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Title: Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion
Authors: Stearns-Reider, Kristen M.
D'Amore, Antonio
Beezhold, Kevin
Rothrauff, Benjamin
Cavalli, Loredana
Wagner, William R.
Vorp, David A.
Tsamis, Alkiviadis
Shinde, Sunita
Zhang, Changqing
Barchowsky, Aaron
Rando, Thomas A.
Tuan, Rocky S.
Ambrosio, Fabrisia
First Published: 30-Mar-2017
Publisher: Wiley for Anatomical Society of Great Britain and Ireland
Citation: Aging Cell, 2017
Abstract: Age-related declines in skeletal muscle regeneration have been attributed to muscle stem cell (MuSC) dysfunction. Aged MuSCs display a fibrogenic conversion, leading to fibrosis and impaired recovery after injury. Although studies have demonstrated the influence of in vitro substrate characteristics on stem cell fate, whether and how aging of the extracellular matrix (ECM) affects stem cell behavior has not been investigated. Here, we investigated the direct effect of the aged muscle ECM on MuSC lineage specification. Quantification of ECM topology and muscle mechanical properties reveals decreased collagen tortuosity and muscle stiffening with increasing age. Age-related ECM alterations directly disrupt MuSC responses, and MuSCs seeded ex vivo onto decellularized ECM constructs derived from aged muscle display increased expression of fibrogenic markers and decreased myogenicity, compared to MuSCs seeded onto young ECM. This fibrogenic conversion is recapitulated in vitro when MuSCs are seeded directly onto matrices elaborated by aged fibroblasts. When compared to young fibroblasts, fibroblasts isolated from aged muscle display increased nuclear levels of the mechanosensors, Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ), consistent with exposure to a stiff microenvironment in vivo. Accordingly, preconditioning of young fibroblasts by seeding them onto a substrate engineered to mimic the stiffness of aged muscle increases YAP/TAZ nuclear translocation and promotes secretion of a matrix that favors MuSC fibrogenesis. The findings here suggest that an age-related increase in muscle stiffness drives YAP/TAZ-mediated pathogenic expression of matricellular proteins by fibroblasts, ultimately disrupting MuSC fate.
DOI Link: 10.1111/acel.12578
ISSN: 1474-9718
eISSN: 1474-9726
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2017. This is an open-access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Description: Additional Supporting Information may be found online in the supporting information tab for this article. Fig. S1 The histomorphometric analysis of collagen type III and elastin in young and old skeletal muscle. Fig. S2 DAPI and Tcf4 staining of fibroblasts isolated from the skeletal muscle of young and old mice. Fig. S3 The microarray gene expression profiling in young and old fibroblasts. Fig. S4 The expression of Pax7 & MyoD in the human muscle stem cells utilized in cell seeding experiments. Fig. S5 The resulting expression of desmin (A) and Tcf4 (B) from MuSCs seeded onto young and old decellularized and solubilized matrices. Fig. S6 The analysis of collagen composition between ECM deposited by young and old fibroblasts. Fig. S7 The dose response of latrunculin A (A) and leptomycin B (B).
Appears in Collections:Published Articles, Dept. of Engineering

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