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.

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.

Metrics

  • 1,243
    views
  • 204
    downloads
  • 7
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

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

Further reading

    1. Developmental Biology
    Mehmet Mahsum Kaplan, Erika Hudacova ... Ondrej Machon
    Research Article

    Hair follicle development is initiated by reciprocal molecular interactions between the placode-forming epithelium and the underlying mesenchyme. Cell fate transformation in dermal fibroblasts generates a cell niche for placode induction by activation of signaling pathways WNT, EDA, and FGF in the epithelium. These successive paracrine epithelial signals initiate dermal condensation in the underlying mesenchyme. Although epithelial signaling from the placode to mesenchyme is better described, little is known about primary mesenchymal signals resulting in placode induction. Using genetic approach in mice, we show that Meis2 expression in cells derived from the neural crest is critical for whisker formation and also for branching of trigeminal nerves. While whisker formation is independent of the trigeminal sensory innervation, MEIS2 in mesenchymal dermal cells orchestrates the initial steps of epithelial placode formation and subsequent dermal condensation. MEIS2 regulates the expression of transcription factor Foxd1, which is typical of pre-dermal condensation. However, deletion of Foxd1 does not affect whisker development. Overall, our data suggest an early role of mesenchymal MEIS2 during whisker formation and provide evidence that whiskers can normally develop in the absence of sensory innervation or Foxd1 expression.

    1. Developmental Biology
    Bin Zhu, Rui Wei ... Pei Liang
    Research Article

    Wing dimorphism is a common phenomenon that plays key roles in the environmental adaptation of aphid; however, the signal transduction in response to environmental cues and the regulation mechanism related to this event remain unknown. Adenosine (A) to inosine (I) RNA editing is a post-transcriptional modification that extends transcriptome variety without altering the genome, playing essential roles in numerous biological and physiological processes. Here, we present a chromosome-level genome assembly of the rose-grain aphid Metopolophium dirhodum by using PacBio long HiFi reads and Hi-C technology. The final genome assembly for M. dirhodum is 447.8 Mb, with 98.50% of the assembled sequences anchored to nine chromosomes. The contig and scaffold N50 values are 7.82 and 37.54 Mb, respectively. A total of 18,003 protein-coding genes were predicted, of which 92.05% were functionally annotated. In addition, 11,678 A-to-I RNA-editing sites were systematically identified based on this assembled M. dirhodum genome, and two synonymous A-to-I RNA-editing sites on CYP18A1 were closely associated with transgenerational wing dimorphism induced by crowding. One of these A-to-I RNA-editing sites may prevent the binding of miR-3036-5p to CYP18A1, thus elevating CYP18A1 expression, decreasing 20E titer, and finally regulating the wing dimorphism of offspring. Meanwhile, crowding can also inhibit miR-3036-5p expression and further increase CYP18A1 abundance, resulting in winged offspring. These findings support that A-to-I RNA editing is a dynamic mechanism in the regulation of transgenerational wing dimorphism in aphids and would advance our understanding of the roles of RNA editing in environmental adaptability and phenotypic plasticity.