NRF2 Orchestrates the Metabolic Shift during Induced Pluripotent Stem Cell Reprogramming

This is an open access article under the CC BY license.-- et al.
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.
K.E.H. and S.J. were partly funded by St George’s University of London Enterprize Fund. J.M.K.M.D. and S.N.W. are funded by ERC grant Somabio (260862). T.R.M. and S.N.W. are funded by the NC3Rs (NC/L001780/1). J.P.B. is funded by MINECO (SAF2013-41177-R), ISCIII (RD12/0043/0021), EU-SP3-People-MC-ITN (608381), and NIH/NIDA (1R21DA037678-01). V.N.K. is funded by Action Medical Research and The Henry Smith Charity (GN2158), and P.J.K. is funded by Barts and the London Charity (417/2088). T.R.M. and J.B. were each funded by EU Horizon2020; BATCure 666918.
Open access funded by European Research Council.