Protein in Extracellular Matrix Seen to Promote Lung Fibrosis in Scleroderma

Netrin-1, a factor produced by the extracellular matrix, drives the production and accumulation of fibrocytes, a fibrosis-promoting cell type in patients with systemic sclerosis (SSc)-induced pulmonary fibrosis, according to a study by Yale University School of Medicine researchers.

Fibrocytes are cells that often reside in the extracellular matrix — the mesh-like scaffold surrounding cells — and have been linked to several inflammatory conditions. The extracellular matrix is known to be more than just a supportive structure — it secretes factors that might affect disease — but little is known about how it might interact with inflammatory cells.

A way to study such possible interplay is by using decellularized matrixes, isolated from both SSc patients and healthy controls. In their study, “Netrin-1 Regulates Fibrocyte Accumulation in the Decellularized Fibrotic Sclerodermatous Lung Microenvironment and in Bleomycin-Induced Pulmonary Fibrosis,“ Yale researchers noted that lung matrixes from SSc patients displayed abnormal anatomical features, enhanced stiffness, and an atypical composition of matrix proteins.

Researchers isolated mononuclear cells, a mix of various immune cells, from the blood of healthy individuals, and cultured them on the decellularized scaffolds derived from the SSc patients. They found that matrixes from patients triggered the development of fibrocytes to a greater extent than those from healthy individuals.

It also appeared that the matrixes’ enhanced stiffness was driving the development of the fibrotic cell type. When immune cells isolated from the controls were cultured on a synthetic stiff scaffold, more fibrocytes developed compared to cells cultured on a softer matrix.

Findings, published in the journal Arthritis & Rheumatology, indicated that the protein netrin-1 was needed for the development of fibrocytes from the cultured cells grown on the matrix. When netrin-1 was blocked using antibodies, researchers detected fewer fibrocytes in the matrixes.

To confirm the protein’s role, the team also treated mice lacking one netrin-1 gene copy with bleomycin — a common way to induce lung fibrosis in animals. The partly netrin-deficient mice produced less collagen, had less fibrosis, and fewer fibrocytes than their non-deficient counterparts.

Based on these findings, the research team suggested that netrin-1 might be a promising drug target in SSc-related lung fibrosis.