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

Nobuo Sasaki, Norman Sachs, Kay Wiebrands, Saskia I.J. Ellenbroek, Arianna Fumagalli, Anna Lyubimova, Harry Begthel, Maaike Den Van Born, Johan H. Van Es, Wouter R. Karthaus, Vivian S.W. Li, Carmen López-Iglesias, Peter J. Peters, Jacco Van Rheenen, Alexander Van Oudenaarden, Hans Clevers

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

208 Citaten (Scopus)


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 investigateanichefunction,weeliminatedDCScellsbyusingthediphtheriatoxin 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.

Originele taal-2Engels
Pagina's (van-tot)E5399-E5407
TijdschriftProceedings of the National Academy of Sciences of the United States of America
Nummer van het tijdschrift37
StatusGepubliceerd - 13 sep. 2016
Extern gepubliceerdJa


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