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

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

Author information

1
Nestlé Research, EPFL Innovation Park, 1015 Lausanne, Switzerland; School of Life Sciences, Ecole Polytechnique Federale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
2
Nestlé Research, EPFL Innovation Park, 1015 Lausanne, Switzerland.
3
Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON K1H8L6, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
4
Institut NeuroMyoGène, Université Claude Bernard Lyon 1, CNRS 5310, INSERM U1217, Lyon, France.
5
Nestlé Research, EPFL Innovation Park, 1015 Lausanne, Switzerland; Département de pharmacologie et physiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, QC, Canada.
6
Nestlé Research, EPFL Innovation Park, 1015 Lausanne, Switzerland; School of Life Sciences, Ecole Polytechnique Federale de Lausanne (EPFL), 1015 Lausanne, Switzerland. Electronic address: jerome.feige@rd.nestle.com.

Abstract

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

PMID:
30686765
PMCID:
PMC6408230
[Available on 2020-03-07]
DOI:
10.1016/j.stem.2018.12.014

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