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Improving cellular fitness of human stem cell-derived islets under hypoxia

ABSTRACT: Stem cell-derived islet cell therapy can effectively treat type 1 diabetes, but its efficacy is hindered by low oxygen supply post-transplantation, particularly in subcutaneous spaces and encapsulation devices, leading to cell dysfunction. The response to hypoxia and effective strategies to alleviate its detrimental effects remain poorly understood. Here, we show that beta cells within stem cell-derived islets gradually undergo a decline in cell identity and metabolic function in hypoxia. This is linked to reduced expression of immediate early genes (EGR1, FOS, and JUN), which downregulates key beta cell transcription factors. We further identified genes important for maintaining beta cell fitness in hypoxia, with EDN3 as a potent player. Elevated EDN3 expression preserves beta cell identity and function in hypoxia by modulating genes involved in beta cell maturation, glucose sensing and regulation. These insights improve the understanding of hypoxias impact on stem cell-derived islets, offering a potential intervention for clinical applications.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Doug Melton

PROVIDER: MSV000097523 | MassIVE | Thu Apr 03 23:59:00 BST 2025

SECONDARY ACCESSION(S): PXD062589

REPOSITORIES: MassIVE

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