Scleroderma pathogenesis: a pivotal role for fibroblasts as effector cells

Abstract

Scleroderma (systemic sclerosis; SSc) is characterised by fibrosis of the skin and internal organs in the context of autoimmunity and vascular perturbation. Overproduction of extracellular matrix components and loss of specialised epithelial structures are analogous to the process of scar formation after tissue injury. Fibroblasts are the resident cells of connective tissue that become activated at sites of damage and are likely to be important effector cells in SSc. Differentiation into myofibroblasts is a hallmark process, although the mechanisms and cellular origins of this important fibroblastic cell are still unclear. This article reviews fibroblast biology in the context of SSc and highlights the potentially important place of fibroblast effector cells in fibrosis. Moreover, the heterogeneity of fibroblast properties, multiplicity of regulatory pathways and diversity of origin for myofibroblasts may underpin clinical diversity in SSc, and provide novel avenues for targeted therapy.

Figure 1

The cellular origins of pathogenic 'activated' fibroblasts in scleroderma. Scleroderma (SSc) fibrosis is characterised by the excessive accumulation of extracellular matrix (ECM) proteins, including type I and type III collagen, by 'activated fibroblasts' or myofibroblasts and leads to the development of pathological scaring and loss of organ function. These cells arise from a differentiation of resident and recruited circulating progenitor cells and collectively are likely to contribute the myofibroblast population. Myofibroblasts have been shown to arise from a number of cellular sources through the differentiation and activation of tissue-resident cells: epithelial to mesenchymal transition; endothelial to mesenchymal transition; fibroblast to myofibroblast transition; pericyte to mesenchymal transition; smooth muscle cell differentiation. In addition the recruitment and differentiation of circulating bone marrow-derived cells (BMDC) and fibrocytes can contribute to the myofibroblast population. SSc fibroblasts also promote a pro-fibrotic microenvironment, secreting growth factors, chemokines and cytokines that can in turn act on resident and infiltrating cells in an autocrine and paracrine manner to expand the reservoir of pro-fibrotic fibroblasts present in SSc fibrotic lesions.