Evolving insights into the cellular and molecular pathogenesis of fibrosis in systemic sclerosis

Abstract

Systemic sclerosis (SSc, scleroderma) is a complex multisystem disease characterized by autoimmunity, vasculopathy, and most notably, fibrosis. Multiple lines of evidence demonstrate a variety of emerging cellular and molecular pathways which are relevant to fibrosis in SSc. The myofibroblast remains the key effector cell in SSc. Understanding the development, differentiation, and function of the myofibroblast is therefore crucial to understanding the fibrotic phenotype of SSc. Studies now show that (1) multiple cell types give rise to myofibroblasts, (2) fibroblasts and myofibroblasts are heterogeneous, and (3) that a large number of (primarily immune) cells have important influences on the transition of fibroblasts to an activated myofibroblasts. In SSc, this differentiation process involves multiple pathways, including well known signaling cascades such as TGF-β and Wnt/β-Catenin signaling, as well as epigenetic reprogramming and a number of more recently defined cellular pathways. After reviewing the major and emerging cellular and molecular mechanisms underlying SSc, this article looks to identify clinical applications where this new molecular knowledge may allow for targeted treatment and personalized medicine approaches.

Figure 1.

Cellular source, immune interaction, and function of scleroderma myofibroblasts. A. Cellular source of myofibroblasts. Myofibroblasts are derived from a diverse group of cells including mesenchymal cells (fibroblasts, endothelial cells, pericytes, adipocytes) and hematopoietic cells (fibrocytes). B. Immune cell interactions with proto-myofibroblasts. Secretion of cytokines by a variety of innate and adaptive immune cells leads to TGF-β activation and epigenetic reprogramming that leads fibroblasts to become activated and develop into activated scleroderma myofibroblasts C. The myofibroblast in scleroderma. Activated myofibroblasts express a number of cell surface receptors and undergo signal transduction that leads to collagen and matrix deposition which drive fibrosis.