1. Cell Biology
  2. Stem Cells and Regenerative Medicine

Modeling the ACVR1R206H mutation in human skeletal muscle stem cells

  1. Emilie Barruet  Is a corresponding author
  2. Steven M Garcia
  3. Jake Wu
  4. Blanca M Morales
  5. Stanley Tamaki
  6. Tania Moody
  7. Jason H Pomerantz
  8. Edward C Hsiao  Is a corresponding author
  1. University of California, San Francisco, United States
https://doi.org/10.7554/eLife.66107
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Cite this article
  1. Emilie Barruet
  2. Steven M Garcia
  3. Jake Wu
  4. Blanca M Morales
  5. Stanley Tamaki
  6. Tania Moody
  7. Jason H Pomerantz
  8. Edward C Hsiao
(2021)
Modeling the ACVR1R206H mutation in human skeletal muscle stem cells
eLife 10:e66107.
https://doi.org/10.7554/eLife.66107
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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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Emilie Barruet

    Departments of Surgery and Orofacial Sciences, Division of Plastic Surgery, Program in Craniofacial Biology, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States
    For correspondence
    emilie.barruet@ucsf.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4593-024X

  2. Steven M Garcia

    Departments of Surgery and Orofacial Sciences, Division of Plastic Surgery, Program in Craniofacial Biology, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7833-6677

  3. Jake Wu

    Departments of Surgery and Orofacial Sciences, Division of Plastic Surgery, Program in Craniofacial Biology, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  4. Blanca M Morales

    Institute for Human Genetics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  5. Stanley Tamaki

    Departments of Surgery and Orofacial Sciences, Division of Plastic Surgery, Program in Craniofacial Biology, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  6. Tania Moody

    Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  7. Jason H Pomerantz

    Departments of Surgery and Orofacial Sciences, Division of Plastic Surgery, Program in Craniofacial Biology, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5107-1883

  8. Edward C Hsiao

    Division of Endocrinology and Metabolism, Department of Medicine Institute for Human Genetics, University of California, San Francisco, San Francisco, United States
    For correspondence
    Edward.Hsiao@ucsf.edu
    Competing interests
    Edward C Hsiao, ECH receives clinical trial research funding from Clementia Pharmaceuticals, an Ipsen company, and Neurocrine Biosciences, Inc., through his institution. ECH received prior funding from Regeneron Pharmaceuticals, through his institution. ECH serves in an unpaid capacity on the international FOP Association Medical Registry Advisory Board, on the International Clinical Council on FOP, and on the Fibrous Dysplasia Foundation Medical Advisory Board. These activities pose no conflicts for the presented research..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8924-106X

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.

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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  1. Emilie Barruet
  2. Steven M Garcia
  3. Jake Wu
  4. Blanca M Morales
  5. Stanley Tamaki
  6. Tania Moody
  7. Jason H Pomerantz
  8. Edward C Hsiao
(2021)
Modeling the ACVR1R206H mutation in human skeletal muscle stem cells
eLife 10:e66107.
https://doi.org/10.7554/eLife.66107

Share this article

https://doi.org/10.7554/eLife.66107

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