Dipeptidyl peptidase-4-mediated fibronectin processing evokes a pro-fibrotic extracellular matrix

Fibronectin serves as a platform to guide and facilitate deposition of collagen and fibrillin microfibrils. During development of fibrotic diseases, altered fibronectin deposition in the extracellular matrix (ECM) is generally an early event. Following this, dysregulated organization of fibrillins and fibrillar collagens occurs. Because fibronectin is an essential orchestrator of healthy ECM, perturbation of its ECM-organizational capacity may be involved in development of fibrosis. To investigate this, we employed recessive dystrophic epidermolysis bullosa (RDEB) as a disease model with progressive, severe dermal fibrosis. Fibroblasts from RDEB donors in 2D and 3D cultures displayed dysregulated fibronectin deposition. Our analyses revealed that increase of pro-fibrotic DPP4+ fibroblasts coincides with altered fibronectin deposition. DPP4 inhibitors normalized deposition of fibronectin and subsequently of fibrillin microfibrils and collagen I. Intriguingly, proteomics, inhibitor and mutagenesis studies disclosed that DPP4 modulates ECM deposition through proteolysis of the fibronectin N-terminus. Our study provides mechanistic insights to the observed pro-fibrotic activities of DPP4 and extends the understanding of fibronectin-guided ECM assembly in health and disease.