1. NRF2 Orchestrates the Metabolic Shift during Induced Pluripotent Stem Cell Reprogramming.
- Author
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Hawkins KE, Joy S, Delhove JM, Kotiadis VN, Fernandez E, Fitzpatrick LM, Whiteford JR, King PJ, Bolanos JP, Duchen MR, Waddington SN, and McKay TR
- Subjects
- Dermis cytology, Dermis metabolism, Fibroblasts cytology, Gene Expression Regulation, Genes, Reporter, Genetic Vectors chemistry, Genetic Vectors metabolism, Glycolysis genetics, Humans, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Induced Pluripotent Stem Cells cytology, Kelch-Like ECH-Associated Protein 1 metabolism, Lentivirus genetics, Lentivirus metabolism, Luciferases genetics, Luciferases metabolism, NF-E2-Related Factor 2 metabolism, NF-kappa B genetics, NF-kappa B metabolism, Oxidative Phosphorylation, Pentose Phosphate Pathway genetics, Reactive Oxygen Species metabolism, Signal Transduction, Transcription Factor AP-1 genetics, Transcription Factor AP-1 metabolism, Transduction, Genetic, Cellular Reprogramming, Fibroblasts metabolism, Induced Pluripotent Stem Cells metabolism, Kelch-Like ECH-Associated Protein 1 genetics, NF-E2-Related Factor 2 genetics
- Abstract
The potential of induced pluripotent stem cells (iPSCs) in disease modeling and regenerative medicine is vast, but current methodologies remain inefficient. Understanding the cellular mechanisms underlying iPSC reprogramming, such as the metabolic shift from oxidative to glycolytic energy production, is key to improving its efficiency. We have developed a lentiviral reporter system to assay longitudinal changes in cell signaling and transcription factor activity in living cells throughout iPSC reprogramming of human dermal fibroblasts. We reveal early NF-κB, AP-1, and NRF2 transcription factor activation prior to a temporal peak in hypoxia inducible factor α (HIFα) activity. Mechanistically, we show that an early burst in oxidative phosphorylation and elevated reactive oxygen species generation mediates increased NRF2 activity, which in turn initiates the HIFα-mediated glycolytic shift and may modulate glucose redistribution to the pentose phosphate pathway. Critically, inhibition of NRF2 by KEAP1 overexpression compromises metabolic reprogramming and results in reduced efficiency of iPSC colony formation., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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