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
Version 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
-
- 1,950
- views
-
- 403
- downloads
-
- 8
- 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)
Tension-driven multi-scale self-organisation in human iPSC-derived muscle fibers
eLife 11:e76649.
https://doi.org/10.7554/eLife.76649
Further reading
-
- Computational and Systems Biology
- Developmental Biology
Organisms utilize gene regulatory networks (GRN) to make fate decisions, but the regulatory mechanisms of transcription factors (TF) in GRNs are exceedingly intricate. A longstanding question in this field is how these tangled interactions synergistically contribute to decision-making procedures. To comprehensively understand the role of regulatory logic in cell fate decisions, we constructed a logic-incorporated GRN model and examined its behavior under two distinct driving forces (noise-driven and signal-driven). Under the noise-driven mode, we distilled the relationship among fate bias, regulatory logic, and noise profile. Under the signal-driven mode, we bridged regulatory logic and progression-accuracy trade-off, and uncovered distinctive trajectories of reprogramming influenced by logic motifs. In differentiation, we characterized a special logic-dependent priming stage by the solution landscape. Finally, we applied our findings to decipher three biological instances: hematopoiesis, embryogenesis, and trans-differentiation. Orthogonal to the classical analysis of expression profile, we harnessed noise patterns to construct the GRN corresponding to fate transition. Our work presents a generalizable framework for top-down fate-decision studies and a practical approach to the taxonomy of cell fate decisions.
-
- Developmental Biology
- Evolutionary Biology
Despite rapid evolution across eutherian mammals, the X-linked MIR-506 family miRNAs are located in a region flanked by two highly conserved protein-coding genes (SLITRK2 and FMR1) on the X chromosome. Intriguingly, these miRNAs are predominantly expressed in the testis, suggesting a potential role in spermatogenesis and male fertility. Here, we report that the X-linked MIR-506 family miRNAs were derived from the MER91C DNA transposons. Selective inactivation of individual miRNAs or clusters caused no discernible defects, but simultaneous ablation of five clusters containing 19 members of the MIR-506 family led to reduced male fertility in mice. Despite normal sperm counts, motility, and morphology, the KO sperm were less competitive than wild-type sperm when subjected to a polyandrous mating scheme. Transcriptomic and bioinformatic analyses revealed that these X-linked MIR-506 family miRNAs, in addition to targeting a set of conserved genes, have more targets that are critical for spermatogenesis and embryonic development during evolution. Our data suggest that the MIR-506 family miRNAs function to enhance sperm competitiveness and reproductive fitness of the male by finetuning gene expression during spermatogenesis.
