Theranostics 2019; 9(14):4241-4254. doi:10.7150/thno.35285
A Combination of Oxo-M and 4-PPBP as a potential regenerative therapeutics for tendon injury
Columbia University College of Dental Medicine, 630 W. 168th street, Vanderbilt Clinic 12-210, New York, NY 10032
Tarafder S, Ricupero C, Minhas S, Yu RJ, Alex AD, Lee CH. A Combination of Oxo-M and 4-PPBP as a potential regenerative therapeutics for tendon injury. Theranostics 2019; 9(14):4241-4254. doi:10.7150/thno.35285. Available from http://www.thno.org/v09p4241.htm
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: Tendon, Regenerative Medicine, Endogenous stem/progenitor cells, Small molecules