The contribution of mesenchymal transitions to the pathogenesis of systemic sclerosis

Abstract

Systemic sclerosis (SSc) is a multifaceted connective tissue disease characterized by widespread vasculopathyand autoimmune reactions that evolve into progressive interstitial, perivascular, and vesselwall fibrosis that affects the skin and multiple internal organs. Such an uncontrolled fibrotic processgradually disrupts the physiologic architecture of the affected tissues and frequently leads to significantorgan dysfunction, thus representing a major cause of death in SSc patients. The main fibrosisorchestrators in SSc are represented by chronically activated myofibroblasts, a peculiar population ofmesenchymal cells combining the extracellular matrix-synthesizing features of fibroblasts with cytoskeletalcharacteristics of contractile smooth muscle cells. Multiple lines of evidence support thenotion that profibrotic myofibroblasts may derive not only from the activation of tissue resident fibroblastsbut also from a variety of additional cell types, including pericytes, epithelial cells, vascular endothelialcells and preadipocytes/adipocytes. Here we overview an emerging picture that espousesthat several cell transitional processes may be novel essential contributors to the pool of profibroticmyofibroblasts in SSc, potentially representing new suitable targets for therapeutic purposes. An indepthdissection of the multiple origins of myofibroblasts and the underlying molecular mechanismsmay be crucial in the process of deciphering the cellular bases of fibrosis persistence and refractorinessto the treatment and, therefore, may help in developing more effective and personalized therapeuticopportunities for SSc patients.