A critical role for heme synthesis and succinate in the regulation of pluripotent states transitions
- University of Namur, Belgium
- University of Washington, United States
Abstract
Using embryonic stem cells (ESCs) in regenerative medicine or in disease modeling requires a complete understanding of these cells. Two main distinct developmental states of ESCs have been stabilized in vitro, a naïve pre-implantation stage and a primed post-implantation stage. Based on two recently published CRISPR-Cas9 knockout functional screens, we show here that the exit of the naïve state is impaired upon heme biosynthesis pathway blockade, linked in mESCs to the incapacity to activate MAPK- and TGFb-dependent signaling pathways after succinate accumulation. In addition, heme synthesis inhibition promotes the acquisition of 2 cell-like cells in a heme-independent manner caused by a mitochondrial succinate accumulation and leakage out of the cell. We further demonstrate that extracellular succinate acts as a paracrine/autocrine signal, able to trigger the 2C-like reprogramming through the activation of its plasma membrane receptor, SUCNR1. Overall, this study unveils a new mechanism underlying the maintenance of pluripotency under the control of heme synthesis.
Data availability
Sequencing data have been deposited in GEO under the accession GSE178089Data files for the western blot images have been added as raw images of scans
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The critical role of heme synthesis in the regulation of pluripotent states is succinate-dependentNCBI Gene Expression Omnibus, GSE178089.
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Author details
Funding
Fonds De La Recherche Scientifique - FNRS
- Marino Caruso
- Sébastien Meurant
- Patricia Renard
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Detraux et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A critical role for heme synthesis and succinate in the regulation of pluripotent states transitions
eLife 12:e78546.
https://doi.org/10.7554/eLife.78546
