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Differentiation of Human Pluripotent Stem Cells Into Pancreatic Beta-Cell Precursors in a 2D Culture System
Published on: December 16, 2021
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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
Summary
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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