作者
Kai‐Yuan Chen, Tara Srinivasan, Kuei‐Ling Tung, Julio M Belmonte, Lihua Wang, Preetish Kadur Lakshminarasimha Murthy, Jiahn Choi, Nikolai Rakhilin, Sarah King, Anastasia Kristine Varanko, Mavee Witherspoon, Nozomi Nishimura, James A Glazier, Steven M Lipkin, Pengcheng Bu, Xiling Shen
发表日期
2017/4
期刊
Molecular Systems Biology
卷号
13
期号
4
页码范围
927
简介
The intestinal epithelium is the fastest regenerative tissue in the body, fueled by fast‐cycling stem cells. The number and identity of these dividing and migrating stem cells are maintained by a mosaic pattern at the base of the crypt. How the underlying regulatory scheme manages this dynamic stem cell niche is not entirely clear. We stimulated intestinal organoids with Notch ligands and inhibitors and discovered that intestinal stem cells employ a positive feedback mechanism via direct Notch binding to the second intron of the Notch1 gene. Inactivation of the positive feedback by CRISPR/Cas9 mutation of the binding sequence alters the mosaic stem cell niche pattern and hinders regeneration in organoids. Dynamical system analysis and agent‐based multiscale stochastic modeling suggest that the positive feedback enhances the robustness of Notch‐mediated niche patterning. This study highlights the importance …
学术搜索中的文章
KY Chen, T Srinivasan, KL Tung, JM Belmonte, L Wang… - Molecular Systems Biology, 2017