Tgfbeta signal inhibition cooperates in the induction of iPSCs and replaces Sox2 and cMyc.
Tgfbeta signal inhibition cooperates in the induction of iPSCs and replaces Sox2 and cMyc.
复制标题
DOI：
10.1016/j.cub.2009.08.025
复制
发表时间：
2009-11-03
期刊：
影响因子：
--
通讯作者：
Hochedlinger K
中科院分区：
文献类型：
--
作者：
Maherali N;Hochedlinger K
转录因子Oct4、Sox2、cMyc和Klf4的异位表达，以及该因子组合的变体，足以赋予多种分化细胞类型多能状态，产生诱导多能干细胞（iPSCs）。诱导多能干细胞的衍生是一个效率极低的过程，其潜在机制在很大程度上是未知的。这种低效率证明存在额外的合作因素，其识别对于理解重编程过程至关重要。此外，多能干细胞的治疗用途依赖于开发有效的非遗传因子传递手段，虽然已经确定了少数替代单个因子的化合物，但它们的使用进一步降低了本已很低的重编程效率。因此，识别增强而不是完全取代重编程因子功能的化合物将是非常有用的。在这里，我们证明了Tgfβ信号通路的抑制在小鼠成纤维细胞的重编程中作为一个合作因子，以剂量依赖的方式更有效和更快地诱导iPSCs，而Tgfβ信号通路的激活阻断了重编程。除了强大的协同效应外，Tgfβ受体抑制剂的使用绕过了外源cMyc或Sox2的需要，突出了其作为合作因子和替代因子的双重作用。鉴定在重编程中起作用的高度表征的途径将为重编程过程的机械解剖开辟新的途径，并促进利用小分子衍生iPSCs。
Ectopic expression of the transcription factors Oct4, Sox2, cMyc, and Klf4, as well as variants of this factor combination, are sufficient to confer a pluripotent state upon several differentiated cell types, generating induced pluripotent stem cells (iPSCs). The derivation of iPSCs is a highly inefficient process with the underlying mechanisms largely unknown. This low efficiency argues for the existence of additional cooperative factors, whose identification is critical for understanding the process of reprogramming. Further, the therapeutic use of iPSCs relies on developing efficient non-genetic means of factor delivery, and while a handful of compounds that replace individual factors have been identified, their use yields a further reduction to the already low efficiency of reprogramming. Thus, the identification of compounds that enhance rather than solely replace the function of the reprogramming factors will be of great use. Here, we demonstrate that inhibition of the Tgfβ signaling pathway acts as a cooperative factor in the reprogramming of murine fibroblasts, enabling more efficient and faster induction of iPSCs in a dose-dependent manner, while activation of Tgfβ signaling blocks reprogramming. In addition to a strong cooperative effect, use of a Tgfβ receptor inhibitor bypasses the requirement of exogenous cMyc or Sox2, highlighting its dual role as both a cooperative and a replacement factor. The identification of a highly characterized pathway that operates in reprogramming will open up new avenues for mechanistic dissection of the reprogramming process, as well as facilitate the derivation of iPSCs using small molecules.
登录
查看更多内容
影响因子：
21.3
作者：
Feng, Bo;Jiang, Jianming;Ng, Huck-Hui
通讯作者：
Ng, Huck-Hui
影响因子：
23.9
作者：
Shi, Yan;Desponts, Caroline;Ding, Sheng
通讯作者：
Ding, Sheng
影响因子：
64.5
作者：
Hanna, Jacob;Markoulaki, Styliani;Jaenisch, Rudolf
通讯作者：
Jaenisch, Rudolf
影响因子：
46.9
作者：
Xu, RH;Chen, X;Thomson, JA
通讯作者：
Thomson, JA
影响因子：
23.9
作者：
Xu RH;Sampsell-Barron TL;Gu F;Root S;Peck RM;Pan G;Yu J;Antosiewicz-Bourget J;Tian S;Stewart R;Thomson JA
通讯作者：
Thomson JA