Sustained mechanical tension governs fibrogenic activation of tendon stromal cells in systemic sclerosis

Abstract

Fibrosis is a pathological outcome of aberrant repair responses in systemic sclerosis and affects many tissues, including tendons. Progressive matrix stiffening is a key feature of this pathological remodeling. How dysregulated tissue mechanics contribute to the persistence of the fibrotic phenotype has been obscured by limited availability of experimental tissue models that are both controllable and capture essential aspects of the tendon biophysical niche. Here, we developed a modular, cantilever-based platform that allows culture of 3D tendon-like constructs under easily variable static tension, emulating this central tendon-specific structure function relationship. The system reveals that elevated matrix tension instigates fibroblast-to-myofibroblast activation eliciting scar-like phenotypes in vitro. By using this mechano-culture system and preclinical and clinical models of systemic sclerosis, we further show that 3D matrix stiffness is inversely correlated with the transcription of major pro-fibrotic collagens, but positively correlate with the expression of markers of stromal-immune interactions. Co-culture of tendon stromal fibroblasts and bone marrow-derived macrophages override stiffness-mediated downregulation of matrix transcription, suggesting that normal tension mediated checkpoints are superseded by the local tissue immune state. Our study highlights the power of 3D reductionist approaches in dissecting the contribution of the elevated matrix tension to the positive feedforward loops between activated fibroblasts and progressive ECM stiffening in systemic sclerosis.