Department of Medicine, Graduate School, Kyung Hee University, Seoul 02447, Korea.
The Institute for Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Cells. 2021 Jun 30;10(7):1649. doi: 10.3390/cells10071649.
Understanding the signaling pathways that regulate the final differentiation of human myoblasts is essential for successful cell transplantation and drug screening for the treatment of muscular dystrophy. In an effort to improve myotube formation from hiPSC-derived myoblasts, we validated a collection of 13 small molecules in a newly established in vitro screening platform for the assessment of myotube formation. The analysis of myotube formation as measured by the fusion index showed that the combinational inhibition of the TGFβ signaling with NOTCH signaling enhances the ability of multi-nucleated myotube production. Combinational treatment of inhibitors for TGFβ and NOTCH signaling pathways improved myotube formation in a dose-dependent manner. This effect was achieved by inhibiting the combinatorial mechanism of signaling. The combination treatment of small molecules effective in inducing multinucleated myotubes was validated in healthy human primary myoblasts. In addition, it was also applied to DMD patient iPSC-derived myoblasts to enhance the generation of multinucleated myotubes.
了解调节人肌母细胞最终分化的信号通路对于成功进行细胞移植和药物筛选以治疗肌肉萎缩症至关重要。为了提高 hiPSC 衍生的肌母细胞形成肌管的能力，我们在新建立的体外筛选平台中验证了 13 种小分子，以评估肌管形成。融合指数测量的肌管形成分析表明，TGFβ 信号与 NOTCH 信号的组合抑制增强了多核肌管产生的能力。TGFβ 和 NOTCH 信号通路抑制剂的组合治疗以剂量依赖的方式改善了肌管形成。这种效果是通过抑制信号的组合机制实现的。在健康的人原代肌母细胞中验证了有效诱导多核肌管形成的小分子组合治疗。此外，还将其应用于 DMD 患者的 iPSC 衍生的肌母细胞中，以增强多核肌管的生成。
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