Lgr5+ intestinal stem cells generate enterocytes and secretory cells. Secretory lineage commitment requires Notch silencing. The Notch ligand Dll1 is expressed by a subset of immediate stem cell daughters. Lineage tracing in Dll1GFP–ires–CreERT2 knock-in mice reveals that single Dll1high cells generate small, short-lived clones containing all four secretory cell types. Lineage specification thus occurs in immediate stem cell daughters through Notch lateral inhibition. Cultured Dll1high cells form long-lived organoids (mini-guts) on brief Wnt3A exposure. When Dll1high cells are genetically marked before tissue damage, stem cell tracing events occur. Thus, secretory progenitors exhibit plasticity by regaining stemness on damage.
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Gene Expression Omnibus
Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).
Marshman, E., Booth, C. & Potten, C. S. The intestinal epithelial stem cell. Bioessays. 24, 91–98 (2002).
Gerbe, F. et al. Distinct ATOH1 and Neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium. J. Cell. Biol. 192, 767–780 (2011).
Cheng, H. & Leblond, C. P. Origin differentiation and renewal of the four main epithelial cell types in the mouse small intestine. I. Columnar cell. Am. J. Anat. 141, 461–479 (1974).
Bjerknes, M. & Cheng, H. Clonal analysis of mouse intestinal epithelial progenitors. Gastroenterology 116, 7–14 (1999).
Cheng, H. & Leblond, C. P. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian Theory of the origin of the four epithelial cell types. Am. J. Anat. 141, 537–561 (1974).
Ireland, H., Houghton, C., Howard, L. & Winton, D. J. Cellular inheritance of a Cre-activated reporter gene to determine Paneth cell longevity in the murine small intestine. Dev. Dynam. 233, 1332–1336 (2005).
Sato, T. et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature. 469, 415–418 (2011).
Riccio, O. et al. Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2. EMBO Rep. 4, 377–383 (2008).
Jensen, J. et al. Control of endodermal endocrine development by Hes-1. Nat. Genet. 24, 36–44 (2000).
Van Es, J. H. et al. Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature. 435, 959–963 (2005).
Yang, Q., Bermingham, N. A., Finegold, M. J. & Zoghbi, H. Y. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science. 294, 2155–2158 (2001).
Shroyer, N. F. et al. Intestine-specific ablation of mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis. Gastroenterology. 132, 2478–2488 (2007).
Van Es, J. H., de Geest, N., van de Born, M., Clevers, H. & Hassan, B. A. Intestinal stem cells lacking the Math1 tumour suppressor are refractory to Notch inhibitors. Nat. Commun. 1, 8 (2010).
Milano, J. et al. Modulation of notch processing by γ-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci. 82, 341–358 (2004).
Wu, Y. et al. Therapeutic antibody targeting of individual Notch receptors. Nature. 464, 1052–1057 (2010).
Pellegrinet, L. et al. Dll1- and dll4-mediated Notch signaling are required for homeostasis of intestinal stem cells. Gastroenterology 140, 1230–1240 (2011).
Crosnier, C. et al. Dll-Notch signalling controls commitment to a secretory fate in the zebrafish intestine. Development. 132, 1093–1104 (2005).
Beckers, J. et al. Expression of the mouse Dll1 gene during organogenesis and fetal development. Mech. Dev. 84, 165–168 (1999).
Stamataki, D. et al. Dll1 expression, cell cycle exit, and commitment to a specific secretory fate coincide within a few hours in the mouse intestinal stem cell system. PLoS One. 6, e24484 (2011).
Von Furstenberg, R. J. et al. Sorting mouse jejunal epithelial cells with CD24 yields a population with characteristics of intestinal stem cells. Am. J. Physiol. Gastrointest Liver Physiol. 300, G409–G417 (2011).
Jenny, M. et al. Neurogenin3 is differentially required for endocrine cell fate specification in the intestinal and gastric epithelium. EMBO J. 21, 6338–6347 (2002).
Noah, T. K., Kazanjian, A., Whitsett, J. & Shroyer, N. F. SAM pointed domain ETS factor (SPDEF) regulates terminal differentiation and maturation of intestinal goblet cells. Exp. Cell Res. 316, 452–465 (2010).
Gregorieff, A. et al. The ets-domain transcription factor Spdef promotes maturation of goblet and Paneth cells in the intestinal epithelium. Gastroenterology 137, 1333–1345 (2009).
Bjerknes, M. & Cheng, H. Cell Lineage metastability in Gfi1-deficient mouse intestinal epithelium. Dev. Biol. 345, 49–63 (2010).
Van der Flier, L. G., Haegebarth, A., Stange, D. E., van de Wetering, M. & Clevers, H. OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells. Gastroenterology 137, 15–17 (2009).
Muñoz, J. et al. The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent ‘+4’ cell markers. EMBO J. 31, 3079–3091 (2012).
Tian, H. et al. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478, 255–259 (2011).
Ireland, H. et al. Inducible Cre-mediated control of gene expression in the murine gastrointestinal tract: effect of loss of β-catenin. Gastroenterology 126, 1236–1246 (2004).
Snippert, H. J. et al. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134–144 (2010).
Raj, A., van den Bogaard, P., Rifkin, S. A., van Oudenaarden, A. & Tyagi, S. Imaging individual mRNA molecules using multiple singly labeled probes. Nat. Methods 10, 877–879 (2008).
Itzkovitz, S. et al. Single-molecule transcript counting of stem-cell markers in the mouse intestine. Nat. Cell Biol. 14, 106–114 (2011).
Schepers, A. G., Vries, R., van den Born, M., van de Wetering, M. & Clevers, H. Lgr5 intestinal stem cells have high telomerase activity and randomly segregate their chromosomes. EMBO J. 30, 1104–1109 (2011).
Sato, T. et al. Single Lgr5 stem cells build crypt–villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).
Axelrod, J. D. Delivering the lateral inhibition punch line: it’s all about the timing. Sci. Signal. 3, pe38 (2010).
Sangiorgi, E. & Capecchi, M. R. Bmi1 is expressed in vivo in intestinal stem cells. Nat. Genet. 40, 915–920 (2008).
Kai, T. et al. Differentiating germ cells can revert into functional stem cells in Drosophila melanogaster ovaries. Nature 428, 564–569 (2004).
Brawley, C. & Matunis, E. Regeneration of male germline stem cells by spermatogonial dedifferentiation in vivo. Science 304, 1331–1334 (2004).
Davies, E. J., Marsh, V. & Clarke, A. R. Origin and maintenance of the intestinal cancer stem cell. Mol. Carcinog 50, 254–263 (2011).
Anderson, E. C., Hessman, C., Levin, T. G., Monroe, M. M. & Wong, M. H. The role of colorectal cancer stem cells in metastatic disease and therapeutic response. Cancers 3, 319–339 (2011).
Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 57, 608–611 (2009).
This research was supported by KWF/HUBR2005-3237 (T.S.), KWF/HUBR2005-3956 (L.Z.), EU/Health-F4-2007-200720 (M.v.d.W.), NIH/NCI Physical Sciences Oncology Center at MIT: U54CA143874 (A.L. and A.v.O.), TI Pharma T3-106 (J.H.v.E. and M.v.d.B.) and NIRM (N.S.).
We thank D. Stange for critically reading the manuscript.
The authors declare no competing financial interests.
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van Es, J., Sato, T., van de Wetering, M. et al. Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nat Cell Biol 14, 1099–1104 (2012). https://doi.org/10.1038/ncb2581
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