Quiescence enables unrestricted cell fate in naive embryonic stem cells

Le Tran Phuc Khoa, Wentao Yang, Mengrou Shan, Li Zhang, Fengbiao Mao, Bo Zhou, Qiang Li, Rebecca Malcore, Clair Harris, Lili Zhao, Rajesh C. Rao, Shigeki Iwase, Sundeep Kalantry, Stephanie L. Bielas, Costas A. Lyssiotis and Yali Dou ()
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Le Tran Phuc Khoa: University of Southern California
Wentao Yang: University of Southern California
Mengrou Shan: University of Michigan Medical School
Li Zhang: University of Michigan Medical School
Fengbiao Mao: Peking University Third Hospital
Bo Zhou: University of Michigan Medical School
Qiang Li: University of Michigan
Rebecca Malcore: University of Michigan Medical School
Clair Harris: University of Michigan Medical School
Lili Zhao: Beaumont Hospital, Wayne
Rajesh C. Rao: University of Michigan
Shigeki Iwase: University of Michigan Medical School
Sundeep Kalantry: University of Michigan Medical School
Stephanie L. Bielas: University of Michigan Medical School
Costas A. Lyssiotis: University of Michigan Medical School
Yali Dou: University of Southern California

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Quiescence in stem cells is traditionally considered as a state of inactive dormancy or with poised potential. Naive mouse embryonic stem cells (ESCs) can enter quiescence spontaneously or upon inhibition of MYC or fatty acid oxidation, mimicking embryonic diapause in vivo. The molecular underpinning and developmental potential of quiescent ESCs (qESCs) are relatively unexplored. Here we show that qESCs possess an expanded or unrestricted cell fate, capable of generating both embryonic and extraembryonic cell types (e.g., trophoblast stem cells). These cells have a divergent metabolic landscape comparing to the cycling ESCs, with a notable decrease of the one-carbon metabolite S-adenosylmethionine. The metabolic changes are accompanied by a global reduction of H3K27me3, an increase of chromatin accessibility, as well as the de-repression of endogenous retrovirus MERVL and trophoblast master regulators. Depletion of methionine adenosyltransferase Mat2a or deletion of Eed in the polycomb repressive complex 2 results in removal of the developmental constraints towards the extraembryonic lineages. Our findings suggest that quiescent ESCs are not dormant but rather undergo an active transition towards an unrestricted cell fate.

Date: 2024
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DOI: 10.1038/s41467-024-46121-1

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