Injury-mediated stiffening persistently activates muscle stem cells through YAP and TAZ mechanotransduction
Autor: | Thomas O. Vogler, Tobin E. Brown, K. Arda Günay, Kendra L. Bannister, Alicia A. Cutler, Bradley Pawlikowski, Jason S. Silver, Bradley B. Olwin, Cameron J. Rogowski, Austin G. Mckay, Olivia J. Bednarski, Kristi S. Anseth, Frank W. DelRio |
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Rok vydání: | 2021 |
Předmět: |
Materials Science
macromolecular substances WWTR1 010402 general chemistry 01 natural sciences Muscle hypertrophy 03 medical and health sciences medicine Myocyte Mechanotransduction Research Articles 030304 developmental biology 0303 health sciences Multidisciplinary Chemistry Regeneration (biology) technology industry and agriculture SciAdv r-articles Skeletal muscle Cell Biology Muscle stiffness musculoskeletal system 0104 chemical sciences Cell biology medicine.anatomical_structure cardiovascular system Stem cell circulatory and respiratory physiology Research Article |
Zdroj: | Science Advances |
ISSN: | 2375-2548 |
DOI: | 10.1126/sciadv.abe4501 |
Popis: | Skeletal muscle stiffening after injury induces proliferation and activation of muscle stem cells via YAP and TAZ signaling. The skeletal muscle microenvironment transiently remodels and stiffens after exercise and injury, as muscle ages, and in myopathic muscle; however, how these changes in stiffness affect resident muscle stem cells (MuSCs) remains understudied. Following muscle injury, muscle stiffness remained elevated after morphological regeneration was complete, accompanied by activated and proliferative MuSCs. To isolate the role of stiffness on MuSC behavior and determine the underlying mechanotransduction pathways, we cultured MuSCs on strain-promoted azide-alkyne cycloaddition hydrogels capable of in situ stiffening by secondary photocrosslinking of excess cyclooctynes. Using pre- to post-injury stiffness hydrogels, we found that elevated stiffness enhances migration and MuSC proliferation by localizing yes-associated protein 1 (YAP) and WW domain–containing transcription regulator 1 (WWTR1; TAZ) to the nucleus. Ablating YAP and TAZ in vivo promotes MuSC quiescence in postinjury muscle and prevents myofiber hypertrophy, demonstrating that persistent exposure to elevated stiffness activates mechanotransduction signaling maintaining activated and proliferating MuSCs. |
Databáze: | OpenAIRE |
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