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Updated: Jan 9, 2026

Differentiation of Human Pluripotent Stem Cells Into Pancreatic Beta-Cell Precursors in a 2D Culture System
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Differentiation of Human Pluripotent Stem Cells Into Pancreatic Beta-Cell Precursors in a 2D Culture System

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

Anne C Lietzke1,2, Emily M Walker1, Elizabeth Bealer3

  • 1Division of Metabolism, Endocrinology and Diabetes and Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.

Nature Communications
|December 10, 2025
PubMed

Insights

Pluripotent stem cell-derived beta cells show immature mitochondrial function, hindering type 1 diabetes (T1D) treatment. Activating PPARα enhances mitochondrial programming, improving beta cell development and insulin secretion for T1D therapy.

Area of Science:

  • Cell Biology
  • Metabolic Disease Research
  • Regenerative Medicine

Background:

  • Pluripotent stem cell-derived islets are a potential renewable source for beta cell replacement in type 1 diabetes (T1D).
  • Functional and metabolic immaturity of these cells may limit their therapeutic efficacy.
  • Mitochondrial transcriptional programming is crucial for cellular function and differentiation.

Purpose of the Study:

  • To investigate the role of mitochondrial transcriptional programming in the functional and metabolic immaturity of stem cell-derived beta (SC-β) cells.
  • To identify factors limiting SC-β cell development and function.
  • To explore therapeutic strategies to enhance SC-β cell maturation and efficacy for T1D treatment.

Main Methods:

  • Transcriptomic profiling to analyze gene expression patterns.
  • Chromatin accessibility assays to assess regulatory element activity.
  • Mitochondrial phenotyping and lipidomics to evaluate metabolic function.
  • In vitro and in vivo studies using PPARα agonist (WY14643) treatment.

Main Results:

  • SC-β cells exhibit reduced oxidative and mitochondrial fatty acid metabolism compared to primary human islets due to impaired mitochondrial transcriptional networks.
  • Reduced glucose-stimulated mitochondrial respiration in SC-islets was not linked to changes in mitochondrial mass, structure, or genome integrity.
  • Limited expression of PPARα targets was observed in SC-islets, suggesting a role in mitochondrial programming and beta cell differentiation.
  • PPARα agonist treatment enhanced mitochondrial gene expression, improved insulin secretion, and increased SC-β cell formation in vitro and after transplantation.

Conclusions:

  • Impaired mitochondrial transcriptional programming, specifically involving PPARα, limits the functional maturation of stem cell-derived beta cells.
  • PPARα activation represents a promising therapeutic target to improve the differentiation and function of SC-β cells for T1D replacement therapy.
  • Enhancing mitochondrial programming is key to overcoming the limitations of current stem cell-derived beta cell therapies for type 1 diabetes.

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