Modeling the ACVR1R206H mutation in human skeletal muscle stem cells
- University of California, San Francisco, United States
Abstract
Abnormalities in skeletal muscle repair can lead to poor function and complications such as scarring or heterotopic ossification (HO). Here, we use fibrodysplasia ossificans progressiva (FOP), a disease of progressive HO caused by ACVR1R206H (Activin receptor type-1 receptor) mutation, to elucidate how ACVR1 affects skeletal muscle repair. Rare and unique primary FOP human muscle stem cells (Hu-MuSCs) isolated from cadaveric skeletal muscle demonstrated increased ECM marker expression, showed skeletal muscle-specific impaired engraftment and regeneration ability. Human induced pluripotent stem cell (iPSC)-derived muscle stem/progenitor cells (iMPCs) single cell transcriptome analyses from FOP also revealed unusually increased ECM and osteogenic marker expression compared to control iMPCs. These results show that iMPCs can recapitulate many aspects of Hu-MuSCs for detailed in vitro study, that ACVR1 is a key regulator of Hu-MuSC function and skeletal muscle repair; and that ACVR1 activation in iMPCs or Hu-MuSCs may contribute to HO by changing the local tissue environment.
Data availability
Sequencing data have been deposited in GEO under accession codes GSE151918. All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 4,5,6. The dataset used for the primary Hu-MuSCs can be found here, https://datadryad.org/stash/landing/show?id=doi%3A10.7272%2FQ65X273X.
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Control and FOP Human iPSC derived myogenic cell single cell RNA sequencingNCBI Gene Expression Omnibus, GSE151918.
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Functionally heterogeneous human satellite cells identified by single cell RNA sequencinghttps://creativecommons.org/publicdomain/zero/1.0/.
Article and author information
Author details
Funding
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR066735)
- Edward C Hsiao
French Muscular Association (Trampoline grant)
- Emilie Barruet
- Edward C Hsiao
Radiant Hope Foundation
- Edward C Hsiao
UCSF Cohort Development Grant
- Edward C Hsiao
California Institute for Regenerative Medicine (TG2-01153)
- Emilie Barruet
UCSF Program for Breakthrough Biomedical Research
- Emilie Barruet
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR072638-03)
- Jason H Pomerantz
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mouse studies were performed using protocols approved by the UCSF Institutional Animal Care and Use Committee. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (AN181101-02A) of the University of California, San Francisco.
Human subjects: Human samples were collected through the University of California - San Francisco Biospecimens and Skeletal Tissues for Rare and Orphan Disease Genetics (BSTROnG) Biobank, using protocols approved by the UCSF Institutional Review Board (10-03053 and 11-06711). All participants provided written consent, which includes consent to collect, use, and publish research data.
Reviewing Editor
- Cheryl Ackert-Bicknell, University of Colorado, United States
Publication history
- Received: December 29, 2020
- Accepted: November 9, 2021
- Accepted Manuscript published: November 10, 2021 (version 1)
- Version of Record published: December 21, 2021 (version 2)
Copyright
© 2021, Barruet 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.
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Modeling the ACVR1R206H mutation in human skeletal muscle stem cells
eLife 10:e66107.
https://doi.org/10.7554/eLife.66107
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