Identification of bipotent progenitors that give rise to myogenic and connective tissues in mouse

  1. Alexandre Grimaldi
  2. Glenda Comai
  3. Sebastien Mella
  4. Shahragim Tajbakhsh  Is a corresponding author
  1. Institut Pasteur, France
  2. CNRS, France

Abstract

How distinct cell fates are manifested by direct lineage ancestry from bipotent progenitors, or by specification of individual cell types is a key question for understanding the emergence of tissues. The interplay between skeletal muscle progenitors and associated connective tissue cells provides a model for examining how muscle functional units are established. Most craniofacial structures originate from the vertebrate-specific neural crest cells except in the dorsal portion of the head, where they arise from cranial mesoderm. Here, using multiple lineage-tracing strategies combined with single cell RNAseq and in situ analyses, we identify bipotent progenitors expressing Myf5 (an upstream regulator of myogenic fate) that give rise to both muscle and juxtaposed connective tissue. Following this bifurcation, muscle and connective tissue cells retain complementary signalling features and maintain spatial proximity. Disrupting myogenic identity shifts muscle progenitors to a connective tissue fate. The emergence of Myf5-derived connective tissue is associated with the activity of several transcription factors, including Foxp2. Interestingly, this unexpected bifurcation in cell fate was not observed in craniofacial regions that are colonised by neural crest cells. Therefore, we propose that an ancestral bi-fated program gives rise to muscle and connective tissue cells in skeletal muscles that are deprived of neural crest cells.

Data availability

scRNAseq datasets are available in open access on DRYAD at the following address: https://datadryad.org/stash/dataset/doi:10.5061/dryad.gf1vhhmrs?. The code that was used to generate the driver regulators is available at this address: https://github.com/TajbakhshLab/DriverRegulators. Source data files have been provided for Figure 3J, Figure 4H, Figure 5F, Figure 5J, Figure 5-figure supplement 1E, Figure 7E and Figure 7G.

The following data sets were generated

Article and author information

Author details

  1. Alexandre Grimaldi

    Stem Cells and Development Unit, Institut Pasteur, Paris, France
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5978-2057
  2. Glenda Comai

    UMR 3738, Department of Developmental and Stem Cell Biology, CNRS, Paris, France
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3244-3378
  3. Sebastien Mella

    Cytometry and Biomarkers UTechS, Institut Pasteur, Paris, France
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8679-5718
  4. Shahragim Tajbakhsh

    Stem Cells and Development Unit, Institut Pasteur, Paris, France
    For correspondence
    shahragim.tajbakhsh@pasteur.fr
    Competing interests
    Shahragim Tajbakhsh, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1809-7202

Funding

Association Française contre les Myopathies (20510)

  • Alexandre Grimaldi

Fondation pour la Recherche Médicale (FDT201904008277)

  • Alexandre Grimaldi

Agence Nationale de la Recherche (ANR-10-LABX-73)

  • Shahragim Tajbakhsh

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animals were handled as per European Community guidelines and the ethics committee of the Institut Pasteur (CETEA) approved protocols (APAFIS#6354-20160809 l2028839).

Reviewing Editor

  1. Marianne E Bronner, California Institute of Technology, United States

Publication history

  1. Received: May 11, 2021
  2. Preprint posted: May 26, 2021 (view preprint)
  3. Accepted: February 25, 2022
  4. Accepted Manuscript published: February 28, 2022 (version 1)
  5. Accepted Manuscript updated: March 15, 2022 (version 2)
  6. Version of Record published: April 20, 2022 (version 3)

Copyright

© 2022, Grimaldi 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

  • 1,031
    Page views
  • 207
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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. Alexandre Grimaldi
  2. Glenda Comai
  3. Sebastien Mella
  4. Shahragim Tajbakhsh
(2022)
Identification of bipotent progenitors that give rise to myogenic and connective tissues in mouse
eLife 11:e70235.
https://doi.org/10.7554/eLife.70235

Further reading

    1. Cell Biology
    2. Developmental Biology
    Ivonne Margarete Sehring et al.
    Research Article

    Successful regeneration requires the coordinated execution of multiple cellular responses to injury. In amputated zebrafish fins, mature osteoblasts dedifferentiate, migrate towards the injury and form proliferative osteogenic blastema cells. We show that osteoblast migration is preceded by cell elongation and alignment along the proximodistal axis, which require actomyosin, but not microtubule turnover. Surprisingly, osteoblast dedifferentiation and migration can be uncoupled. Using pharmacological and genetic interventions, we found that NF-ĸB and retinoic acid signalling regulate dedifferentiation without affecting migration, while the complement system and actomyosin dynamics affect migration but not dedifferentiation. Furthermore, by removing bone at two locations within a fin ray, we established an injury model containing two injury sites. We found that osteoblasts dedifferentiate at and migrate towards both sites, while accumulation of osteogenic progenitor cells and regenerative bone formation only occur at the distal-facing injury. Together, these data indicate that osteoblast dedifferentiation and migration represent generic injury responses that are differentially regulated and can occur independently of each other and of regenerative growth. We conclude that successful fin bone regeneration appears to involve the coordinated execution of generic and regeneration-specific responses of osteoblasts to injury.

    1. Developmental Biology
    2. Neuroscience
    Ashtyn T Wiltbank et al.
    Research Article

    Efficient neurotransmission is essential for organism survival and is enhanced by myelination. However, the genes that regulate myelin and myelinating glial cell development have not been fully characterized. Data from our lab and others demonstrates that cd59, which encodes for a small GPI-anchored glycoprotein, is highly expressed in developing zebrafish, rodent, and human oligodendrocytes (OLs) and Schwann cells (SCs), and that patients with CD59 dysfunction develop neurological dysfunction during early childhood. Yet, the function of Cd59 in the developing nervous system is currently undefined. In this study, we demonstrate that cd59 is expressed in a subset of developing SCs. Using cd59 mutant zebrafish, we show that developing SCs proliferate excessively and nerves may have reduced myelin volume, altered myelin ultrastructure, and perturbed node of Ranvier assembly. Finally, we demonstrate that complement activity is elevated in cd59 mutants and that inhibiting inflammation restores SC proliferation, myelin volume, and nodes of Ranvier to wildtype levels. Together, this work identifies Cd59 and developmental inflammation as key players in myelinating glial cell development, highlighting the collaboration between glia and the innate immune system to ensure normal neural development.