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<p>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 (<i>EGR1</i>, <i>FOS</i>, and <i>JUN</i>), which downregulates key β cell transcription factors. We further identified genes important for maintaining β cell fitness in hypoxia, with <i>EDN3</i> as a potent player. Elevated <i>EDN3</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月23日

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  • Xi Wang,
  • Shlomi Brielle,
  • Jennifer Kenty-Ryu,
  • Nataly Korover,
  • Danny Bavli,
  • Ramona Pop,
  • Douglas A. Melton

摘要

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.