TGFβ-activated kinase 1 (Tak1) regulates mesenchymal stem cell proliferation through stabilization of Yap1/Taz proteins,STEM CELLS

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TGFβ-activated kinase 1 (Tak1) regulates mesenchymal stem cell proliferation through stabilization of Yap1/Taz proteins
STEM CELLS ( IF 4.0 ) Pub Date : 2019-11-18 , DOI: 10.1002/stem.3083
Yuta Onodera ₁ , Takeshi Teramura ₁ , Toshiyuki Takehara ₁ , Kanji Fukuda ₁

Affiliation

Bone marrow‐derived mesenchymal stem cells (BMMSCs) are multipotent stem cells capable of differentiation into a variety of cell types, proliferation, and production of clinically useful secretory factors. These advantages make BMMSCs highly useful for cell transplantation therapy. However, the molecular network underlying BMMSC proliferation remains poorly understood. Here, we showed that TGFβ‐activated kinase 1 (Tak1) is a critical molecule that regulates the activation of cell cycling and that Tak1 inhibition leads to quiescence in BMMSCs both in vivo and in vitro. Mechanistically, Tak1 was phosphorylated by growth factor stimulations, allowing it to bind and stabilize Yap1/Taz, which could then be localized to the nucleus. We also demonstrated that the quiescence induction by inhibiting Tak1 increased oxidized stress tolerance and improved BMMSC engraftment in intramuscular and intrabone marrow cell transplantation models. This study reveals a novel pathway controlling BMMSC proliferation and suggests a useful method to improve the therapeutic effect of BMMSC transplantation. Stem Cells 2019;37:1595–1605

中文翻译：

TGFβ 活化激酶 1 (Tak1) 通过稳定 Yap1/Taz 蛋白来调节间充质干细胞增殖

骨髓间充质干细胞 (BMMSCs) 是多能干细胞，能够分化为多种细胞类型、增殖并产生临床有用的分泌因子。这些优势使 BMMSCs 在细胞移植治疗中非常有用。然而，BMMSC 增殖的分子网络仍然知之甚少。在这里，我们发现 TGFβ 活化激酶 1 (Tak1) 是调节细胞周期激活的关键分子，并且抑制 Tak1 会导致体内和体外 BMMSC 静止。从机制上讲，Tak1 被生长因子刺激磷酸化，使其结合并稳定 Yap1/Taz，然后可以定位到细胞核。我们还证明了通过抑制 Tak1 的静止诱导增加了氧化应激耐受性并改善了肌肉内和骨髓内细胞移植模型中的 BMMSC 植入。该研究揭示了控制 BMMSC 增殖的新途径，并提出了一种提高 BMMSC 移植治疗效果的有用方法。干细胞 2019；37：1595–1605

更新日期：2019-11-18

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