. Our approach enabled us identify heterogeneity lineage dynamics within mesenchyme, showing it contributed exocrine acinar state. Finally, generated an interactive web resource for investigating development research community.

Language: Английский

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Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient

Cell, Journal Year: 2024, Volume and Issue: 187(22), P. 6152 - 6164.e18

Published: Sept. 25, 2024

Language: Английский

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Repression of latent NF-κB enhancers by PDX1 regulates β cell functional heterogeneity

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(1), P. 90 - 102.e7

Published: Jan. 1, 2024

Interactions between lineage-determining and activity-dependent transcription factors determine single-cell identity function within multicellular tissues through incompletely known mechanisms. By assembling a atlas of chromatin state human islets, we identified β cell subtypes governed by either high or low activity the factor pancreatic duodenal homeobox-1 (PDX1). cells with reduced PDX1 displayed increased accessibility at latent nuclear κB (NF-κB) enhancers. Pdx1 hypomorphic mice exhibited de-repression NF-κB impaired glucose tolerance night. Three-dimensional analyses in tandem immunoprecipitation (ChIP) sequencing revealed that silences circadian inflammatory enhancers long-range contacts involving SIN3A. Conversely, Bmal1 ablation disrupted genome-wide DNA binding. Finally, antagonizing interleukin (IL)-1β receptor, an target, improved insulin secretion islets. Our studies reveal functional single defined gradient identify as target for insulinotropic therapy.

Language: Английский

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Pancreatic islet transplantation: current advances and challenges

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: June 3, 2024

Diabetes is a prevalent chronic disease that traditionally requires severe reliance on medication for treatment. Oral and exogenous insulin can only temporarily maintain blood glucose levels do not cure the disease. Most patients need life-long injections of insulin. In recent years, advances in islet transplantation have significantly advanced treatment diabetes, allowing to discontinue avoid complications.Long-term follow-up results from reports suggest they provide significant therapeutic benefit although still require immunotherapy, suggesting importance future strategies. Although organ shortage remains primary obstacle development transplantation, new sources cells, such as stem cells porcine been proposed, are gradually being incorporated into clinical research. Further research sites, subcutaneous space mesenteric fat, may eventually replace traditional portal vein intra-islet cell infusion. Additionally, immunological rejection reaction will be resolved through combined application immunosuppressant agents, encapsulation technology, most promising mesenchymal cells/regulatory T therapy. This review summarizes progress achieved discusses potential solutions challenges faced.

Language: Английский

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Maternal circadian rhythms during pregnancy dictate metabolic plasticity in offspring

Cell Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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TETs compete with DNMT3 activity in pluripotent cells at thousands of methylated somatic enhancers

Nature Genetics, Journal Year: 2020, Volume and Issue: 52(8), P. 819 - 827

Published: June 8, 2020

Language: Английский

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