Novel Mechanism Contributing To Skin Fibrosis in Systemic Sclerosis Identified

Researchers at UCL-Medical School in the United Kingdom recently reported in the journal PLoS One findings supporting a mechanism that leads to skin fibrosis in systemic sclerosis patients. The study is entitled “Partially Evoked Epithelial-Mesenchymal Transition (EMT) Is Associated with Increased TGFβ Signaling within Lesional Scleroderma Skin.”

Systemic sclerosis is a rare, chronic autoimmune disease in which the body’s own immune system attacks healthy tissues resulting in a hardening and tightening of the connective tissues due to excessive collagen deposition. The disease usually affects the skin, but it can also affect internal organs such as the lungs, heart, blood vessels, kidneys and the digestive tract.

In systemic sclerosis patients, the expression of transforming growth factor (TGF)-beta is induced. TGF-beta plays a central role in the development of lung fibrosis, as it is thought to induce cell differentiation into myofibroblasts, cells that are involved in tissue that are able to secrete excessive amounts of extracellular matrix, which can potentially lead to fibrosis (scarring) and tissue destruction.

The source of myofibroblasts in fibrotic conditions like systemic sclerosis is not clear. It has been suggested that myofibroblasts could be produced by the activation of local fibroblasts, recruitment of fibrocyte progenitors, or through an epithelial to mesenchymal transition (EMT) process. EMT is known to be involved in lung fibrosis, but its role on skin fibrosis is unclear.

TGB-beta signaling and persistent inflammation are known to be capable of inducing EMT, and both features have been reported in the skin of systemic sclerosis patients. In the study, researchers tested the hypothesis that EMT is involved in skin fibrosis in systemic sclerosis patients, contributing to the increased population of myofibroblasts.

Using skin samples from systemic sclerosis patients and healthy controls along with cell culture models of EMT, researchers found that TGF-beta signaling was active in keratinocytes (epidermal cells) from systemic sclerosis patients, and that keratinocytes exhibited a phenotype usually associated with tissue repair.

Researchers reported that it was possible to induce intense EMT in keratinocytes in vitro; a process accompanied by the loss of E-cadherin and increased expression of SNAI1/2, which are direct targets of TGF-beta playing a role in EMT during development and in tissue repair. On the other hand, in systemic sclerosis skin samples, the active TGF-beta signaling was accompanied by a partial EMT-like change with induction of only SNAI1 and no loss of E-cadherin. The results led the team to suggest that EMT is induced in systemic sclerosis but there might not be a full transition from epithelial to mesenchymal cells.

The research team concluded that the TGF-beta signaling pathway is strongly involved with systemic sclerosis pathogenesis. Researchers showed that the epidermis of systemic sclerosis patients exhibits alterations that resemble a partial EMT, namely with the activation of the TGF-beta signaling and increased levels of SNAI1. The team concluded that their findings support a model where systemic sclerosis epidermal cells adopt some mesenchymal features possibly contributing to fibrosis, although they do no fully transform into myofibroblasts. The authors believe that these cells might represent a new cell type important for systemic sclerosis pathogenesis.