期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 37, 页码 E5399-E5407出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1607327113
关键词
intestinal stem cell; niche; Lgr5; Reg4; deep crypt secretory cells
资金
- Japan Society for the Promotion of Science (JSPS) postdoctoral Fellowships for Research Abroad
- Astellas Foundation for Research on Metabolic Disorders
- National Institutes of Health (NIH)/Massachusetts Institute of Technology (MIT) [5710002735]
- Skolteck (SkTech) Skolokovo
- European Union (EU) FP7 Tornado
- Grants-in-Aid for Scientific Research [16H07176] Funding Source: KAKEN
- Medical Research Council [MC_UP_1202/7] Funding Source: researchfish
- The Francis Crick Institute [10105] Funding Source: researchfish
- MRC [MC_UP_1202/7] Funding Source: UKRI
Leucine-rich repeat-containing G-protein coupled receptor 5-positive (Lgr5(+)) stem cells reside at crypt bottoms of the small and large intestine. Small intestinal Paneth cells supply Wnt3, EGF, and Notch signals to neighboring Lgr5(+) stem cells. Whereas the colon lacks Paneth cells, deep crypt secretory (DCS) cells are intermingled with Lgr5(+) stem cells at crypt bottoms. Here, we report regenerating isletderived family member 4 (Reg4) as a marker of DCS cells. To investigate a niche function, we eliminatedDCS cells by using the diphtheriatoxin receptor gene knocked into themurine Reg4 locus. Ablation of DCS cells results in loss of stem cells from colonic crypts and disrupts gut homeostasis and colon organoid growth. In agreement, sorted Reg4(+) DCS cells promote organoid formation of single Lgr5(+) colon stem cells. DCS cells can be massively produced from Lgr5(+) colon stem cells in vitro by combined Notch inhibition and Wnt activation. We conclude that Reg4(+) DCS cells serve as Paneth cell equivalents in the colon crypt niche.
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