Healthy Tendon Stem Cell‐Derived Exosomes Promote Tendon‐To‐Bone Healing of Aged Chronic Rotator Cuff Tears by Breaking the Positive‐Feedback Cross‐Talk between Senescent Tendon Stem Cells and Macrophages through the Modulation of Macrophage Polarization

Abstract The re‐tear rate of rotator cuff tears (RCT) after surgical repair is high, especially in aged patients with chronic tears. Senescent tendon stem cells (s‐TSCs) generally exist in aged and chronically torn rotator cuff tendons and are closely associated with impaired tendon‐to‐bone healing results. The present study found a positive feedback cross‐talk between s‐TSCs and macrophages. The conditioned medium (CM) from s‐STCs can promote macrophage polarization mainly toward the M1 phenotype, whose CM reciprocally accelerated further s‐TSC senescence. Additional healthy tendon stem‐cells derived exosomes (h‐TSC‐Exos) can break this positive feedback cross‐talk by skewing macrophage polarization from the M1 phenotype to the M2 phenotype, attenuating s‐TSCs senescence. S‐TSC senescence acceleration or attenuation effects induced by M1 or M2 macrophages are associated with the inhibition or activation of the bone morphogenetic protein 4 signaling pathway following RNA sequencing analysis. Using an aged‐chronic rotator cuff tear rat model, it is found that h‐TSC‐Exos can shift the microenvironment in the tendon‐to‐bone interface from a pro‐inflammatory to an anti‐inflammatory type at the acute postoperative stage and improve the tendon‐to‐bone healing results, which are associated with the rejuvenated s‐TSCs. Therefore, this study proposed a potential strategy to improve the healing of aged chronic RCT.