Lateral confined growth of cells activates Lef1 dependent pathways to regulate cell-state transitions.
Lateral confined growth of cells activates Lef1 dependent pathways to regulate cell-state transitions.
复制标题
DOI：
10.1038/s41598-022-21596-4
复制
发表时间：
2022-10-15
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
组织微环境中长期持续的机械化学信号调节细胞状态转换。在最近的工作中，我们发现成纤维细胞的横向限制生长诱导去分化程序。然而，这种机械诱导的细胞状态转变的分子机制知之甚少。在本文中，我们确定Lef 1作为一个关键的体细胞转录因子的机械调节去分化途径。应用于延时RNA-seq数据的网络优化方法将Lef 1依赖性信号传导识别为这种细胞状态转变的潜在调节剂。我们发现Lef 1敲低导致成纤维细胞去分化的下调，并且Lef 1直接与下游重编程因子的启动子区域相互作用。我们还评估了Lef 1的潜在上游激活途径，包括Smad 4，Atf 2，NFkB和β-catenin途径，从而确定Smad 4和Atf 2可能是Lef 1激活的关键。总的来说，我们描述了一个重要的机械转导途径，包括Lef 1，激活后，通过渐进的横向细胞限制，导致成纤维细胞去分化。
Long-term sustained mechano-chemical signals in tissue microenvironment regulate cell-state transitions. In recent work, we showed that laterally confined growth of fibroblasts induce dedifferentiation programs. However, the molecular mechanisms underlying such mechanically induced cell-state transitions are poorly understood. In this paper, we identify Lef1 as a critical somatic transcription factor for the mechanical regulation of de-differentiation pathways. Network optimization methods applied to time-lapse RNA-seq data identify Lef1 dependent signaling as potential regulators of such cell-state transitions. We show that Lef1 knockdown results in the down-regulation of fibroblast de-differentiation and that Lef1 directly interacts with the promoter regions of downstream reprogramming factors. We also evaluate the potential upstream activation pathways of Lef1, including the Smad4, Atf2, NFkB and Beta-catenin pathways, thereby identifying that Smad4 and Atf2 may be critical for Lef1 activation. Collectively, we describe an important mechanotransduction pathway, including Lef1, which upon activation, through progressive lateral cell confinement, results in fibroblast de-differentiation.
登录
查看更多内容
影响因子：
3.9
作者：
Kim DH;Xing T;Yang Z;Dudek R;Lu Q;Chen YH
通讯作者：
Chen YH
影响因子：
4.5
作者：
Grumolato, Luca;Liu, Guizhong;Aaronson, Stuart A.
通讯作者：
Aaronson, Stuart A.
影响因子：
5.3
作者：
Hsu, SC;Galceran, J;Grosschedl, R
通讯作者：
Grosschedl, R
DOI：
10.1016/j.bbrc.2011.06.044
发表时间：
2011-07-08
影响因子：
3.1
作者：
Kim, Chang Gun;Chung, Il-Yup;Shin, Soon Young
通讯作者：
Shin, Soon Young
影响因子：
7.3
作者：
Huang SS;Fraenkel E
通讯作者：
Fraenkel E