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<p>The success of stem cell-derived islet (SC-islet) therapy for type 1 diabetes is limited by poor graft survival in the hypoxic post-transplantation microenvironment. While the response of SC-islets to chronic hypoxia has been studied, a direct comparison to primary human islets during the acute hypoxic phase has not been performed. Here, we conduct a comparative single-cell transcriptomic and functional analysis of human SC-islets and primary islets exposed to acute hypoxia (1% O<sub>2</sub>) over 48&#xa0;h. Our analysis reveals two divergent response patterns. Primary islets exhibit an energy-conserving response, suppressing β-cell identity genes (<i>PDX1</i>, <i>MAFA</i>) and pro-apoptotic factors like <i>DDIT3</i>, while shifting toward metabolic quiescence. In contrast, the SC-islet response is characterized by lineage instability, a significant metabolic shift toward glycolysis, and the activation of pro-apoptotic pathways. Functionally, these transcriptomic differences result in a loss of glucose-stimulated insulin secretion in both islet types, but through different mechanisms: a suppression of secretion in primary islets versus dysregulated, glucose-unresponsive insulin release in SC-islets. These findings demonstrate that SC-islets are particularly vulnerable under hypoxic stress, exhibiting an unstable, plastic phenotype. This comparative dataset provides a resource for developing source-specific therapeutic interventions to overcome the hypoxic barrier and improve the efficacy of cell replacement therapies.</p>

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Divergent cell-type specific hypoxia responses in human stem cell-derived and primary islets

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月12日

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  • Kameron Bradley,
  • Camryn Moore,
  • Matthew Ishahak,
  • Marlie M. Maestas,
  • Daniel A. Veronese-Paniagua,
  • Jeffrey R. Millman

摘要

The success of stem cell-derived islet (SC-islet) therapy for type 1 diabetes is limited by poor graft survival in the hypoxic post-transplantation microenvironment. While the response of SC-islets to chronic hypoxia has been studied, a direct comparison to primary human islets during the acute hypoxic phase has not been performed. Here, we conduct a comparative single-cell transcriptomic and functional analysis of human SC-islets and primary islets exposed to acute hypoxia (1% O2) over 48 h. Our analysis reveals two divergent response patterns. Primary islets exhibit an energy-conserving response, suppressing β-cell identity genes (PDX1, MAFA) and pro-apoptotic factors like DDIT3, while shifting toward metabolic quiescence. In contrast, the SC-islet response is characterized by lineage instability, a significant metabolic shift toward glycolysis, and the activation of pro-apoptotic pathways. Functionally, these transcriptomic differences result in a loss of glucose-stimulated insulin secretion in both islet types, but through different mechanisms: a suppression of secretion in primary islets versus dysregulated, glucose-unresponsive insulin release in SC-islets. These findings demonstrate that SC-islets are particularly vulnerable under hypoxic stress, exhibiting an unstable, plastic phenotype. This comparative dataset provides a resource for developing source-specific therapeutic interventions to overcome the hypoxic barrier and improve the efficacy of cell replacement therapies.