Modeling the ACVR1 R206H mutation in human skeletal muscle stem cells

• Published in: eLife Vol. 10
• Main Authors: Barruet, Emilie, Garcia, Steven M, Wu, Jake, Morales, Blanca M, Tamaki, Stanley, Moody, Tania, Pomerantz, Jason H, Hsiao, Edward C
• Format: Journal Article
• Language: English
• Published: England 10-11-2021
• Subjects: 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; ACVR1; stem cells; fibrodysplasia ossificans progressivav FOP; cell biology; human satellite cells hu-SCs; regenerative medicine; heterotopic ossification; human induced pluripotent stem cells iPSCs; human; human muscle stem cells hu-MuSCs
• ISSN: 2050-084X

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
(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.