UC MSCs Educated Tenon (METn) Stimulates Tendon Regeneration Through Rejuvenation of the Complex and Tendon-Derived Cells (TDCs)

Aging, linked to reduced tendon healing and higher injury susceptibility, is associated to the high incidence of rotator cuff (RC) tears in the elderly. Even after RC repair, disordered neofibrovascular scar tissue often occurs, lowering mechanical strength, and tendon-derived cell (TDC) senescence has been suggested as one of the causes. Age reduces the efficacy of mesenchymal stem cell (MSC) therapy for tendon regeneration. However, certain biomaterial exposure may increase MSC differentiation and paracrine effects. We aimed to develop and evaluate an optimal tenon-MSC complex (TSC) for tendon regeneration and investigate its efficacy and antisenescence mechanisms in aged and degenerated TDCs. We proposed a novel method to isolate a maximum quantity of tenon with col6-rich pericellular matrix (PCM) per gram of tendon, utilizing 2% collagenase. In a fibrin 3D gel culture system, rejuvenated METn (TSC) had higher tenogenic marker expression, collagen fiber quantity, and quality than MSC-only or METc (TDC-MSC complex). METn could repair DNA damage and improve cellular metabolism in senescent TDCs by releasing antisenescence factors. TDCs, which overcomes senescence by the METn_CM treatment, also produced a higher quality tendon matrix. In conclusion, this study demonstrates that rejuvenated and functional TSC significantly enhances tendon regeneration by countering senescence in aged and degenerated TDCs, offering a safe approach to enhance the therapeutic potential of autologous senescent MSCs from the elderly.