Hydrogel biomaterials that stiffen and soften on demand reveal that skeletal muscle stem cells harbor a mechanical memory.

Autor:	Madl CM; Department of Microbiology and Immunology, Baxter Laboratory for Stem Cell Biology, Stanford University, Stanford, CA 94305.; Department of Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA 19104., Wang YX; Department of Microbiology and Immunology, Baxter Laboratory for Stem Cell Biology, Stanford University, Stanford, CA 94305., Holbrook CA; Department of Microbiology and Immunology, Baxter Laboratory for Stem Cell Biology, Stanford University, Stanford, CA 94305., Su S; Department of Microbiology and Immunology, Baxter Laboratory for Stem Cell Biology, Stanford University, Stanford, CA 94305., Shi X; Department of Physiology, Perelman School of Medicine and Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104., Byfield FJ; Department of Physiology, Perelman School of Medicine and Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104., Wicki G; Department of Microbiology and Immunology, Baxter Laboratory for Stem Cell Biology, Stanford University, Stanford, CA 94305.; Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne, Lausanne CH-1015, Switzerland., Flaig IA; Department of Microbiology and Immunology, Baxter Laboratory for Stem Cell Biology, Stanford University, Stanford, CA 94305.; Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne, Lausanne CH-1015, Switzerland., Blau HM; Department of Microbiology and Immunology, Baxter Laboratory for Stem Cell Biology, Stanford University, Stanford, CA 94305.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Aug 27; Vol. 121 (35), pp. e2406787121. Date of Electronic Publication: 2024 Aug 20.
DOI:	10.1073/pnas.2406787121
Abstrakt:	Muscle stem cells (MuSCs) are specialized cells that reside in adult skeletal muscle poised to repair muscle tissue. The ability of MuSCs to regenerate damaged tissues declines markedly with aging and in diseases such as Duchenne muscular dystrophy, but the underlying causes of MuSC dysfunction remain poorly understood. Both aging and disease result in dramatic increases in the stiffness of the muscle tissue microenvironment from fibrosis. MuSCs are known to lose their regenerative potential if cultured on stiff plastic substrates. We sought to determine whether MuSCs harbor a memory of their past microenvironment and if it can be overcome. We tested MuSCs in situ using dynamic hydrogel biomaterials that soften or stiffen on demand in response to light and found that freshly isolated MuSCs develop a persistent memory of substrate stiffness characterized by loss of proliferative progenitors within the first three days of culture on stiff substrates. MuSCs cultured on soft hydrogels had altered cytoskeletal organization and activity of Rho and Rac guanosine triphosphate hydrolase (GTPase) and Yes-associated protein mechanotransduction pathways compared to those on stiff hydrogels. Pharmacologic inhibition identified RhoA activation as responsible for the mechanical memory phenotype, and single-cell RNA sequencing revealed a molecular signature of the mechanical memory. These studies highlight that microenvironmental stiffness regulates MuSC fate and leads to MuSC dysfunction that is not readily reversed by changing stiffness. Our results suggest that stiffness can be circumvented by targeting downstream signaling pathways to overcome stem cell dysfunction in aged and disease states with aberrant fibrotic tissue mechanics. Competing Interests: Competing interests statement:H.M.B. is a named inventor on patent applications held by Stanford University regarding prostaglandin signaling and muscle regeneration licensed to Epirium Bio. Y.X.W., C.A.H., and H.M.B. are named inventors on a patent application held by Stanford University for processing of multiplex microscopy images. H.M.B. is a cofounder of Myoforte Therapeutics, which was acquired by Epirium Bio, and receives consulting fees and has equity and stock options from Epirium Bio. C.M.M., S.S, X.S., F.J.B., G.W., and I.A.F. declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Databáze:	MEDLINE
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