#CHIR 99021 ; #2520691 ;
Elife. 2023 Jul 10;12:e78546. doi: 10.7554/eLife.78546.
Damien Detraux 1 2, Marino Caruso 1, Louise Feller 1, Maude Fransolet 1, Sébastien Meurant 1, Julie Mathieu 2 3, Thierry Arnould 1, Patricia Renard 1
Affiliations expand
- PMID: 37428012
- PMCID: PMC10425175
- DOI: 10.7554/eLife.78546
Free PMC article
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 TGFβ-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.