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Updated: Jun 14, 2025
Differentiation of Human Pluripotent Stem Cells Into Pancreatic Beta-Cell Precursors in a 2D Culture System
Published on: December 16, 2021
Limitations in PPAR⍺-dependent mitochondrial programming restrain the differentiation of human stem cell-derived β
Abstract:
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 observed 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 found 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 PPAR⍺, which regulate mitochondrial programming, yet whose functions in β cell differentiation are unknown. Importantly, treatment with WY14643, a potent PPAR⍺ agonist, induced expression of mitochondrial targets, improved insulin secretion, and increased the formation of SC-β cells both in vitro and following transplantation. Thus, PPAR⍺-dependent mitochondrial programming promotes the differentiation of SC-β cells and may be a promising target to improve β cell replacement efforts for T1D.
Insights
Mitochondrial programming is crucial for developing mature stem cell-derived beta cells for type 1 diabetes treatment. Enhancing this process improves insulin secretion and beta cell formation, offering new therapeutic avenues.
Area of Science:
- Stem cell biology
- Metabolic research
- Diabetes therapeutics
Background:
- Pluripotent stem cell (SC)-derived islets are a potential renewable source for beta cell replacement in type 1 diabetes (T1D).
- Functional and metabolic immaturity of SC-derived beta (SC-β) cells can limit their therapeutic efficacy.
- Mitochondrial dysfunction is implicated in the immaturity of SC-β cells.
Purpose of the Study:
- To investigate the role of mitochondrial transcriptional programming in the maturation of SC-β cells.
- To identify molecular targets for improving SC-β cell function and therapeutic potential.
Main Methods:
- Transcriptomic profiling
- Chromatin accessibility assays
- Mitochondrial phenotyping
- Lipidomics analyses
- Treatment with PPARIZ agonist (WY14643)
Main Results:
- SC-β cells exhibit reduced oxidative and mitochondrial fatty acid metabolism compared to primary human islets, linked to impaired mitochondrial transcriptional networks.
- Reduced glucose-stimulated mitochondrial respiration in SC-islets was not due to changes in mitochondrial mass, structure, or genome.
- SC-islets showed limited expression of PPARIZ and PPARγ targets, which regulate mitochondrial programming.
- PPARIZ agonist treatment enhanced mitochondrial gene expression, improved insulin secretion, and promoted SC-β cell formation and maturation in vitro and in vivo.
Conclusions:
- Limitations in mitochondrial transcriptional programming hinder SC-β cell maturation.
- PPARIZ activation is a promising strategy to enhance SC-β cell differentiation and maturation for T1D therapy.
- Targeting mitochondrial programming offers a novel approach to improve stem cell-based beta cell replacement strategies.
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