title: A Wnt-TGFβ2 axis induces a fibrogenic program in muscle stem cells from dystrophic mice.
abstract: We have previously observed that Wnt signaling activates a fibrogenic program in adult muscle stem cells, called satellite cells, during aging. We genetically labeled satellite cells in a mouse model of Duchenne muscular dystrophy to follow their fate during the progression of the disease. We observed that a fraction of satellite cells had a reduced myogenic potential and showed enhanced expression of profibrotic genes compared to age-matched controls. By combining in vitro and in vivo results, we found that expression of transforming growth factor-β2 (TGFβ2) was induced in response to elevated canonical Wnt signaling in dystrophic muscles and that the resulting increase in TGFβ activity affected the behavior of satellite cells in an autocrine or paracrine fashion. Indeed, pharmacological inhibition of the TGFβ pathway in vivo reduced the fibrogenic characteristics of satellite cells. These studies shed new light on the cellular and molecular mechanisms responsible for stem cell dysfunction in dystrophic muscle and may contribute to the development of more effective and specific therapeutic approaches for the prevention of muscle fibrosis.
authors.affiliation: Paul F. Glenn Laboratories for the Biology of Aging and Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Biressi
authors.affiliation: Paul F. Glenn Laboratories for the Biology of Aging and Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA. Anatomy Department, Institute of Biomedical Sciences, University of São Paulo, 2415 Lineu Prestes Avenue, São Paulo, São Paulo 05508-000, Brazil.
authors.forename: Elen H
authors.initials: EH
authors.lastname: Miyabara
authors.affiliation: Paul F. Glenn Laboratories for the Biology of Aging and Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Suchitra D
authors.initials: SD
authors.lastname: Gopinath
authors.affiliation: Paul F. Glenn Laboratories for the Biology of Aging and Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Poppy M M
authors.initials: PM
authors.lastname: Carlig
authors.affiliation: Paul F. Glenn Laboratories for the Biology of Aging and Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA. Neurology Service, VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, USA. rando@stanford.edu.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rando
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D004195:Disease Models, Animal; D005355:Fibrosis; D005786:Gene Expression Regulation; D008297:Male; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D024510:Muscle Development; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*; D015854:Up-Regulation; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: C509042:Tgfb2 protein, mouse; D053781:Transforming Growth Factor beta2; D051153:Wnt Proteins