Restoration ofPKM1improves functional maturation of human stem-cell derived-β cell by regulating PEP metabolism DOI Creative Commons

Haopeng Lin,

Deqi Chen, Feng Zhang

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 15, 2024

Abstract Human stem cell-derived β (SC-β) cells still exhibit limited glucose response required for insulin secretion due to glycolytic bottlenecks, yet how these metabolic abnormalities impact and functional maturation of SC-β remains unclear. In this study, we identified a checkpoint located at PEP accumulation that impeded the maturation, which was rescued by restoration pyruvate kinase 1 ( PKM1 ). Glucose-tracing metabolomics in human islets revealed abnormal resting condition, resulting impaired calcium upon high or metabolite stimulation. Mechanistically, elevated significantly raised intracellular basal levels, leading downregulated expression genes involved TCA cycle elucidated single cell transcriptomics. Furthermore, activity kinase, metabolizes PEP, notably reduced low expression. By overexpressing PKM1, impairment TCA-related caused reversed via modulating metabolism, enhanced responses Together, discovered novel role PKM1-regulated metabolism mediating cells. This study highlights importance reprogramming advancing therapy approaches diabetes treatment.

Язык: Английский

Restoration ofPKM1improves functional maturation of human stem-cell derived-β cell by regulating PEP metabolism DOI Creative Commons

Haopeng Lin,

Deqi Chen, Feng Zhang

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 15, 2024

Abstract Human stem cell-derived β (SC-β) cells still exhibit limited glucose response required for insulin secretion due to glycolytic bottlenecks, yet how these metabolic abnormalities impact and functional maturation of SC-β remains unclear. In this study, we identified a checkpoint located at PEP accumulation that impeded the maturation, which was rescued by restoration pyruvate kinase 1 ( PKM1 ). Glucose-tracing metabolomics in human islets revealed abnormal resting condition, resulting impaired calcium upon high or metabolite stimulation. Mechanistically, elevated significantly raised intracellular basal levels, leading downregulated expression genes involved TCA cycle elucidated single cell transcriptomics. Furthermore, activity kinase, metabolizes PEP, notably reduced low expression. By overexpressing PKM1, impairment TCA-related caused reversed via modulating metabolism, enhanced responses Together, discovered novel role PKM1-regulated metabolism mediating cells. This study highlights importance reprogramming advancing therapy approaches diabetes treatment.

Язык: Английский

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