NRF2 Orchestrates the Metabolic Shift during Induced Pluripotent Stem Cell Reprogramming
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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2016-03-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124716300705 |
| _version_ | 1818955175648296960 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Kate E. Hawkins |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T10:33:53Z |
| format | Article |
| id | doaj.art-272ceabc933b4f23acf31d95556d9320 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-20T10:33:53Z |
| publishDate | 2016-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-272ceabc933b4f23acf31d95556d93202022-12-21T19:43:39ZengElsevierCell Reports2211-12472016-03-011481883189110.1016/j.celrep.2016.02.003NRF2 Orchestrates the Metabolic Shift during Induced Pluripotent Stem Cell ReprogrammingKate E. Hawkins0Shona Joy1Juliette M.K.M. Delhove2Vassilios N. Kotiadis3Emilio Fernandez4Lorna M. Fitzpatrick5James R. Whiteford6Peter J. King7Juan P. Bolanos8Michael R. Duchen9Simon N. Waddington10Tristan R. McKay11Stem Cell Group, Cardiovascular and Cell Sciences Research Institute, St. George’s University of London, Cranmer Terrace, London SW17 0RE, UKStem Cell Group, Cardiovascular and Cell Sciences Research Institute, St. George’s University of London, Cranmer Terrace, London SW17 0RE, UKStem Cell Group, Cardiovascular and Cell Sciences Research Institute, St. George’s University of London, Cranmer Terrace, London SW17 0RE, UKDepartment of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UKInstitute of Functional Biology and Genomics, University of Salamanca-CSIC, 37007 Salamanca, SpainStem Cell Group, Cardiovascular and Cell Sciences Research Institute, St. George’s University of London, Cranmer Terrace, London SW17 0RE, UKWilliam Harvey Research Institute, Charterhouse Square, Queen Mary University of London, London EC1M 6BQ, UKWilliam Harvey Research Institute, Charterhouse Square, Queen Mary University of London, London EC1M 6BQ, UKInstitute of Functional Biology and Genomics, University of Salamanca-CSIC, 37007 Salamanca, SpainDepartment of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UKWits/SAMRC Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South AfricaStem Cell Group, Cardiovascular and Cell Sciences Research Institute, St. George’s University of London, Cranmer Terrace, London SW17 0RE, UKThe 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.http://www.sciencedirect.com/science/article/pii/S2211124716300705 |
| spellingShingle | 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 NRF2 Orchestrates the Metabolic Shift during Induced Pluripotent Stem Cell Reprogramming Cell Reports |
| title | NRF2 Orchestrates the Metabolic Shift during Induced Pluripotent Stem Cell Reprogramming |
| title_full | NRF2 Orchestrates the Metabolic Shift during Induced Pluripotent Stem Cell Reprogramming |
| title_fullStr | NRF2 Orchestrates the Metabolic Shift during Induced Pluripotent Stem Cell Reprogramming |
| title_full_unstemmed | NRF2 Orchestrates the Metabolic Shift during Induced Pluripotent Stem Cell Reprogramming |
| title_short | NRF2 Orchestrates the Metabolic Shift during Induced Pluripotent Stem Cell Reprogramming |
| title_sort | nrf2 orchestrates the metabolic shift during induced pluripotent stem cell reprogramming |
| url | http://www.sciencedirect.com/science/article/pii/S2211124716300705 |
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