title: Three distinct cell populations express extracellular matrix proteins and increase in number during skeletal muscle fibrosis.
abstract: Tissue extracellular matrix (ECM) provides structural support and creates unique environments for resident cells (Bateman JF, Boot-Handford RP, Lamandé SR.Nat Rev Genet10: 173-183, 2009; Kjaer M.Physiol Rev84: 649-98, 2004). However, the identities of cells responsible for creating specific ECM components have not been determined. In striated muscle, the identity of these cells becomes important in disease when ECM changes result in fibrosis and subsequent increased tissue stiffness and dysfunction. Here we describe a novel approach to isolate and identify cells that maintain the ECM in both healthy and fibrotic muscle. Using a collagen I reporter mouse, we show that there are three distinct cell populations that express collagen I in both healthy and fibrotic skeletal muscle. Interestingly, the number of collagen I-expressing cells in all three cell populations increases proportionally in fibrotic muscle, indicating that all cell types participate in the fibrosis process. Furthermore, while some profibrotic ECM and ECM-associated genes are significantly upregulated in fibrotic muscle, the fibrillar collagen gene expression profile is not qualitatively altered. This suggests that muscle fibrosis in this model results from an increased number of collagen I-expressing cells and not the initiation of a specific fibrotic collagen gene expression program. Finally, in fibrotic muscle, we show that these collagen I-expressing cell populations differentially express distinct ECM proteins-fibroblasts express the fibrillar components of ECM, fibro/adipogenic progenitors cells differentially express basal laminar proteins, and skeletal muscle progenitor cells differentially express genes important for the satellite cell.
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, California.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Chapman
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, California.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Mukund
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, California.
authors.forename: Shankar
authors.initials: S
authors.lastname: Subramaniam
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California.
authors.forename: David
authors.initials: D
authors.lastname: Brenner
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, California; rlieber@ric.org.|Department of Orthopaedic Surgery, University of California San Diego, La Jolla, California.|Department of Veteran's Affairs, La Jolla, California; and.|Rehabilitation Institute of Chicago, Chicago, Illinois.
authors.forename: Richard L
authors.identifier: http://orcid.org/0000-0002-7203-4520
authors.initials: RL
authors.lastname: Lieber
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis* / Q000145:classification; D005260:Female; D005355:Fibrosis; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000145:classification; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology*; D015854:Up-Regulation
chemical_list: D016326:Extracellular Matrix Proteins; D009124:Muscle Proteins; D003094:Collagen
keywords: collagen; extracellular matrix; fibrosis; skeletal muscle