PDGFRα signalling promotes fibrogenic responses in collagen-producing cells in Duchenne muscular dystrophy

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. PDGFR 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 PDGFR+, Col1a1-GFP+ matrix-forming fibroblasts, whereas muscle fibres do not become fibroblasts but are an important source of the PDGFR ligand, PDGF-AA. While in toxin injury/repair of muscle PDGFR, 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 PDGFRD842V 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 PDGFR/ tyrosine kinase inhibitor, reduced fibrosis, improved muscle strength, and was associated with decreased activity of Src, a downstream effector of PDGFR signalling. These observations are consistent with a model in which PDGFR 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 PDGFR pathway is a potential new target for treatment of progressive DMD. (c) 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.