Tendons injuries frequently result in scar-like tissue with poor biochemical structure and mechanical properties. We have recently reported that CD146+ perivascular originated tendon stem/progenitor cells (TSCs), playing critical roles in tendon healing. Here, we identified highly efficient small molecules that selectively activate endogenous TSCs for tendon regeneration. Methods: From a pool of ERK1/2 and FAK agonists, Oxo-M and 4-PPBP were identified, and their roles in tenogenic differentiation of TSCs and in vivo tendon healing were investigated. Controlled delivery of Oxo-M and 4-PPBP was applied via PLGA µS. Signaling studies were conducted to determine the mechanism for specificity of Oxo-M and 4-PPBP to CD146+ TSCs. Results: A combination of Oxo-M and 4-PPBP synergistically increased the expressions of tendon-related gene markers in TSCs. In vivo, delivery of Oxo-M and 4-PPBP significantly enhanced healing of fully transected rat patellar tendons (PT), with functional restoration and reorganization of collagen fibrous structure. Our signaling study suggested that Oxo-M and 4-PPBP specifically targets CD146+ TSCs via non-neuronal muscarinic acetylcholine receptors (AChR) and σ1 receptor (σ1) signaling. Principal conclusions: Our findings demonstrate a significant potential of Oxo-M and 4-PPBP as a regenerative therapeutics for tendon injuries.
Keywords: Endogenous stem/progenitor cells; Regenerative Medicine; Small molecules; Tendon.