Aging Disrupts Muscle Stem Cell Function by Impairing Matricellular WISP1 Secretion from Fibro-Adipogenic Progenitors

Cell Stem Cell. 2019 Mar 7;24(3):433-446.e7. doi: 10.1016/j.stem.2018.12.014. Epub 2019 Jan 24.


Research on age-related regenerative failure of skeletal muscle has extensively focused on the phenotypes of muscle stem cells (MuSCs). In contrast, the impact of aging on regulatory cells in the MuSC niche remains largely unexplored. Here, we demonstrate that aging impairs the function of mouse fibro-adipogenic progenitors (FAPs) and thereby indirectly affects the myogenic potential of MuSCs. Using transcriptomic profiling, we identify WNT1 Inducible Signaling Pathway Protein 1 (WISP1) as a FAP-derived matricellular signal that is lost during aging. WISP1 is required for efficient muscle regeneration and controls the expansion and asymmetric commitment of MuSCs through Akt signaling. Transplantation of young FAPs or systemic treatment with WISP1 restores the myogenic capacity of MuSCs in aged mice and rescues skeletal muscle regeneration. Our work establishes that loss of WISP1 from FAPs contributes to MuSC dysfunction in aged skeletal muscles and demonstrates that this mechanism can be targeted to rejuvenate myogenesis.

Keywords: CCN4; WISP1; aging; fibro-adipogenic progenitors; matricellular signaling; muscle stem cells; regeneration; satellite cell; skeletal muscle; stem cell niche.

Publication types

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

MeSH terms

  • Adipocytes / cytology
  • Adipocytes / metabolism*
  • Adipogenesis
  • Aging / metabolism*
  • Animals
  • CCN Intercellular Signaling Proteins / deficiency
  • CCN Intercellular Signaling Proteins / metabolism*
  • Cells, Cultured
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / metabolism*
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / metabolism*
  • Stem Cells / cytology
  • Stem Cells / metabolism*


  • CCN Intercellular Signaling Proteins
  • CCN4 protein, human
  • CCN4 protein, mouse
  • Proto-Oncogene Proteins