Limitations in mitochondrial programming restrain the differentiation and maturation of human stem cell-derived β cells
Lietzke, A. C.; Bealer, E.; Crumley, K.; King, J.; Stendahl, A. M.; Zhu, J.; Pearson, G. L.; Levi-DAncona, E.; Henry-Kanarek, B.; Reck, E. C.; Arnipalli, M.; Sidarala, V.; Walker, E. M.; Pennathur, S.; Madsen, J. G. S.; Shea, L. D.; Soleimanpour, S. A.
Show abstract
Pluripotent stem cell (SC)-derived islets offer hope as a renewable source for {beta} 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 {beta} (SC-{beta}) cells. Utilizing transcriptomic profiling, assessments of chromatin accessibility, mitochondrial phenotyping, and lipidomics analyses, we observed that SC-{beta} 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 {beta} 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-{beta} cells both in vitro and following transplantation. Thus, PPAR-dependent mitochondrial programming promotes the differentiation of SC-{beta} cells and may be a promising target to improve {beta} cell replacement efforts for T1D.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease 97%
- A human omentum-specific mesothelial-like stromal population inhibits adipogenesis through IGFBP2 secretion 95%
- Human skeletal muscle CD90+ fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetes patients 95%
Similar papers in this journal
Similar papers in this journal
- Permanent Neonatal diabetes-causing Insulin mutations have dominant negative effects on beta cell identity 96%
- Interruption of glucagon signaling augments islet non-alpha cell proliferation in SLC7A2- and mTOR-dependent manners 96%
- Chemical induction of gut β-like-cells by combined FoxO1/Notch inhibition as a glucose-lowering treatment for diabetes 96%
Similar papers in this journal
- Target deconvolution of an insulin hypersecretion-inducer acting through VDAC1 with a distinct transcriptomic signature in beta-cells 96%
- Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene 95%
- Chronic intermittent fasting impairs β-cell maturation and function in adolescent mice 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.