Limitations in PPAR⍺-dependent mitochondrial programming restrain the differentiation of human stem cell-derived β...

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.