BACKGROUND The unmet medical needs in repairing large muscle defects promote the development of tissue regeneration strategy. The use of bioactive molecules in combination with biomaterial scaffold has become an area of great interest. SW033291, a small-molecule inhibitor targeting 15-hydroxyprostaglandin dehydrogenase (15-PDGH) and subsequently elevating the production of prostaglandin E2 (PGE2), has been proved to accelerate the recovery and potentiate the regeneration of multiple tissues including the bone, liver, and colon. The limited understanding of the potential therapeutic effects on myogenesis motivated us to investigate the role of SW033291 in regulating muscle-derived stem cell (MDSC) myogenic differentiation and MDSC-mediated muscle regeneration. METHODS The characteristics of rat MDSCs, including cell-specific markers and myogenic differentiation potential, were determined. MDSCs were incubated with SW033291 to evaluate PGE2 production and cytotoxicity. The effects of SW033291 on MDSC myogenic differentiation were assessed by quantitative real-time polymerase chain reaction (qPCR), western blot, and immunocytochemistry. The fibrin gel containing MDSCs and SW033291 was used for muscle regeneration in a tibialis anterior muscle defect model. RESULTS Our data demonstrated that MDSCs were well-tolerated to SW033291 and treatment with SW033291 significantly promoted the production of PGE2 by MDSCs. In vitro analysis showed that SW033291 enhanced the myogenic differentiation and myotube formation by upregulating a series of myogenic markers. Additionally, the activation of PI3K/Akt pathway was involved in the mechanism underlying these promotive effects. Then, in situ casting of fibrin gel containing MDSCs and SW033291 was used to repair the tibialis anterior muscle defect; the addition of SW033291 significantly promoted myofiber formation within the defect region with mild immune response, less fibrosis, and sufficient vascularization. CONCLUSION SW033291 acted as a positive regulator of MDSC myogenic differentiation, and incorporating the compound with MDSCs in fibrin gel could serve as an effective method to repair large skeletal muscle defects.

中文翻译：

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SW033291对源自肌肉的干细胞的肌发生和肌肉再生的影响。

背景技术在修复大的肌肉缺陷中未满足的医疗需求促进了组织再生策略的发展。将生物活性分子与生物材料支架结合使用已经成为人们非常感兴趣的领域。SW033291是靶向15-羟基前列腺素脱氢酶（15-PDGH）并随后提高前列腺素E2（PGE2）的小分子抑制剂，已被证明可加速恢复并增强包括骨骼，肝脏和骨骼在内的多种组织的再生。结肠。对肌发生的潜在治疗作用的有限了解促使我们研究SW033291在调节肌肉衍生干细胞（MDSC）肌发生分化和MDSC介导的肌肉再生中的作用。方法大鼠MDSC的特征 确定包括细胞特异性标志物和成肌分化潜能。MDSC与SW033291一起孵育，以评估PGE2的产生和细胞毒性。通过定量实时聚合酶链反应（qPCR），蛋白质印迹和免疫细胞化学评估SW033291对MDSC肌源性分化的影响。含有MDSC和SW033291的纤维蛋白凝胶用于胫骨前肌缺损模型的肌肉再生。结果我们的数据表明，MDSCs对SW033291的耐受性良好，而SW033291的处理显着促进了MDSCs产生PGE2。体外分析表明，SW033291通过上调一系列成肌标志物来增强成肌分化和肌管形成。另外，PI3K / Akt途径的激活参与了这些促进作用的潜在机制。然后，原位浇铸含有MDSC和SW033291的纤维蛋白凝胶修复胫骨前肌缺损。SW033291的加入可显着促进缺损区域的肌纤维形成，具有轻度的免疫反应，较少的纤维化和足够的血管形成。结论SW033291是MDSC肌源性分化的正向调节剂，该化合物与MDSCs掺入纤维蛋白凝胶中可作为修复大面积骨骼肌缺损的有效方法。SW033291的加入可显着促进缺损区域的肌纤维形成，具有轻度的免疫反应，较少的纤维化和足够的血管形成。结论SW033291是MDSC肌源性分化的正向调节剂，该化合物与MDSCs掺入纤维蛋白凝胶中可作为修复大面积骨骼肌缺损的有效方法。SW033291的添加可显着促进缺陷区域内的肌纤维形成，并具有轻度的免疫反应，较少的纤维化和足够的血管形成。结论SW033291是MDSC肌源性分化的正向调节剂，该化合物与MDSCs掺入纤维蛋白凝胶中可作为修复大面积骨骼肌缺损的有效方法。