Single-Cell Reference Mapping and Transcriptomic Analysis Identify Fibroblast-Related ECM Remodeling During...

Tendinopathy involves pathological extracellular matrix (ECM) remodeling and dysregulated fibroblast activity, yet the functional stratification of fibroblast subpopulations during disease and repair remains unclear. Although electroacupuncture (EA) shows clinical potential, its cellular mechanisms in tendon healing are not fully understood. Here, we integrated publicly available single-cell RNA sequencing datasets with bulk transcriptomic profiling from a murine Achilles tendinopathy model to establish a tendon cellular reference atlas and characterize MMP2⁺ fibroblast-associated ECM remodeling states, including High_ECM and Low_ECM programs. EA significantly improves pain sensitivity, locomotor function, and collagen organization while reducing fibrotic adhesions. Transcriptomic analysis reveals that EA reverses inflammatory and matrix-degradation pathways and upregulates collagen-assembly and ECM-receptor interaction genes. Integrated single-cell reference mapping and bulk transcriptomic analysis revealed that EA-associated tendon repair was accompanied by enrichment of ECM-related transcriptional programs overlapping with MMP2⁺ fibroblast-associated ECM remodeling states. Single-cell co-expression analysis identified coordinated expression patterns of key ECM-related genes. Our study suggests that EA-associated tendon repair is accompanied by modulation of ECM-related molecular programs overlapping with fibroblast-associated ECM remodeling states, providing new insights into the molecular framework underlying tendon repair after ECM injury.