Limitations in mitochondrial programming restrain the maturation of human stem cell-derived β cells

Pluripotent stem cell-derived (SC) islets offer a renewable source for β cell replacement for type 1 diabetes, yet functional and metabolic immaturity may limit their long-term therapeutic efficacy. Here, we describe that limitations in mitochondrial transcriptional programming prevent the maturation of SC-β cells. We observe several alterations in SC-islet mitochondria compared to human islets, including reductions in mitochondrial respiration, expression of OXPHOS machinery, and mitochondrial lipid metabolism. Surprisingly, these effects were not related to reductions in mitochondrial mass, genome integrity, or structure. Transcriptomic profiling throughout differentiation to SC-islets revealed several unstudied candidates in β cell maturation that regulate programming of mitochondrial oxidative and fatty acid metabolism, including the nuclear receptors PPAR⍺ and PPARγ. Indeed, treatment of SC-islets with WY14643, a potent PPAR⍺ agonist with PPARγ activity, promoted expression of mitochondrial targets, improved insulin secretion, and increased the presence of β cells both in vitro and upon transplantation into immunodeficient mice. Mitochondria are vital to fuel β cell insulin release; however, our studies here revealed the potential for targeting mitochondrial programming to enhance the differentiation and metabolic maturation of SC-β cells.