Year: 2016
Type: article
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.
Source: Cell Reports
Institutions: St George's, University of London, University College London, South African Medical Research Council, University of the Witwatersrand, Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca, Instituto de Biología Funcional y Genómica, Manchester Metropolitan University, Queen Mary University of London, William Harvey Research Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: Barts Charity, Action Medical Research, European Commission, National Centre for the Replacement, Refinement and Reduction of Animals in Research, Henry Smith Charity, Ministerio de Economía y Competitividad, National Centre for the Replacement Refinement and Reduction of Animals in Research, Versus Arthritis, National Institutes of Health, Medical Research Council, Biotechnology and Biological Sciences Research Council, European Research Council, Instituto de Salud Carlos III, National Institute on Drug Abuse
Awards: G1309145341, G1563102252, In situ quantification of metabolic function using fluorescence lifetime imaging, G1748714818, G2190297704, G3150777681, G3263169712, G3477398706, INFLUENCE OF CANNABINOIDS ON ASTROCYTE-NEURONAL METABOLIC INTERACTIONS, Developing new therapies for Batten disease, G4253578915, G6859060030, G7099667406, G7211016466, G7393738420, G7442288438, G8645782315
OpenAlex ID: W2276858159