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.
authors: Hubrecht Institute for Developmental Biology and Stem Cell Research, 3584 CT, Utrecht, The Netherlands; Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands;
authors: Nobuo
authors: N
authors: Sasaki
authors: Hubrecht Institute for Developmental Biology and Stem Cell Research, 3584 CT, Utrecht, The Netherlands; Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands;
authors: Norman
authors: N
authors: Sachs
authors: Hubrecht Institute for Developmental Biology and Stem Cell Research, 3584 CT, Utrecht, The Netherlands; Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands;
authors: Kay
authors: K
authors: Wiebrands
authors: Hubrecht Institute for Developmental Biology and Stem Cell Research, 3584 CT, Utrecht, The Netherlands; Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands;
authors: Saskia I J
authors: SI
authors: Ellenbroek
authors: Hubrecht Institute for Developmental Biology and Stem Cell Research, 3584 CT, Utrecht, The Netherlands; Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands;
authors: Arianna
authors: A
authors: Fumagalli
authors: Hubrecht Institute for Developmental Biology and Stem Cell Research, 3584 CT, Utrecht, The Netherlands; Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands;
authors: Anna
authors: A
authors: Lyubimova
authors: Hubrecht Institute for Developmental Biology and Stem Cell Research, 3584 CT, Utrecht, The Netherlands; Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands;
authors: Harry
authors: H
authors: Begthel
authors: Hubrecht Institute for Developmental Biology and Stem Cell Research, 3584 CT, Utrecht, The Netherlands; Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands;
authors: Maaike
authors: M
authors: van den Born
authors: Hubrecht Institute for Developmental Biology and Stem Cell Research, 3584 CT, Utrecht, The Netherlands; Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands;
authors: Johan H
authors: JH
authors: van Es
authors: Hubrecht Institute for Developmental Biology and Stem Cell Research, 3584 CT, Utrecht, The Netherlands; Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands;
authors: Wouter R
authors: WR
authors: Karthaus
authors: Hubrecht Institute for Developmental Biology and Stem Cell Research, 3584 CT, Utrecht, The Netherlands; Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands;
authors: Vivian S W
authors: VS
authors: Li
authors: The Institute of Nanoscopy, Maastricht University, 6211 LK, Maastricht, The Netherlands.
authors: Carmen
authors: C
authors: López-Iglesias
authors: The Institute of Nanoscopy, Maastricht University, 6211 LK, Maastricht, The Netherlands.
authors: Peter J
authors: PJ
authors: Peters
authors: Hubrecht Institute for Developmental Biology and Stem Cell Research, 3584 CT, Utrecht, The Netherlands; Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands;
authors: Jacco
authors: J
authors: van Rheenen
authors: Hubrecht Institute for Developmental Biology and Stem Cell Research, 3584 CT, Utrecht, The Netherlands; Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands;
authors: Alexander
authors: A
authors: van Oudenaarden
authors: Hubrecht Institute for Developmental Biology and Stem Cell Research, 3584 CT, Utrecht, The Netherlands; Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands; h.clevers@hubrecht.eu.
authors: Hans
authors: H
authors: Clevers
mesh_terms: D000818:Animals; D003106:Colon / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009940:Organoids / Q000254:growth & development / Q000378:metabolism; D000073718:Pancreatitis-Associated Proteins; D019879:Paneth Cells / Q000166:cytology / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics; D055153:Stem Cell Niche / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: C493597:Lgr5 protein, mouse; D009363:Neoplasm Proteins; D000073718:Pancreatitis-Associated Proteins; C546117:REG4 protein, mouse; D043562:Receptors, G-Protein-Coupled; D051880:Receptors, Notch
keywords: Lgr5; Reg4; deep crypt secretory cells; intestinal stem cell; niche