Mohawk Promotes the Tenogenesis of Mesenchymal Stem Cells Through Activation of the TGFβ Signaling Pathway

The transcription factor Mohawk (Mkx) is expressed in developing tendons and is an important regulator of tenogenic differentiation. However, the exact roles of Mkx in tendinopathy and tendon repair remain unclear. Using gene expression Omnibus datasets and immunofluorescence assays, we found that Mkx expression level was dramatically lower in human tendinopathy tissue and it is activated at specific stages of tendon development. In mesenchymal stem cells (MSCs), ectopic Mkx expression strikingly promoted tenogenesis more efficiently than Scleraxis (Scx), a well‐known master transcription factor of tendon. Significantly higher levels of tenogenic gene expression and collagen fibril growth were observed with Mkx versus Scx. Interestingly, it was observed that Mkx dramatically upregulated Scx through binding to the Tgfb2 promoter. Additionally, the transplantation of Mkx‐expressing‐MSC sheets promoted tendon repair in a mouse model of Achilles‐tendon defect. Taken together, these data shed light on previously unrecognized roles of Mkx in tendinopathy, tenogenesis, and tendon repair as well as in regulating the TGFβ pathway. Stem Cells 2015;33:443–455 摘要 转录因子Mohawk（Mkx）在发育中的肌腱中表达, 是肌腱细胞分化的重要调节因子。然而, Mkx在肌腱病和肌腱修复中的确切作用仍不清楚。采用基因表达Omnibus数据集和免疫荧光分析, 我们发现人体肌腱病组织中Mkx的表达水平显著降低, 但其在肌腱发育的特定阶段被活化。在间充质干细胞（MSC）中, 相比众所周知的肌腱主转录因子（Scx）, 异位性Mkx表达促进肌腱发生的效果更显著。观察到Mkx的肌腱发生基因表达和胶原纤维生长水平显著高于Scx。有趣的是, 我们观察到Mkx通过与Tgfb2启动子结合显著上调了Scx。另外, 在跟腱缺陷小鼠模型中, 表达Mkx的MSC片移植促进了肌腱修复。综上所述, 这些数据阐明了此前未被认识到的Mkx在肌腱病、肌腱发生和肌腱修复以及调节TGFβ通路中的作用。