title: PDGFRα signalling promotes fibrogenic responses in collagen-producing cells in Duchenne muscular dystrophy.
abstract: Fibrosis is a characteristic of Duchenne muscular dystrophy (DMD), yet the cellular and molecular mechanisms responsible for DMD fibrosis are poorly understood. Utilizing the Collagen1a1-GFP transgene to identify cells producing Collagen-I matrix in wild-type mice exposed to toxic injury or those mutated at the dystrophin gene locus (mdx) as a model of DMD, we studied mechanisms of skeletal muscle injury/repair and fibrosis. PDGFRα is restricted to Sca1+, CD45- mesenchymal progenitors. Fate-mapping experiments using inducible CreER/LoxP somatic recombination indicate that these progenitors expand in injury or DMD to become PDGFRα+, Col1a1-GFP+ matrix-forming fibroblasts, whereas muscle fibres do not become fibroblasts but are an important source of the PDGFRα ligand, PDGF-AA. While in toxin injury/repair of muscle PDGFRα, signalling is transiently up-regulated during the regenerative phase in the DMD model and in human DMD it is chronically overactivated. Conditional expression of the constitutively active PDGFRα D842V mutation in Collagen-I+ fibroblasts, during injury/repair, hindered the repair phase and instead promoted fibrosis. In DMD, treatment of mdx mice with crenolanib, a highly selective PDGFRα/β tyrosine kinase inhibitor, reduced fibrosis, improved muscle strength, and was associated with decreased activity of Src, a downstream effector of PDGFRα signalling. These observations are consistent with a model in which PDGFRα activation of mesenchymal progenitors normally regulates repair of the injured muscle, but in DMD persistent and excessive activation of this pathway directly drives fibrosis and hinders repair. The PDGFRα pathway is a potential new target for treatment of progressive DMD. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
authors: Department of Pathology, School of Medicine, University of Washington, WA, USA.
authors: Nicholas
authors: N
authors: Ieronimakis
authors: Department of Pathology, Albert Einstein College of Medicine, NY, USA.
authors: Aislinn
authors: A
authors: Hays
authors: Department of Pathology, School of Medicine, University of Washington, WA, USA.
authors: Amalthiya
authors: A
authors: Prasad
authors: Department of Anatomy, School of Dentistry, Mahidol University, Thailand.
authors: Kajohnkiart
authors: K
authors: Janebodin
authors: Department of Pathology, School of Medicine, University of Washington, WA, USA.|Department of Medicine, School of Medicine, University of Washington, WA, USA.|Discovery Research, Biogen Inc, Cambridge, MA, USA.
authors: Jeremy S
authors: JS
authors: Duffield
authors: Department of Pathology, Albert Einstein College of Medicine, NY, USA.|Montefiore Medical Center, Bronx, NY, USA.
authors: Morayma
authors: M
authors: Reyes
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis*; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D005355:Fibrosis; D008297:Male; D008822:Mice, Transgenic; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009154:Mutation; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D012038:Regeneration / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D001562:Benzimidazoles; D024042:Collagen Type I; D016189:Dystrophin; D004791:Enzyme Inhibitors; D010880:Piperidines; D011505:Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; C577197:crenolanib
keywords: Duchenne muscular dystrophy; PDGFRα signalling; collagen-producing cells; fibrosis; skeletal muscle