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 van den 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

doi:10.1073/pnas.1607327113

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 van den 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

Hubrecht Institute

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

215 Citaten (Scopus)

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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.

Originele taal-2	Engels
Tijdschrift	Proceedings of the National Academy of Sciences of the United States of America
DOI's	https://doi.org/10.1073/pnas.1607327113
Status	Gepubliceerd - 29 aug. 2016

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10.1073/pnas.1607327113

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Sasaki, N., Sachs, N., Wiebrands, K., Ellenbroek, S. I. J., Fumagalli, A., Lyubimova, A., Begthel, H., van den Born, M., van Es, J. H., Karthaus, W. R., Li, V. S. W., López-Iglesias, C., Peters, P. J., van Rheenen, J., van Oudenaarden, A., & Clevers, H. (2016). Reg4+ deep crypt secretory cells function as epithelial niche for Lgr5+ stem cells in colon. Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.1607327113

@article{6cd923a9f61940a3ab28399576e456f5,

title = "Reg4+ deep crypt secretory cells function as epithelial niche for Lgr5+ stem cells in colon",

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.",

author = "Nobuo Sasaki and Norman Sachs and Kay Wiebrands and Ellenbroek, {Saskia I J} and Arianna Fumagalli and Anna Lyubimova and Harry Begthel and {van den Born}, Maaike and {van Es}, {Johan H} and Karthaus, {Wouter R} and Li, {Vivian S W} and Carmen L{\'o}pez-Iglesias and Peters, {Peter J} and {van Rheenen}, Jacco and {van Oudenaarden}, Alexander and Hans Clevers",

year = "2016",

month = aug,

day = "29",

doi = "10.1073/pnas.1607327113",

language = "English",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

}

Sasaki, N, Sachs, N, Wiebrands, K, Ellenbroek, SIJ, Fumagalli, A, Lyubimova, A, Begthel, H, van den Born, M, van Es, JH , Karthaus, WR, Li, VSW, López-Iglesias, C, Peters, PJ, van Rheenen, J, van Oudenaarden, A & Clevers, H 2016, 'Reg4+ deep crypt secretory cells function as epithelial niche for Lgr5+ stem cells in colon', Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.1607327113

Reg4+ deep crypt secretory cells function as epithelial niche for Lgr5+ stem cells in colon. / Sasaki, Nobuo; Sachs, Norman; Wiebrands, Kay et al.
In: Proceedings of the National Academy of Sciences of the United States of America, 29.08.2016.

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

TY - JOUR

T1 - Reg4+ deep crypt secretory cells function as epithelial niche for Lgr5+ stem cells in colon

AU - Sasaki, Nobuo

AU - Sachs, Norman

AU - Wiebrands, Kay

AU - Ellenbroek, Saskia I J

AU - Fumagalli, Arianna

AU - Lyubimova, Anna

AU - Begthel, Harry

AU - van den Born, Maaike

AU - van Es, Johan H

AU - Karthaus, Wouter R

AU - Li, Vivian S W

AU - López-Iglesias, Carmen

AU - Peters, Peter J

AU - van Rheenen, Jacco

AU - van Oudenaarden, Alexander

AU - Clevers, Hans

PY - 2016/8/29

Y1 - 2016/8/29

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1607327113

DO - 10.1073/pnas.1607327113

M3 - Article

C2 - 27573849

SN - 0027-8424

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

ER -

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

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