Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts.
Homeostasis of self-renewing small intestinal crypts results from neutral competition between Lgr5 stem cells, which are small cycling cells located at crypt bottoms. Lgr5 stem cells are interspersed between terminally differentiated Paneth cells that are known to produce bactericidal products such as lysozyme and cryptdins/defensins. Single Lgr5-expressing stem cells can be cultured to form long-lived, self-organizing crypt-villus organoids in the absence of non-epithelial niche cells. Here we find a close physical association of Lgr5 stem cells with Paneth cells in mice, both in vivo and in vitro. CD24(+) Paneth cells express EGF, TGF-α, Wnt3 and the Notch ligand Dll4, all essential signals for stem-cell maintenance in culture. Co-culturing of sorted stem cells with Paneth cells markedly improves organoid formation. This Paneth cell requirement can be substituted by a pulse of exogenous Wnt. Genetic removal of Paneth cells in vivo results in the concomitant loss of Lgr5 stem cells. In colon crypts, CD24(+) cells residing between Lgr5 stem cells may represent the Paneth cell equivalents. We conclude that Lgr5 stem cells compete for essential niche signals provided by a specialized daughter cell, the Paneth cell.
Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, the Netherlands.
Toshiro
T
Sato
Johan H
JH
van Es
Hugo J
HJ
Snippert
Daniel E
DE
Stange
Robert G
RG
Vries
Maaike
M
van den Born
Nick
N
Barker
Noah F
NF
Shroyer
Marc
M
van de Wetering
Hans
H
Clevers
D000818:Animals; D051927:CD24 Antigen / Q000378:metabolism; D002452:Cell Count; D049109:Cell Proliferation; D018920:Coculture Techniques; D006801:Humans; D007422:Intestines / Q000166:cytology*; D051379:Mice; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D019879:Paneth Cells / Q000166:cytology* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D055153:Stem Cell Niche / Q000166:cytology* / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D060508:Wnt3 Protein
D051927:CD24 Antigen; C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled; C555507:WNT3 protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; C555508:Wnt3 protein, mouse