Priming of Mesenchymal Stem Cells for Tendon Regeneration: Mechanisms and Clinical Translation

Rotator cuff tears remain a major cause of shoulder dysfunction; however, retears and incomplete healing persist despite advances in surgical repair. Conventional techniques fail to restore the native tendon-bone interface, resulting in mechanically inferior scar tissue. Mesenchymal stem cell (MSC)-based augmentation has emerged as a promising biological strategy. However, naïve MSCs exhibit limited survival and integration in the hypoxic and inflammatory microenvironments of degenerative tendons. Recent advances in MSC priming using cytokines, hypoxia, and mechanical conditioning have enhanced angiogenesis, immunomodulation, and tenogenic differentiation. Primed MSCs and their extracellular vesicles facilitated organised collagen architecture and fibrocartilage formation and enhanced biomechanical competence at the repair interface, resulting in earlier mechanical stability and more durable tendon healing. The remaining challenges include the standardisation of priming protocols, scalable manufacturing, and validation of potency assays. This review synthesises emerging evidence on MSC priming for tendon regeneration, crucially assesses its histological and biomechanical foundations, and elucidates its translational potential for achieving biologically integrated and clinically durable rotator cuff repair.