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.
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
-
- 2,226
- views
-
- 432
- downloads
-
- 16
- 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
-
- Developmental Biology
Maternal obesity has deleterious effects on the process of establishing oocyte DNA methylation; yet the underlying mechanisms remain unclear. Here, we found that maternal obesity disrupted the genomic methylation of oocytes using a high-fat diet (HFD) induced mouse model, at least a part of which was transmitted to the F2 oocytes and livers via females. We further examined the metabolome of serum and found that the serum concentration of melatonin was reduced. Exogenous melatonin treatment significantly reduced the hyper-methylation of HFD oocytes, and the increased expression of DNMT3a and DNMT1 in HFD oocytes was also decreased. These suggest that melatonin may play a key role in the disrupted genomic methylation in the oocytes of obese mice. To address how melatonin regulates the expression of DNMTs, the function of melatonin was inhibited or activated upon oocytes. Results revealed that melatonin may regulate the expression of DNMTs via the cAMP/PKA/CREB pathway. These results suggest that maternal obesity induces genomic methylation alterations in oocytes, which can be partly transmitted to F2 in females, and that melatonin is involved in regulating the hyper-methylation of HFD oocytes by increasing the expression of DNMTs via the cAMP/PKA/CREB pathway.
-
- Developmental Biology
- Neuroscience
Two major ligand-receptor signaling axes – endothelin Edn3 and its receptor Ednrb, and glial-derived neurotrophic factor (GDNF) and its receptor Ret – are required for migration of enteric nervous system (ENS) progenitors to the hindgut. Mutations in either component cause colonic aganglionosis, also called Hirschsprung disease. Here, we have used Wnt1Cre and Pax2Cre in mice to show that these driver lines label distinct ENS lineages during progenitor migration and in their terminal hindgut fates. Both Cre lines result in Hirschsprung disease when combined with conditional Ednrb or conditional Ret alleles. In vitro explant assays and analysis of lineage-labeled mutant embryos show that GDNF but not Edn3 is a migration cue for cells of both lineages. Instead, Edn3-Ednrb function is required in both for GDNF responsiveness albeit in different ways: by expanding the Ret+ population in the Pax2Cre lineage, and by supporting Ret function in Wnt1Cre-derived cells. Our results demonstrate that two distinct lineages of progenitors give rise to the ENS, and that these divergently utilize endothelin signaling to support migration to the hindgut.
