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A Notch positive feedback in the intestinal stem cell niche is essential for stem cell self-renewal.

TitleA Notch positive feedback in the intestinal stem cell niche is essential for stem cell self-renewal.
Publication TypeJournal Article
Year of Publication2017
AuthorsChen, K-Y, Srinivasan, T, Tung, K-L, Belmonte, JM, Wang, L, Murthy, PKadur Laks, Choi, J, Rakhilin, N, King, S, Varanko, AKristine, Witherspoon, M, Nishimura, N, Glazier, JA, Lipkin, SM, Bu, P, Shen, X
JournalMol Syst Biol
Volume13
Issue4
Pagination927
Date Published2017 Apr 28
ISSN1744-4292
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.

DOI10.15252/msb.20167324
Alternate JournalMol. Syst. Biol.
PubMed ID28455349
PubMed Central IDPMC5408779
Grant ListR01 GM095990 / GM / NIGMS NIH HHS / United States
R01 GM114254 / GM / NIGMS NIH HHS / United States