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

被引：34

作者：

Chen, Kai-Yuan ^{[1
,2
]}

Srinivasan, Tara ^{[3
]}

Tung, Kuei-Ling ^{[4
]}

Belmonte, Julio M. ^{[5
,6
]}

Wang, Lihua ^{[2
,4
]}

Murthy, Preetish Kadur Lakshminarasimha ^{[7
]}

Choi, Jiahn ^{[2
]}

Rakhilin, Nikolai ^{[1
,2
]}

King, Sarah ^{[3
]}

Varanko, Anastasia Kristine ^{[4
]}

Witherspoon, Mavee ^{[7
]}

Nishimura, Nozomi ^{[3
]}

Glazier, James A. ^{[5
,6
]}

Lipkin, Steven M. ^{[8
,9
,10
]}

Bu, Pengcheng ^{[2
,11
]}

Shen, Xiling ^{[1
,2
,3
]}

机构：

[1] Cornell Univ, Sch Elect & Comp Engn, Ithaca, NY USA

[2] Duke Univ, Dept Biomed Engn, Durham, NC 27706 USA

[3] Cornell Univ, Dept Biomed Engn, Ithaca, NY USA

[4] Cornell Univ, Dept Biol & Environm Engn, Ithaca, NY USA

[5] Indiana Univ, Biocomplex Inst, Bloomington, IN USA

[6] Indiana Univ, Dept Phys, Bloomington, IN 47405 USA

[7] Cornell Univ, Sch Mech Aerosp Engn, Ithaca, NY USA

[8] Weill Cornell Med Coll, Dept Med, New York, NY USA

[9] Weill Cornell Med Coll, Dept Med Genet, New York, NY USA

[10] Weill Cornell Med Coll, Dept Surg, New York, NY USA

[11] Chinese Acad Sci, Inst Biophys, Key Lab RNA Biol, Key Lab Prot & Peptide Pharmaceut, Beijing, Peoples R China

来源：

MOLECULAR SYSTEMS BIOLOGY | 2017年 / 13卷 / 04期

基金：

美国国家科学基金会;

关键词：

gene editing; intestine stem cell; Notch signaling; organoid; positive feedback; LINEAGE COMMITMENT; LATERAL INHIBITION; PROGENITOR CELLS; IN-VITRO; DIFFERENTIATION; ROBUSTNESS; ACTIVATION; CRYPT; LGR5; COLON;

D O I：

10.15252/msb.20167324

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：16

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