Enteroendocrine and tuft cells support Lgr5 stem cells on Paneth cell depletion

Johan H van Es; Kay Wiebrands; Carmen López-Iglesias; Marc van de Wetering; Laura Zeinstra; Maaike van den Born; Jeroen Korving; Nobuo Sasaki; Peter J Peters; Alexander van Oudenaarden; Hans Clevers

doi:10.1073/pnas.1801888117

Enteroendocrine and tuft cells support Lgr5 stem cells on Paneth cell depletion

Johan H van Es, Kay Wiebrands, Carmen López-Iglesias, Marc van de Wetering, Laura Zeinstra, Maaike van den Born, Jeroen Korving, Nobuo Sasaki, Peter J Peters, Alexander van Oudenaarden, Hans Clevers

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

Abstract

Cycling intestinal Lgr5+ stem cells are intermingled with their terminally differentiated Paneth cell daughters at crypt bottoms. Paneth cells provide multiple secreted (e.g., Wnt, EGF) as well as surface-bound (Notch ligand) niche signals. Here we show that ablation of Paneth cells in mice, using a diphtheria toxin receptor gene inserted into the P-lysozyme locus, does not affect the maintenance of Lgr5+ stem cells. Flow cytometry, single-cell sequencing, and histological analysis showed that the ablated Paneth cells are replaced by enteroendocrine and tuft cells. As these cells physically occupy Paneth cell positions between Lgr5 stem cells, they serve as an alternative source of Notch signals, which are essential for Lgr5+ stem cell maintenance. Our combined in vivo results underscore the adaptive flexibility of the intestine in maintaining normal tissue homeostasis.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
DOIs	https://doi.org/10.1073/pnas.1801888117
Publication status	E-pub ahead of print - 16 Dec 2019

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van Es, J. H., Wiebrands, K., López-Iglesias, C., van de Wetering, M., Zeinstra, L., van den Born, M., Korving, J., Sasaki, N., Peters, P. J., van Oudenaarden, A., & Clevers, H. (2019). Enteroendocrine and tuft cells support Lgr5 stem cells on Paneth cell depletion. Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.1801888117

@article{7d2f87ec87fd44fd93e669eae2da4c7d,

title = "Enteroendocrine and tuft cells support Lgr5 stem cells on Paneth cell depletion",

abstract = "Cycling intestinal Lgr5+ stem cells are intermingled with their terminally differentiated Paneth cell daughters at crypt bottoms. Paneth cells provide multiple secreted (e.g., Wnt, EGF) as well as surface-bound (Notch ligand) niche signals. Here we show that ablation of Paneth cells in mice, using a diphtheria toxin receptor gene inserted into the P-lysozyme locus, does not affect the maintenance of Lgr5+ stem cells. Flow cytometry, single-cell sequencing, and histological analysis showed that the ablated Paneth cells are replaced by enteroendocrine and tuft cells. As these cells physically occupy Paneth cell positions between Lgr5 stem cells, they serve as an alternative source of Notch signals, which are essential for Lgr5+ stem cell maintenance. Our combined in vivo results underscore the adaptive flexibility of the intestine in maintaining normal tissue homeostasis.",

author = "{van Es}, {Johan H} and Kay Wiebrands and Carmen L{\'o}pez-Iglesias and {van de Wetering}, Marc and Laura Zeinstra and {van den Born}, Maaike and Jeroen Korving and Nobuo Sasaki and Peters, {Peter J} and {van Oudenaarden}, Alexander and Hans Clevers",

year = "2019",

month = dec,

day = "16",

doi = "10.1073/pnas.1801888117",

language = "English",

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

issn = "0027-8424",

publisher = "National Academy of Sciences",

}

van Es, JH, Wiebrands, K, López-Iglesias, C, van de Wetering, M, Zeinstra, L, van den Born, M, Korving, J, Sasaki, N, Peters, PJ, van Oudenaarden, A & Clevers, H 2019, 'Enteroendocrine and tuft cells support Lgr5 stem cells on Paneth cell depletion', Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.1801888117

TY - JOUR

T1 - Enteroendocrine and tuft cells support Lgr5 stem cells on Paneth cell depletion

AU - van Es, Johan H

AU - Wiebrands, Kay

AU - López-Iglesias, Carmen

AU - van de Wetering, Marc

AU - Zeinstra, Laura

AU - van den Born, Maaike

AU - Korving, Jeroen

AU - Sasaki, Nobuo

AU - Peters, Peter J

AU - van Oudenaarden, Alexander

AU - Clevers, Hans

PY - 2019/12/16

Y1 - 2019/12/16

N2 - Cycling intestinal Lgr5+ stem cells are intermingled with their terminally differentiated Paneth cell daughters at crypt bottoms. Paneth cells provide multiple secreted (e.g., Wnt, EGF) as well as surface-bound (Notch ligand) niche signals. Here we show that ablation of Paneth cells in mice, using a diphtheria toxin receptor gene inserted into the P-lysozyme locus, does not affect the maintenance of Lgr5+ stem cells. Flow cytometry, single-cell sequencing, and histological analysis showed that the ablated Paneth cells are replaced by enteroendocrine and tuft cells. As these cells physically occupy Paneth cell positions between Lgr5 stem cells, they serve as an alternative source of Notch signals, which are essential for Lgr5+ stem cell maintenance. Our combined in vivo results underscore the adaptive flexibility of the intestine in maintaining normal tissue homeostasis.

AB - Cycling intestinal Lgr5+ stem cells are intermingled with their terminally differentiated Paneth cell daughters at crypt bottoms. Paneth cells provide multiple secreted (e.g., Wnt, EGF) as well as surface-bound (Notch ligand) niche signals. Here we show that ablation of Paneth cells in mice, using a diphtheria toxin receptor gene inserted into the P-lysozyme locus, does not affect the maintenance of Lgr5+ stem cells. Flow cytometry, single-cell sequencing, and histological analysis showed that the ablated Paneth cells are replaced by enteroendocrine and tuft cells. As these cells physically occupy Paneth cell positions between Lgr5 stem cells, they serve as an alternative source of Notch signals, which are essential for Lgr5+ stem cell maintenance. Our combined in vivo results underscore the adaptive flexibility of the intestine in maintaining normal tissue homeostasis.

U2 - 10.1073/pnas.1801888117

DO - 10.1073/pnas.1801888117

M3 - Article

C2 - 31843916

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 -

Enteroendocrine and tuft cells support Lgr5 stem cells on Paneth cell depletion

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