Increased PDGFRα Activation Disrupts Connective Tissue Development and Drives Systemic Fibrosis

PDGF signaling regulates the development of mesenchymal cell types in the embryo and in the adult, but the role of receptor activation in tissue homeostasis has not been investigated. We have generated conditional knockin mice with mutations in PDGFR alpha that drive increased kinase activity under the control of the endogenous PDGFR alpha promoter. In embryos, increased PDGFR alpha signaling leads to hyperplasia of stromal fibroblasts, which disturbs normal smooth muscle tissue in radially patterned organs. In adult mice, elevated PDGFR alpha signaling also increases connective tissue growth, leading to a progressive fibrosis phenotype in multiple organs. Increased PDGFR alpha signaling in an Ink4a/Arf-deficient genetic background leads to accelerated fibrosis, suggesting a new role for tumor suppressors in attenuating fibrotic diseases. These results highlight the role of PDGFR alpha in normal connective tissue development and homeostasis and demonstrate a pivotal role for PDGFR alpha signaling in systemic fibrosis diseases.