Journal
CELL DEATH AND DIFFERENTIATION
Volume 22, Issue 7, Pages 1094-1105Publisher
SPRINGERNATURE
DOI: 10.1038/cdd.2015.24
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Funding
- AIRC [11599]
- European Community's Seventh Framework Programme ENDOSTEM [241440]
- Epigenomics Flagship Project (EPIGEN) of the MIUR-CNR
- Italian Ministry of Education-University-Research (MIUR-PRIN)
- Medical Research in Italy [RBNE08HM7T-003]
- Italian Ministry of Education-University-Research (PON Cluster IRMI)
- Fondazione Telethon Funding Source: Custom
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Increasing evidence indicates that metabolism is implicated in the control of stem cell identity. Here, we demonstrate that embryonic stem cell (ESC) behaviour relies on a feedback loop that involves the non-essential amino acid L-Proline (L-Pro) in the modulation of the Gcn2-Eif2 alpha-Atf4 amino acid starvation response (AAR) pathway that in turn regulates L-Pro biosynthesis. This regulatory loop generates a highly specific intrinsic shortage of L-Pro that restricts proliferation of tightly packed domed-like ESC colonies and safeguards ESC identity. Indeed, alleviation of this nutrient stress condition by exogenously provided L-Pro induces proliferation and modifies the ESC phenotypic and molecular identity towards that of mesenchymal-like, invasive pluripotent stem cells. Either pharmacological inhibition of the prolyl-tRNA synthetase by halofuginone or forced expression of Atf4 antagonises the effects of exogenous L-Pro. Our data provide unprecedented evidence that L-Pro metabolism and the nutrient stress response are functionally integrated to maintain ESC identity.
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