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Proc Natl Acad Sci U S A. 2016 Sep 13;113(37):E5399-407. doi: 10.1073/pnas.1607327113. Epub 2016 Aug 29.

Reg4+ deep crypt secretory cells function as epithelial niche for Lgr5+ stem cells in colon.

Author information

1
Hubrecht Institute for Developmental Biology and Stem Cell Research, 3584 CT, Utrecht, The Netherlands; Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands;
2
The Institute of Nanoscopy, Maastricht University, 6211 LK, Maastricht, The Netherlands.
3
Hubrecht Institute for Developmental Biology and Stem Cell Research, 3584 CT, Utrecht, The Netherlands; Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands; h.clevers@hubrecht.eu.

Abstract

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 islet-derived family member 4 (Reg4) as a marker of DCS cells. To investigate a niche function, we eliminated DCS cells by using the diphtheria-toxin receptor gene knocked into the murine 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.

KEYWORDS:

Lgr5; Reg4; deep crypt secretory cells; intestinal stem cell; niche

PMID:
27573849
PMCID:
PMC5027439
DOI:
10.1073/pnas.1607327113
[Indexed for MEDLINE]
Free PMC Article

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