Tension-driven multi-scale self-organisation in human iPSC-derived muscle fibers

  1. Qiyan Mao  Is a corresponding author
  2. Achyuth Acharya
  3. Alejandra Rodríguez-delaRosa
  4. Fabio Marchiano
  5. Benoit Dehapiot
  6. Ziad Al Tanoury
  7. Jyoti Rao
  8. Margarete Díaz-Cuadros
  9. Arian Mansur
  10. Erica Wagner
  11. Claire Chardes
  12. Vandana Gupta
  13. Pierre-François Lenne
  14. Bianca H Habermann
  15. Olivier Theodoly
  16. Olivier Pourquié  Is a corresponding author
  17. Frank Schnorrer  Is a corresponding author
  1. Aix Marseille University, CNRS, IDBM, France
  2. Brigham and Women's Hospital, United States
  3. Harvard Stem Cell Institute, United States
  4. Aix Marseille University, CNRS, LAI, France
  5. Harvard Medical School, United States

Abstract

Human muscle is a hierarchically organised tissue with its contractile cells called myofibers packed into large myofiber bundles. Each myofiber contains periodic myofibrils built by hundreds of contractile sarcomeres that generate large mechanical forces. To better understand the mechanisms that coordinate human muscle morphogenesis from tissue to molecular scales, we adopted a simple in vitro system using induced pluripotent stem cell-derived human myogenic precursors. When grown on an unrestricted two-dimensional substrate, developing myofibers spontaneously align and self-organise into higher-order myofiber bundles, which grow and consolidate to stable sizes. Following a transcriptional boost of sarcomeric components, myofibrils assemble into chains of periodic sarcomeres that emerge across the entire myofiber. More efficient myofiber bundling accelerates the speed of sarcomerogenesis suggesting that tension generated by bundling promotes sarcomerogenesis. We tested this hypothesis by directly probing tension and found that tension build-up precedes sarcomere assembly and increases within each assembling myofibril. Furthermore, we found that myofiber ends stably attach to other myofibers using integrin-based attachments and thus myofiber bundling coincides with stable myofiber bundle attachment in vitro. A failure in stable myofiber attachment results in a collapse of the myofibrils. Overall, our results strongly suggest that mechanical tension across sarcomeric components as well as between differentiating myofibers is key to coordinate the multi-scale self-organisation of muscle morphogenesis.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for all Figures; Table S1 contains the analysis of the sequencing data shown in Figure 3

The following previously published data sets were used

Article and author information

Author details

  1. Qiyan Mao

    Turing Centre for Living Systems, Aix Marseille University, CNRS, IDBM, Marseille, France
    For correspondence
    qiyan.mao@univ-amu.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5564-0457
  2. Achyuth Acharya

    Turing Centre for Living Systems, Aix Marseille University, CNRS, IDBM, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Alejandra Rodríguez-delaRosa

    Department of Pathology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Fabio Marchiano

    Turing Centre for Living Systems, Aix Marseille University, CNRS, IDBM, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Benoit Dehapiot

    Turing Centre for Living Systems, Aix Marseille University, CNRS, IDBM, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7559-5497
  6. Ziad Al Tanoury

    Department of Pathology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jyoti Rao

    Department of Pathology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Margarete Díaz-Cuadros

    Department of Pathology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Arian Mansur

    Harvard Stem Cell Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Erica Wagner

    Department of Pathology, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Claire Chardes

    Turing Centre for Living Systems, Aix Marseille University, CNRS, IDBM, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
  12. Vandana Gupta

    Department of Medicine, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4057-8451
  13. Pierre-François Lenne

    Turing Centre for Living Systems, Aix Marseille University, CNRS, IDBM, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1066-7506
  14. Bianca H Habermann

    Turing Centre for Living Systems, Aix Marseille University, CNRS, IDBM, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2457-7504
  15. Olivier Theodoly

    Turing Centre for Living Systems, Aix Marseille University, CNRS, LAI, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
  16. Olivier Pourquié

    Department of Genetics, Harvard Medical School, Boston, United States
    For correspondence
    pourquie@genetics.med.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
  17. Frank Schnorrer

    Turing Centre for Living Systems, Aix Marseille University, CNRS, IDBM, Marseille, France
    For correspondence
    frank.schnorrer@univ-amu.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9518-7263

Funding

Human Frontier Science Program (RGP0052/2018)

  • Frank Schnorrer

Agence Nationale de la Recherche (ANR-18-CE45-0016-01 MITO-DYNAMICS)

  • Bianca H Habermann

Agence Nationale de la Recherche (Agence Nationale de la Recherche (ANR))

  • Fabio Marchiano

Agence Nationale de la Recherche (ANR-10-INBS-04-01)

  • Pierre-François Lenne

Agence Nationale de la Recherche (ANR-16-CONV-0001)

  • Frank Schnorrer

Aix-Marseille Université (ANR-16-CONV-0001)

  • Frank Schnorrer

Turing Centre for Living Systems (ANR-16-CONV-0001)

  • Frank Schnorrer

Eunice Kennedy Shriver National Institute of Child Health and Human Development (F31HD100033)

  • Margarete Díaz-Cuadros

la Caixa" Foundation " (LCF/BQ/AA18/11680032)

  • Alejandra Rodríguez-delaRosa

Human Frontier Science Program (RGP0052/2018)

