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<p>Pluripotent stem cell (SC)-derived islets offer hope as a renewable source for β cell replacement for type 1 diabetes (T1D), yet functional and metabolic immaturity may limit their long-term therapeutic potential. Here, we show that limitations in mitochondrial transcriptional programming impede the formation of SC-derived β (SC-β) cells. Utilizing transcriptomic profiling, assessments of chromatin accessibility, mitochondrial phenotyping, and lipidomics analyses, we observe that SC-β cells exhibit reduced oxidative and mitochondrial fatty acid metabolism compared to primary human islets that are related to limitations in key mitochondrial transcriptional networks. Surprisingly, we find that reductions in glucose-stimulated mitochondrial respiration in SC-islets were not associated with alterations in mitochondrial mass, structure, or genome integrity. In contrast, SC-islets show limited expression of targets of PPARα, which regulate mitochondrial programming, yet whose functions in β cell differentiation are unknown. Importantly, treatment with WY14643, a potent PPARα agonist, induces expression of mitochondrial targets, improves insulin secretion, and increases the formation of SC-β cells both in vitro and following transplantation. Thus, PPARα-dependent mitochondrial programming promotes the differentiation of SC-β cells and may be a promising target to improve β cell replacement efforts for T1D.</p>

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Limitations in PPARα-dependent mitochondrial programming restrain the differentiation of human stem cell-derived β cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月10日

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  • Anne C. Lietzke,
  • Emily M. Walker,
  • Elizabeth Bealer,
  • Kelly Crumley,
  • Jessica King,
  • Ava M. Stendahl,
  • Jie Zhu,
  • Gemma L. Pearson,
  • Elena Levi-D’Ancona,
  • Belle Henry-Kanarek,
  • Rebecca K. Davidson,
  • Jin Li,
  • Emma C. Reck,
  • Yifei Wu,
  • Manikanta Arnipalli,
  • John-Paul Pham,
  • Lakshmi Mundada,
  • Vaibhav Sidarala,
  • Todd J. Herron,
  • Maria M. Coronel,
  • Subramaniam Pennathur,
  • Jesper G. S. Madsen,
  • Lonnie D. Shea,
  • Scott A. Soleimanpour

摘要

Pluripotent stem cell (SC)-derived islets offer hope as a renewable source for β cell replacement for type 1 diabetes (T1D), yet functional and metabolic immaturity may limit their long-term therapeutic potential. Here, we show that limitations in mitochondrial transcriptional programming impede the formation of SC-derived β (SC-β) cells. Utilizing transcriptomic profiling, assessments of chromatin accessibility, mitochondrial phenotyping, and lipidomics analyses, we observe that SC-β cells exhibit reduced oxidative and mitochondrial fatty acid metabolism compared to primary human islets that are related to limitations in key mitochondrial transcriptional networks. Surprisingly, we find that reductions in glucose-stimulated mitochondrial respiration in SC-islets were not associated with alterations in mitochondrial mass, structure, or genome integrity. In contrast, SC-islets show limited expression of targets of PPARα, which regulate mitochondrial programming, yet whose functions in β cell differentiation are unknown. Importantly, treatment with WY14643, a potent PPARα agonist, induces expression of mitochondrial targets, improves insulin secretion, and increases the formation of SC-β cells both in vitro and following transplantation. Thus, PPARα-dependent mitochondrial programming promotes the differentiation of SC-β cells and may be a promising target to improve β cell replacement efforts for T1D.