Single cell atlas decodes the molecular dynamics of scar repair after human rotator cuff tear

Irreversible fibrotic scarring after rotator cuff tear (RCT) compromises the mechanical properties of the healing tendon, yet the underlying mechanisms remain poorly understood. Here, we analyzed the histological features of human RCT scars, characterized by disruption of tendon architecture, disorganized collagen fibrils, and imbalance in type I/III collagen ratios and fibril diameters. Using single-cell RNA sequencing of tendon stumps from patients with RCT, we deconvolved the cellular and molecular landscape of the fibrotic scarring microenvironment. Heterogenous pro-fibrotic subclusters were identified and validated to participate into scar formation, including tendon stem cell, senescent tenocyte, SOX9-driven pro-fibrotic macrophage, and pro-fibrotic endothelial cells undergoing endothelial-mesenchymal transition (EndoMT). Furthermore, we found that osteopontin and TGF-β signaling were key drivers of extracellular matrix deposition, and their blockade ameliorated fibrotic scarring after RCT. Collectively, our study dissected the dynamic scarring microenvironment in human RCT and highlights potential therapeutic targets for preventing pathological scar formation.