TY - JOUR
T1 - Diverse effector and regulatory functions of fibro/adipogenic progenitors during skeletal muscle fibrosis in muscular dystrophy
AU - Wang, Xingyu
AU - Chen, Jianming
AU - Homma, Sachiko T.
AU - Wang, Yinhang
AU - Smith, Gregory R.
AU - Ruf-Zamojski, Frederique
AU - Sealfon, Stuart C.
AU - Zhou, Lan
N1 - Funding Information:
Research reported in this publication was supported by the National Institute of Arthritis And Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number 1R01AR074428 (LZ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2022 The Author(s)
PY - 2023/1/20
Y1 - 2023/1/20
N2 - Fibrosis is a prominent pathological feature of skeletal muscle in Duchenne muscular dystrophy (DMD). The commonly used disease mouse model, mdx5cv, displays progressive fibrosis in the diaphragm but not limb muscles. We use single-cell RNA sequencing to determine the cellular expression of the genes involved in extracellular matrix (ECM) production and degradation in the mdx5cv diaphragm and quadriceps. We find that fibro/adipogenic progenitors (FAPs) are not only the primary source of ECM but also the predominant cells that express important ECM regulatory genes, including Ccn2, Ltbp4, Mmp2, Mmp14, Timp1, Timp2, and Loxs. The effector and regulatory functions are exerted by diverse FAP clusters which are different between diaphragm and quadriceps, indicating their activation by different tissue microenvironments. FAPs are more abundant in diaphragm than in quadriceps. Our findings suggest that the development of anti-fibrotic therapy for DMD should target not only the ECM production but also the pro-fibrogenic regulatory functions of FAPs.
AB - Fibrosis is a prominent pathological feature of skeletal muscle in Duchenne muscular dystrophy (DMD). The commonly used disease mouse model, mdx5cv, displays progressive fibrosis in the diaphragm but not limb muscles. We use single-cell RNA sequencing to determine the cellular expression of the genes involved in extracellular matrix (ECM) production and degradation in the mdx5cv diaphragm and quadriceps. We find that fibro/adipogenic progenitors (FAPs) are not only the primary source of ECM but also the predominant cells that express important ECM regulatory genes, including Ccn2, Ltbp4, Mmp2, Mmp14, Timp1, Timp2, and Loxs. The effector and regulatory functions are exerted by diverse FAP clusters which are different between diaphragm and quadriceps, indicating their activation by different tissue microenvironments. FAPs are more abundant in diaphragm than in quadriceps. Our findings suggest that the development of anti-fibrotic therapy for DMD should target not only the ECM production but also the pro-fibrogenic regulatory functions of FAPs.
KW - Genetics
KW - Musculoskeletal medicine
UR - http://www.scopus.com/inward/record.url?scp=85144836513&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2022.105775
DO - 10.1016/j.isci.2022.105775
M3 - Article
AN - SCOPUS:85144836513
SN - 2589-0042
VL - 26
JO - iScience
JF - iScience
IS - 1
M1 - 105775
ER -