Modeling the ACVR1R206H mutation in human skeletal muscle stem cells

Elife. 2021 Nov 10:10:e66107. doi: 10.7554/eLife.66107.

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 extracellular matric (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.

Keywords: ACVR1; cell biology; fibrodysplasia ossificans progressivav FOP; heterotopic ossification; human; human induced pluripotent stem cells iPSCs; human muscle stem cells hu-MuSCs; human satellite cells hu-SCs; regenerative medicine; stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / genetics*
  • Activin Receptors, Type I / metabolism
  • Adult
  • Animals
  • Female
  • Humans
  • Induced Pluripotent Stem Cells / physiology*
  • Mice
  • Middle Aged
  • Muscle Fibers, Skeletal / physiology*
  • Mutation*
  • Myositis Ossificans / genetics
  • Myositis Ossificans / metabolism
  • Myositis Ossificans / physiopathology*
  • Ossification, Heterotopic / genetics
  • Ossification, Heterotopic / metabolism
  • Ossification, Heterotopic / physiopathology
  • Signal Transduction / physiology

Substances

  • ACVR1 protein, human
  • Activin Receptors, Type I