Limitations in PPARα-dependent mitochondrial programming restrain the differentiation of human stem cell-derived β cells.
Summary
SC-derived β cells are metabolically immature due to limited PPARα-driven mitochondrial transcriptional networks, not deficits in mitochondrial mass/structure. Pharmacologic PPARα activation (WY14643) restores mitochondrial targets, enhances insulin secretion, and increases SC-β formation in vitro and after transplantation.
Key Findings
- SC-β cells show reduced oxidative and mitochondrial fatty acid metabolism due to limited mitochondrial transcriptional programming.
- Deficits are not due to mitochondrial mass, structure, or genome integrity.
- PPARα target expression is limited in SC-islets; WY14643 induces mitochondrial targets and improves insulin secretion.
- PPARα activation increases SC-β formation in vitro and following transplantation.
Clinical Implications
PPARα agonism could be integrated into differentiation protocols or peritransplant conditioning to improve function and numbers of therapeutic SC-β cells for diabetes cell therapy.
Why It Matters
Provides a tractable mitochondrial programming lever (PPARα) to improve maturation and yield of SC-β cells, a core barrier to scalable β-cell replacement therapy in T1D.
Limitations
- Preclinical study; clinical-grade PPARα agonist translation and safety in this context remain to be established
- Potential off-target metabolic effects of PPARα activation require evaluation
Future Directions
Incorporate PPARα activation into GMP-compliant differentiation pipelines and test long-term graft function, safety, and durability in large-animal models and early-phase clinical studies.
Study Information
- Study Type
- Basic/Mechanistic Research
- Research Domain
- Treatment/Pathophysiology
- Evidence Level
- III - Controlled preclinical experimental evidence with in vivo transplantation validation
- Study Design
- OTHER