An injury-responsive Rac-to-Rho GTPase switch drives activation of muscle stem cells through rapid cytoskeletal remodeling

Allison P Kann; Margaret Hung; Wei Wang; Jo Nguyen; Penney M Gilbert; Zhuhao Wu; Robert S Krauss

doi:10.1016/j.stem.2022.04.016

An injury-responsive Rac-to-Rho GTPase switch drives activation of muscle stem cells through rapid cytoskeletal remodeling

Cell Stem Cell. 2022 Jun 2;29(6):933-947.e6. doi: 10.1016/j.stem.2022.04.016. Epub 2022 May 20.

Authors

Allison P Kann¹, Margaret Hung¹, Wei Wang², Jo Nguyen³, Penney M Gilbert⁴, Zhuhao Wu², Robert S Krauss⁵

Affiliations

¹ Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
² Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
³ Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S3G9, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S3E1, Canada.
⁴ Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S3G9, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S3E1, Canada; Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S3G5, Canada.
⁵ Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: robert.krauss@mssm.edu.

Abstract

Many tissues harbor quiescent stem cells that are activated upon injury, subsequently proliferating and differentiating to repair tissue damage. Mechanisms by which stem cells sense injury and transition from quiescence to activation, however, remain largely unknown. Resident skeletal muscle stem cells (MuSCs) are essential orchestrators of muscle regeneration and repair. Here, with a combination of in vivo and ex vivo approaches, we show that quiescent MuSCs have elaborate, Rac GTPase-promoted cytoplasmic projections that respond to injury via the upregulation of Rho/ROCK signaling, facilitating projection retraction and driving downstream activation events. These early events involve rapid cytoskeletal rearrangements and occur independently of exogenous growth factors. This mechanism is conserved across a broad range of MuSC activation models, including injury, disease, and genetic loss of quiescence. Our results redefine MuSC activation and present a central mechanism by which quiescent stem cells initiate responses to injury.

Keywords: GTPase; Rac1; Rho; cytoskeleton; mechanosignaling; muscle stem cell; quiescence; satellite cell; stem cell activation; stem cell niche.

Publication types

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

MeSH terms

Muscle Fibers, Skeletal / metabolism
Muscle, Skeletal
Myoblasts / metabolism
Satellite Cells, Skeletal Muscle* / metabolism
Stem Cells / metabolism
rho GTP-Binding Proteins* / metabolism

Substances

rho GTP-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding