@article{8daff517683d45e0943b0e1a188e4b7f,
title = "An injury-responsive Rac-to-Rho GTPase switch drives activation of muscle stem cells through rapid cytoskeletal remodeling",
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",
author = "Kann, {Allison P.} and Margaret Hung and Wei Wang and Jo Nguyen and Gilbert, {Penney M.} and Zhuhao Wu and Krauss, {Robert S.}",
note = "Funding Information: We thank Anna Kolstad for assistance with perfusion experiments and Philippe Soriano, Paul Wassarman, and Nicole Dubois for critical reading of the manuscript. This work was funded by a National Institute of Arthritis and Musculoskeletal and Skin Diseases grant to R.S.K. (AR070231), a Natural Sciences and Engineering Research Council grant to P.M.G. (RGPIN-2019-07144), a fellowship of the training program in stem cell research from the New York State Department of Health to A.P.K. (NYSTEM-C32561GG), a National Institute of Child Health and Development Training Grant fellowship to M.H. (T32 HD075735), a Connaught International Scholarship and Cecil Yip Doctoral Award to J.N. and the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai (P30 CA196521-Cancer Center Support Grant). Microscopy was performed at the Microscopy CoRE at the Icahn School of Medicine at Mount Sinai. Model images and schematics were created with BioRender.com. Conceptualization, A.P.K. and R.S.K.; methodology, A.P.K. and R.S.K.; validation and formal analysis, A.P.K.; investigation, A.P.K. M.H. W.W. and J.N.; writing – original draft, A.P.K. and R.S.K.; writing – review & editing, A.P.K. and R.S.K.; visualization, A.P.K.; supervision, R.S.K. Z.W. and P.M.G.; funding acquisition, A.P.K. R.S.K. M.H. J.N. and P.M.G. All authors approved the final manuscript. The authors declare no competing interests. Funding Information: We thank Anna Kolstad for assistance with perfusion experiments and Philippe Soriano, Paul Wassarman, and Nicole Dubois for critical reading of the manuscript. This work was funded by a National Institute of Arthritis and Musculoskeletal and Skin Diseases grant to R.S.K. ( AR070231 ), a Natural Sciences and Engineering Research Council grant to P.M.G. ( RGPIN-2019-07144 ), a fellowship of the training program in stem cell research from the New York State Department of Health to A.P.K. ( NYSTEM-C32561GG ), a National Institute of Child Health and Development Training Grant fellowship to M.H. ( T32 HD075735 ), a Connaught International Scholarship and Cecil Yip Doctoral Award to J.N., and the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai ( P30 CA196521 - Cancer Center Support Grant ). Microscopy was performed at the Microscopy CoRE at the Icahn School of Medicine at Mount Sinai. Model images and schematics were created with BioRender.com . Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = jun,
day = "2",
doi = "10.1016/j.stem.2022.04.016",
language = "English",
volume = "29",
pages = "933--947.e6",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "6",
}