Peyer's patch M cells derived from Lgr5(+) stem cells require SpiB and are induced by RankL in cultured "miniguts".
Peyer's patches consist of domains of specialized intestinal epithelium overlying gut-associated lymphoid tissue (GALT). Luminal antigens reach the GALT by translocation through epithelial gatekeeper cells, the so-called M cells. We recently demonstrated that all epithelial cells required for the digestive functions of the intestine are generated from Lgr5-expressing stem cells. Here, we show that M cells also derive from these crypt-based Lgr5 stem cells. The Ets family transcription factor SpiB, known to control effector functions of bone marrow-derived immune cells, is specifically expressed in M cells. In SpiB(-/-) mice, M cells are entirely absent, which occurs in a cell-autonomous fashion. It has been shown that Tnfsf11 (RankL) can induce M cell development in vivo. We show that in intestinal organoid ("minigut") cultures, stimulation with RankL induces SpiB expression within 24 h and expression of other M cell markers subsequently. We conclude that RankL-induced expression of SpiB is essential for Lgr5 stem cell-derived epithelial precursors to develop into M cells.
Hubrecht Institute for Developmental Biology and Stem Cell Research, Utrecht, and University Medical Centre Utrecht, Utrecht, The Netherlands.
Wim
W
de Lau
Pekka
P
Kujala
Kerstin
K
Schneeberger
Sabine
S
Middendorp
Vivian S W
VS
Li
Nick
N
Barker
Anton
A
Martens
Frans
F
Hofhuis
Rodney P
RP
DeKoter
Peter J
PJ
Peters
Edward
E
Nieuwenhuis
Hans
H
Clevers
D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D047108:Embryonic Development; D049452:Green Fluorescent Proteins / Q000235:genetics; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D007422:Intestines / Q000196:embryology; D051379:Mice; D018345:Mice, Knockout; D010581:Peyer's Patches / Q000166:cytology* / Q000196:embryology / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis*; D013234:Stem Cells / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis
D004268:DNA-Binding Proteins; C493597:Lgr5 protein, mouse; D050783:Proto-Oncogene Proteins c-ets; D053245:RANK Ligand; D043562:Receptors, G-Protein-Coupled; C514177:Spi-B protein, mouse; C505689:Tnfsf11 protein, mouse; D014157:Transcription Factors; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins