NRF2 Orchestrates the Metabolic Shift during Induced Pluripotent Stem Cell Reprogramming.

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.

• Authors: Kate E Hawkins, Shona Joy, Juliette M K M Delhove, Vassilios N Kotiadis, Emilio Fernandez, Lorna M Fitzpatrick, James R Whiteford, Peter J King, Juan P Bolanos, Michael R Duchen, Simon N Waddington, Tristan R McKay
• Journal: Cell reports (Cell Rep) Vol. 14 Issue 8 Pg. 1883-91 (Mar 01 2016) ISSN: 2211-1247 [Electronic] United States
• PMID: 26904936 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• KEAP1 protein, human
• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• NF-kappa B
• NFE2L2 protein, human
• Reactive Oxygen Species
• Transcription Factor AP-1
• Luciferases

Topics

• Cellular Reprogramming
• Dermis (cytology, metabolism)
• Fibroblasts (cytology, metabolism)
• Gene Expression Regulation
• Genes, Reporter
• Genetic Vectors (chemistry, metabolism)
• Glycolysis (genetics)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Induced Pluripotent Stem Cells (cytology, metabolism)
• Kelch-Like ECH-Associated Protein 1 (genetics, metabolism)
• Lentivirus (genetics, metabolism)
• Luciferases (genetics, metabolism)
• NF-E2-Related Factor 2 (genetics, metabolism)
• NF-kappa B (genetics, metabolism)
• Oxidative Phosphorylation
• Pentose Phosphate Pathway (genetics)
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• Transcription Factor AP-1 (genetics, metabolism)
• Transduction, Genetic