Abstract
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.
| Original language | English |
|---|---|
| Article number | 35(10) |
| Pages (from-to) | 2184-2197 |
| Number of pages | 14 |
| Journal | Stem Cells |
| Volume | 35 |
| Issue number | 10 |
| Early online date | 27 Aug 2017 |
| DOIs | |
| Publication status | Published - 1 Oct 2017 |
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Keywords
- Hepatic differentiation
- Mitochondria
- Oxidative phosphorylation
- Stem cells
- Wnt/β-catenin
Cite this
}
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. / Wanet, Anaïs; Caruso, Marino; Domelevo Entfellner, Jean Baka; Najar, Mehdi; Fattaccioli, Antoine; Demazy, Catherine; Evraerts, Jonathan; El-Kehdy, Hoda; Pourcher, Guillaume; Sokal, Etienne; Arnould, Thierry; Tiffin, Nicki; Najimi, Mustapha; Renard, Patricia.
In: Stem Cells, Vol. 35, No. 10, 35(10), 01.10.2017, p. 2184-2197.Research output: Contribution to journal › Article
TY - JOUR
T1 - 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
AU - Wanet, Anaïs
AU - Caruso, Marino
AU - Domelevo Entfellner, Jean Baka
AU - Najar, Mehdi
AU - Fattaccioli, Antoine
AU - Demazy, Catherine
AU - Evraerts, Jonathan
AU - El-Kehdy, Hoda
AU - Pourcher, Guillaume
AU - Sokal, Etienne
AU - Arnould, Thierry
AU - Tiffin, Nicki
AU - Najimi, Mustapha
AU - Renard, Patricia
PY - 2017/10/1
Y1 - 2017/10/1
N2 - 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.
AB - 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.
KW - Hepatic differentiation
KW - Mitochondria
KW - Oxidative phosphorylation
KW - Stem cells
KW - Wnt/β-catenin
UR - http://www.scopus.com/inward/record.url?scp=85028303948&partnerID=8YFLogxK
U2 - 10.1002/stem.2688
DO - 10.1002/stem.2688
M3 - Article
VL - 35
SP - 2184
EP - 2197
JO - Stem Cells
JF - Stem Cells
SN - 1066-5099
IS - 10
M1 - 35(10)
ER -