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.

中文翻译：

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Oxo-M和4-PPBP的组合作为肌腱损伤的潜在再生疗法。

肌腱损伤经常导致生化结构和机械性能较差的疤痕样组织。我们最近报道了CD146 +血管周围起源的肌腱干/祖细胞（TSC），在肌腱愈合中起着至关重要的作用。在这里，我们发现了高效的小分子，它们选择性地激活内源性TSC进行肌腱再生。方法：从ERK1 / 2和FAK激动剂库中鉴定出Oxo-M和4-PPBP，并研究它们在TSCs肌腱分化和体内肌腱愈合中的作用。通过PLGA µS进行Oxo-M和4-PPBP的受控输送。进行了信号传导研究，以确定Oxo-M和4-PPBP对CD146 + TSC的特异性机制。结果：Oxo-M和4-PPBP的组合可协同增加TSC中肌腱相关基因标志物的表达。在体内，Oxo-M和4-PPBP的递送可显着增强完全横断的大鼠pa肌腱（PT）的愈合，并具有胶原纤维结构的功能性恢复和重组。我们的信号传导研究表明，Oxo-M和4-PPBP通过非神经毒蕈碱型乙酰胆碱受体（AChR）和σ1受体（σ1）信号传导特异性靶向CD146 + TSC。主要结论：我们的发现表明Oxo-M和4-PPBP作为肌腱损伤的再生疗法具有巨大潜力。我们的信号传导研究表明，Oxo-M和4-PPBP通过非神经毒蕈碱型乙酰胆碱受体（AChR）和σ1受体（σ1）信号传导特异性靶向CD146 + TSC。主要结论：我们的发现表明Oxo-M和4-PPBP作为肌腱损伤的再生疗法具有巨大潜力。我们的信号传导研究表明，Oxo-M和4-PPBP通过非神经毒蕈碱型乙酰胆碱受体（AChR）和σ1受体（σ1）信号传导特异性靶向CD146 + TSC。主要结论：我们的发现表明Oxo-M和4-PPBP作为肌腱损伤的再生疗法具有巨大潜力。