A Notch positive feedback in the intestinal stem cell niche is essential for stem cell self‐renewal
Abstract
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 of feedback mechanisms in spatiotemporal control of the stem cell niche.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 01, 2017
- Source ID
- 10.15252/msb.20167324
Entities
People
- Anastasia Kristine Varanko
- James A. Glazier
- Jiahn Choi
- Julio M Belmonte
- Kai-Yuan Chen
- Kuei‐ling Tung
- Lihua Wang
- Mavee Witherspoon
- Nikolai Rakhilin
- Nozomi Nishimura
- Pengcheng Bu
- Preetish Kadur Lakshminarasimha Murthy
- Sarah King
- Steven M. Lipkin
- Tara Srinivasan
- Xiling Shen
Organizations
- Cornell University
- Duke University
- Indiana University
- National Institute of General Medical Sciences
- National Science Foundation
- United States Department of Defense
- Weill Cornell Medicine