  • Olivier Pourquié

Centre National de la Recherche Scientifique

  • Frank Schnorrer

Centre National de la Recherche Scientifique

  • Pierre-François Lenne

Centre National de la Recherche Scientifique

  • Bianca H Habermann

European Research Council (ERC-2019-SyG 856118)

  • Frank Schnorrer

Aix-Marseille Université (ANR-11-IDEX-0001-02)

  • Frank Schnorrer

Agence Nationale de la Recherche (MUSCLE-FORCES)

  • Frank Schnorrer

Agence Nationale de la Recherche (ANR-18-CE45-0016-01 MITO-DYNAMICS)

  • Frank Schnorrer

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

Reviewing Editor

  1. Guy Tanentzapf, University of British Columbia, Canada

Version history

  1. Preprint posted: October 25, 2021 (view preprint)
  2. Received: December 23, 2021
  3. Accepted: August 2, 2022
  4. Accepted Manuscript published: August 3, 2022 (version 1)
  5. Version of Record published: August 15, 2022 (version 2)

Copyright

© 2022, Mao 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

  • 1,875
    Page views
  • 393
    Downloads
  • 3
    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. Qiyan Mao
  2. Achyuth Acharya
  3. Alejandra Rodríguez-delaRosa
  4. Fabio Marchiano
  5. Benoit Dehapiot
  6. Ziad Al Tanoury
  7. Jyoti Rao
  8. Margarete Díaz-Cuadros
  9. Arian Mansur
  10. Erica Wagner
  11. Claire Chardes
  12. Vandana Gupta
  13. Pierre-François Lenne
  14. Bianca H Habermann
  15. Olivier Theodoly
  16. Olivier Pourquié
  17. Frank Schnorrer
(2022)
Tension-driven multi-scale self-organisation in human iPSC-derived muscle fibers
eLife 11:e76649.
https://doi.org/10.7554/eLife.76649

Share this article

https://doi.org/10.7554/eLife.76649

Further reading

    1. Developmental Biology
    2. Evolutionary Biology
    Paul Knabl, Alexandra Schauer ... Grigory Genikhovich
    Research Article

    BMP signaling has a conserved function in patterning the dorsal-ventral body axis in Bilateria and the directive axis in anthozoan cnidarians. So far, cnidarian studies have focused on the role of different BMP signaling network components in regulating pSMAD1/5 gradient formation. Much less is known about the target genes downstream of BMP signaling. To address this, we generated a genome-wide list of direct pSMAD1/5 target genes in the anthozoan Nematostella vectensis, several of which were conserved in Drosophila and Xenopus. Our ChIP-seq analysis revealed that many of the regulatory molecules with documented bilaterally symmetric expression in Nematostella are directly controlled by BMP signaling. We identified several so far uncharacterized BMP-dependent transcription factors and signaling molecules, whose bilaterally symmetric expression may be indicative of their involvement in secondary axis patterning. One of these molecules is zswim4-6, which encodes a novel nuclear protein that can modulate the pSMAD1/5 gradient and potentially promote BMP-dependent gene repression.

    1. Biochemistry and Chemical Biology
    2. Developmental Biology
    Sima Stroganov ,  Talia   Harris  ... Michal Neeman
    Research Article

    Background: Fetal growth restriction (FGR) is a pregnancy complication in which a newborn fails to achieve its growth potential, increasing the risk of perinatal morbidity and mortality. Chronic maternal gestational hypoxia, as well as placental insufficiency are associated with increased FGR incidence; however, the molecular mechanisms underlying FGR remain unknown.

    Methods: Pregnant mice were subjected to acute or chronic hypoxia (12.5% O2) resulting in reduced fetal weight. Placenta oxygen transport was assessed by blood oxygenation level dependent (BOLD) contrast magnetic resonance imaging (MRI). The placentae were analyzed via immunohistochemistry and in situ hybridization. Human placentae were selected from FGR and matched controls and analyzed by immunohistochemistry (IHC). Maternal and cord sera were analyzed by mass spectrometry.

    Results: We show that murine acute and chronic gestational hypoxia recapitulates FGR phenotype and affects placental structure and morphology. Gestational hypoxia decreased labyrinth area, increased the incidence of red blood cells (RBCs) in the labyrinth while expanding the placental spiral arteries (SpA) diameter. Hypoxic placentae exhibited higher hemoglobin-oxygen affinity compared to the control. Placental abundance of Bisphosphoglycerate mutase (BPGM) was upregulated in the syncytiotrophoblast and spiral artery trophoblast cells (SpA TGCs) in the murine gestational hypoxia groups compared to the control. Hif1a levels were higher in the acute hypoxia group compared to the control. In contrast, human FGR placentae exhibited reduced BPGM levels in the syncytiotrophoblast layer compared to placentae from healthy uncomplicated pregnancies. Levels of 2,3 BPG, the product of BPGM, were lower in cord serum of human FGR placentae compared to control. Polar expression of BPGM, was found in both human and mouse placentae syncytiotrophoblast, with higher expression facing the maternal circulation. Moreover, in the murine SpA TGCs expression of BPGM was concentrated exclusively in the apical cell side, in direct proximity to the maternal circulation.

    Conclusions: This study suggests a possible involvement of placental BPGM in maternal-fetal oxygen transfer, and in the pathophysiology of FGR.

    Funding: This work was supported by the Weizmann Krenter Foundation and the Weizmann - Ichilov (Tel Aviv Sourasky Medical Center) Collaborative Grant in Biomedical Research, and by the Minerva Foundation (to MN), by the ISF KillCorona grant 3777/19 (to MN, MK).