Increased PDGFRα Activation Disrupts Connective Tissue Development and Drives Systemic Fibrosis

Abstract

SUMMARY 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 PDGFRα that drive increased kinase activity under the control of the endogenous PDGFRα promoter. In embryos, increased PDGFRα signaling leads to hyperplasia of stromal fibroblasts that disturbs normal smooth muscle tissue in radially patterned organs. In adult mice, elevated PDGFRα signaling also increases connective tissue growth, leading to a progressive fibrosis phenotype in multiple organs. Increased PDGFRα 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 PDGFRα in normal connective tissue development and homeostasis, and demonstrate a pivotal role for PDGFRα signaling in systemic fibrosis diseases.

Telocytes are the physiological counterpart of inflammatory fibroid polyps and PDGFRA‐mutant GISTs

“…However, a third type of GI lesion, consisting of an intramural diffuse stromal proliferation variably referred to as “submucosal fibrous thickening,” “intestinal fibrosis,” “increased submucosal connective tissue,” “thickened submucosa” or “expanded submucosa”, has often been described in this genetic setting, both in humans and in mice 8, 9, 10. It consists of a CD34+ stromal proliferation, that variously involves the entire thickness of the GI tract, often heavily affecting the submucosa (Figure 1A‐C).…”

“…However, to date, no ICCH has been detected either in human germline PDGFRA ‐mutants or in mice generated for the conditional expression of mutant PDGFRA , arguing against a relationship between ICCs and PDGFRA ‐driven GISTs. Conversely, GI stromal cell hyperplasia has been described in these conditions, especially at submucosal level 7, 8, 9, 10…”

Epitope Specificity Determines Pathogenicity and Detectability of Anti–Platelet‐Derived Growth Factor Receptor α Autoantibodies in Systemic Sclerosis

“…Human PDGFRa has been implicated in a variety of diseases, including cancer, atherosclerosis, and fibrosis (31)(32)(33); however, the PDGFRa domains critical for disease pathogenesis are not completely defined. In vitro mutagenesis (26) and crystallographic studies (34) have indicated that the amino acid residues involved in receptor binding by PDGF are located in the Ig-like extracellular domains 1, 2, and 3.…”

Cell-Extracellular Matrix Interactions in Normal and Diseased Skin

“…Increased PDGFRa signaling is sufficient to drive excessive fibroblast proliferation and ECM deposition, and acts either independently or downstream from TGF-b (Olson and Soriano 2009). CTGF, which also modulates fibroblast growth and ECM synthesis, is induced by TGF-b (Ihn 2005).…”

“…Fibrosis is a hallmark of many connective tissue diseases, including scleroderma and systemic sclerosis (reviewed by Ihn 2005;Krieg et al 2007;Olson and Soriano 2009). One of the factors expressed by keratinocytes that promotes fibroblast activation in systemic sclerosis is IL1-a (Aden et al 2010).…”