A critical role for heme synthesis and succinate in the regulation of pluripotent states transitions

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

The following data sets were generated

Article and author information

Author details

  1. Damien Detraux

    Laboratory of Biochemistry and Cell Biology, University of Namur, Namur, Belgium
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9704-2076
  2. Marino Caruso

    Laboratory of Biochemistry and Cell Biology, University of Namur, Namur, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  3. Louise Feller

    Laboratory of Biochemistry and Cell Biology, University of Namur, Namur, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  4. Maude Fransolet

    Laboratory of Biochemistry and Cell Biology, University of Namur, Namur, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  5. Sébastien Meurant

    Laboratory of Biochemistry and Cell Biology, University of Namur, Namur, Belgium
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0711-9605
  6. Julie Mathieu

    Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Thierry Arnould

    Laboratory of Biochemistry and Cell Biology, University of Namur, Namur, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  8. Patricia Renard

    Laboratory of Biochemistry and Cell Biology, University of Namur, Namur, Belgium
    For correspondence
    patsy.renard@unamur.be
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4144-3353

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.

Reviewing Editor

  1. Simón Méndez-Ferrer, University of Cambridge, United Kingdom

Version history

  1. Preprint posted: March 11, 2022 (view preprint)
  2. Received: March 11, 2022
  3. Accepted: July 8, 2023
  4. Accepted Manuscript published: July 10, 2023 (version 1)
  5. Version of Record published: August 14, 2023 (version 2)

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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  1. Damien Detraux
  2. Marino Caruso
  3. Louise Feller
  4. Maude Fransolet
  5. Sébastien Meurant
  6. Julie Mathieu
  7. Thierry Arnould
  8. Patricia Renard
(2023)
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

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https://doi.org/10.7554/eLife.78546

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