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

Xi Wang, Shlomi Brielle (), Jennifer Kenty-Ryu, Nataly Korover, Danny Bavli, Ramona Pop and Douglas A. Melton ()
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Xi Wang: Harvard University
Shlomi Brielle: Harvard University
Jennifer Kenty-Ryu: Harvard University
Nataly Korover: Harvard University
Danny Bavli: Harvard University
Ramona Pop: Harvard University
Douglas A. Melton: Harvard University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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 β 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 β cell transcription factors. We further identified genes important for maintaining β cell fitness in hypoxia, with EDN3 as a potent player. Elevated EDN3 expression preserves β cell identity and function in hypoxia by modulating genes involved in β cell maturation, glucose sensing and regulation. These insights improve the understanding of hypoxia’s impact on stem cell-derived islets, offering a potential intervention for clinical applications.

Date: 2025
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DOI: 10.1038/s41467-025-59924-7

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