Acellular ECM Proteomics: Versican expression from lung fibroblasts is an autologous fibrotic brake

The activation and accumulation of lung fibroblasts, leading to excessive extracellular matrix (ECM) deposition, is a pathogenic hallmark of Idiopathic Pulmonary Fibrosis (IPF), a lethal and currently incurable disease. The collagen-rich fibrotic ECM perpetuates fibroblast activation and accumulation, which includes the promotion of podosome formation and ECM invasion. Proteoglycans (PGs), a significant component of the interstitial ECM, fine-tune the overall tissue architecture determined by fibrous proteins and regulate several ECM-controlled signalling pathways. In this report, increased expression of Versican (VCAN ), a multifunctional PG, was detected in human and mouse pulmonary fibrosis, predominantly in monocytic cells and fibroblasts. Genetic reduction of Vcan expression in mice promoted collagen expression and modulated pulmonary ECM composition and structure, exacerbating pulmonary fibrosis and delaying its resolution. Reduced ECM Vcan levels resulted in longer, thicker, and more tangled collagen fibrils, which stimulated podosome formation in fibroblasts and their ECM invasion. Moreover, the decrease of Vcan in the ECM and the ensuing reorganisation stimulated Tenascin-C (TNC) expression from fibroblasts, which was further shown to be a potent, TLR4-dependent, autologous podosome inducer, promoting ECM invasion. Thus, Vcan expression from fibroblasts serves as an autologous fibrotic brake, controlling the underlying ECM composition, structure and mechanotransduction, and suppressing fibroblast invasion and pulmonary fibrosis.