Department of Orthopedic Surgery and Sports Medicine Center, The First Affiliated Hospital and The First Clinical College, Jinan University, Guangzhou.
IAN WO Medical Center, Macau Special Administrative Region, Macau.
Eur J Histochem. 2021 Sep 7;65(3):3297. doi: 10.4081/ejh.2021.3297.
Rotator cuff tear (RCT) is a common tendon injury, but the mechanisms of tendon healing remain incompletely understood. Elucidating the molecular mechanisms of tenogenic differentiation is essential to develop novel therapeutic strategies in clinical treatment of RCT. The long noncoding RNA H19 plays a regulatory role in tenogenic differentiation and tendon healing, but its detailed mechanism of action remains unknown. To elucidate the role of H19 in tenogenic differentiation and tendon healing, tendon-derived stem cells were harvested from the Achilles tendons of Sprague Dawley rats and a rat model of cuff tear was established for the exploration of the function of H19 in promoting tenogenic differentiation. The results showed that H19 overexpression promoted, while H19 silencing suppressed, tenogenic differentiation of tendon-derived stem cells (TDSCs). Furthermore, bioinformatic analyses and a luciferase reporter gene assay showed that H19 directly targeted and inhibited miR-140-5p to promote tenogenic differentiation. Further, inhibiting miR-140-5p directly increased VEGFA expression, revealing a novel regulatory axis between H19, miR-140-5p, and VEGFA in modulating tenogenic differentiation. In rats with RTC, implantation of H19-overexpressing TDSCs at the lesion promoted tendon healing and functional recovery. In general, the data suggest that H19 promotes tenogenic differentiation and tendon-bone healing by targeting miR-140-5p and increasing VEGFA levels. Modulation of the H19/miR-140-5p/VEGFA axis in TDSCs is a new potential strategy for clinical treatment of tendon injury.
肩袖撕裂（RCT）是一种常见的肌腱损伤，但肌腱愈合的机制仍不完全清楚。阐明肌腱发生分化的分子机制对于开发 RCT 临床治疗的新治疗策略至关重要。长链非编码 RNA H19 在肌腱发生分化和肌腱愈合中起调节作用，但其详细的作用机制尚不清楚。为了阐明 H19 在肌腱发生分化和肌腱愈合中的作用，从小鼠跟腱中采集肌腱源性干细胞，并建立肩袖撕裂大鼠模型，以探索 H19 在促进肌腱发生分化中的作用。结果表明，H19 的过表达促进了肌腱源性干细胞（TDSCs）的肌腱发生分化，而 H19 的沉默则抑制了其分化。此外，生物信息学分析和荧光素酶报告基因检测表明，H19 可直接靶向并抑制 miR-140-5p，从而促进肌腱发生分化。进一步研究表明，抑制 miR-140-5p 可直接增加 VEGFA 的表达，揭示了 H19、miR-140-5p 和 VEGFA 在调节肌腱发生分化中的新调控轴。在 RCT 大鼠中，在损伤部位植入 H19 过表达的 TDSCs 可促进肌腱愈合和功能恢复。总之，这些数据表明，H19 通过靶向 miR-140-5p 并增加 VEGFA 水平促进肌腱发生分化和肌腱骨愈合。TDSCs 中 H19/miR-140-5p/VEGFA 轴的调节可能是肌腱损伤临床治疗的一种新策略。
