Abstract
Systemic sclerosis (SSc) is a spreading fibrotic disease affecting the skin and internal organs. We aimed to model pathogenic fibroblast migration in SSc in order to identify enhancing factors, measure the effect of migrating cells on underlying extracellular matrix (ECM) and test possible therapeutic inhibitors. Novel patterned collagen substrates were used to investigate alignment and migration of skin and lung fibroblasts from SSc patients and healthy controls. Normal lung but not skin fibroblasts consistently elongated and aligned with underlying collagen and migrated dependent on PDGF or serum. SSc lung fibroblasts remained growth factor dependent, did not migrate more rapidly and were less restricted to alignment of the collagen. Multiple collagen proline and lysine-modifying enzymes were identified in SSc but not control fibroblast extracellular matrix preparations, indicating differential levels of ECM modification by the diseased cells. Profiling of migrating cells revealed a possible SCF/c-Kit paracrine mechanism contributing to migration via a subpopulation of cells. Heparin, which binds ligands including PDGF and SCF, and imatininib which blocks downstream tyrosine kinase receptors, both inhibited lung fibroblast migration individually but showed synergy in SSc cells. Pathologic lung fibroblasts from SSc patients modify ECM during migration but remain growth factor dependent and sensitive to inhibitors.
Highlights
The most frequent pathologic pattern in SSc pulmonary disease is non-specific interstitial pneumonitis (NSIP) in which lymphocytic infiltration and inflammatory changes variably accompany extensive fibrotic remodelling[5]
In fibrosis, activated myofibroblasts originate from a number of sources including resident fibroblasts, epithelial cells undergoing epithelial to mesenchymal transition (EMT), perivascular cells and blood derived monocytes[12]
Migration of the lung cells was dependent on the presence of fetal calf serum (FCS) (Fig. 1A,B), or platelet derived growth factor (PDGF)-BB (0.1–2 ng/ml) (Fig. 1C)
Summary
The most frequent pathologic pattern in SSc pulmonary disease is non-specific interstitial pneumonitis (NSIP) in which lymphocytic infiltration and inflammatory changes variably accompany extensive fibrotic remodelling[5]. More specific therapies currently under evaluation include tyrosine kinase inhibitors such as imatinib, found to benefit mouse models of fibrosis and to attenuate the progression of lung involvement in one open trial in SSc8, 9, and nintedanib, shown to slow disease progression in idiopathic pulmonary fibrosis[10, 11]. A better understanding of the mechanisms underlying fibroblast migration might identify targets that could be inhibited in order to block the recruitment of cells into fibrotic lesions. In order to assess the migration of fibroblasts, slides coated with patterned collagen fibres were used to model the extracellular matrix. They included a woven randomly aligned pattern to model uninjured extracellular matrix and an aligned pattern modelling scar tissue. Broad screening methods were used to investigate possible modification of the underlying matrix by proteins secreted by migrating cells, and to profile the phosphorylation changes
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