The Transcription Factor 7-Like 2-Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha Axis Connects Mitochondrial Biogenesis and Metabolic Shift with Stem Cell Commitment to Hepatic Differentiation

Anaïs Wanet, Marino Caruso, Jean Baka Domelevo Entfellner, Mehdi Najar, Antoine Fattaccioli, Catherine Demazy, Jonathan Evraerts, Hoda El-Kehdy, Guillaume Pourcher, Etienne Sokal, Thierry Arnould, Nicki Tiffin, Mustapha Najimi, Patricia Renard

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Résumé

Increasing evidence supports that modifications in the mitochondrial content, oxidative phosphorylation (OXPHOS) activity, and cell metabolism influence the fate of stem cells. However, the regulators involved in the crosstalk between mitochondria and stem cell fate remains poorly characterized. Here, we identified a transcriptional regulatory axis, composed of transcription factor 7-like 2 (TCF7L2) (a downstream effector of the Wnt/β-catenin pathway, repressed during differentiation) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) (the master regulator of mitochondrial biogenesis, induced during differentiation), coupling the loss of pluripotency and early commitment to differentiation, to the initiation of mitochondrial biogenesis and metabolic shift toward OXPHOS. PGC-1α induction during differentiation is required for both mitochondrial biogenesis and commitment to the hepatocytic lineage, and TCF7L2 repression is sufficient to increase PGC-1α expression, mitochondrial biogenesis and OXPHOS activity. We further demonstrate that OXPHOS activity is required for the differentiation toward the hepatocytic lineage, thus providing evidence that bi-directional interactions control stem cell differentiation and mitochondrial abundance and activity. Stem Cells 2017;35:2184–2197.

langue originaleAnglais
Numéro d'article35(10)
Pages (de - à)2184-2197
Nombre de pages14
journalStem Cells
Volume35
Numéro de publication10
Date de mise en ligne précoce27 août 2017
Les DOIs
étatPublié - 1 oct. 2017

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