Mechanical gating of tendon fibrogenic transcription in systemic sclerosis

Abstract

Abstract Fibrosis arises from aberrant tissue repair in systemic sclerosis and is characterized by progressive stiffening across multiple tissues, including tendons. How altered tissue mechanics sustain fibrotic remodeling remains poorly understood, in part because of limited experimental models that capture key biophysical features of fibrosis. Here we develop a modular cantilever-based mechano-culture platform that enables tendon-like constructs to be maintained under controlled static tension. We show that elevated matrix tension induces fibroblast-to-myofibroblast activation and scar-like phenotypes in vitro. Analysis of preclinical and clinical models of systemic sclerosis reveals that increased three-dimensional matrix stiffness inversely correlates with transcription of major profibrotic collagens, while positively regulating genes associated with stromal–immune interactions. Co-culture with bone marrow–derived macrophages overrides tension-dependent suppression of matrix gene expression, suggesting that immune cues can supersede mechanical checkpoints. These findings demonstrate how tissue mechanics orchestrates reciprocal interactions between stromal and immune compartments to drive progressive fibrosis, and establish a reductionist platform for dissecting mechano-regulatory pathways in fibrotic diseases.