Tension-driven multi-scale self-organisation in human iPSC-derived muscle fibers
- Aix Marseille University, CNRS, IDBM, France
- Brigham and Women's Hospital, United States
- Harvard Stem Cell Institute, United States
- Aix Marseille University, CNRS, LAI, France
- 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
-
GSE164874_SecondaryDifferentiation_raw_counts.xlsxNCBI Gene Expression Omnibus, GSE164874.
Article and author information
Author details
Pierre-François Lenne
Bianca H Habermann
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
- Guy Tanentzapf, University of British Columbia, Canada
Publication history
- Preprint posted: October 25, 2021 (view preprint)
- Received: December 23, 2021
- Accepted: August 2, 2022
- Accepted Manuscript published: August 3, 2022 (version 1)
- 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
-
- 1,391
- Page views
-
- 353
- 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)
Tension-driven multi-scale self-organisation in human iPSC-derived muscle fibers
eLife 11:e76649.
https://doi.org/10.7554/eLife.76649
Further reading
-
- Developmental Biology
- Evolutionary Biology
Genetic studies in human and mice have established a dual role for Vsx genes in retina development: an early function in progenitors’ specification, and a later requirement for bipolar-cells fate determination. Despite their conserved expression patterns, it is currently unclear to which extent Vsx functions are also conserved across vertebrates, as mutant models are available only in mammals. To gain insight into vsx function in teleosts, we have generated vsx1 and vsx2 CRISPR/Cas9 double knockouts (vsxKO) in zebrafish. Our electrophysiological and histological analyses indicate severe visual impairment and bipolar cells depletion in vsxKO larvae, with retinal precursors being rerouted toward photoreceptor or Müller glia fates. Surprisingly, neural retina is properly specified and maintained in mutant embryos, which do not display microphthalmia. We show that although important cis-regulatory remodelling occurs in vsxKO retinas during early specification, this has little impact at a transcriptomic level. Our observations point to genetic redundancy as an important mechanism sustaining the integrity of the retinal specification network, and to Vsx genes regulatory weight varying substantially among vertebrate species.
-
- Developmental Biology
Single-cell transcriptome analysis of zebrafish cells clarifies the signalling pathways controlling skin formation and reveals that some cells produce proteins required for human teeth to acquire their enamel.
