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WIREs Syst Biol Med

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Gut stem cells in tissue renewal and disease: methods, markers, and myths

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Pamela Rizk, Nick Barker

Published Online: May 29 2012

DOI: 10.1002/wsbm.1176

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Homeostasis in adult tissue is maintained by the activity of a minor population of long‐lived resident stem cells. These adult stem cells are defined by two essential attributes, self‐renewal and multipotency, and their physiological activity is regulated by a specialized microenvironment, the stem cell niche. These adult stem cells are generally considered to divide infrequently, and cell expansion is mainly achieved through the rapid proliferation of transit amplifying progenitors before they undergo terminal differentiation. Organs that operate in abrasive environments, such as the mucosa of the skin, intestine, and stomach, display a higher tissue turnover rate, which consequently places them at higher risk of developing cancer. Indeed, colorectal cancer (CRC) is one of the most frequent cancers worldwide, with over a million new cases every year. Our understanding of stem cell function in tissue homeostasis and their potential role in cancer development has been greatly hampered by the lack of reliable specific biomarkers, but recent discoveries of membrane bound biomarkers promise great progress in the field. Here we review the current advances toward identifying the stem cells of the gastrointestinal tract and in understanding their microenvironmental regulation, and also discuss their implications for human cancer. WIREs Syst Biol Med 2012. doi: 10.1002/wsbm.1176

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Figure 1.

Cellular architecture of the intestinal crypt epithelium. (a) Epithelial homeostasis is driven by cycling Lgr5+ crypt base columnar (CBC) cells (green) located at the base of the crypt. These generate rapidly cycling transit amplifying (TA) cells which migrate up the crypt‐villus axis and differentiate over a period of 2 days. They have fully matured by the time of crypt exit, and will exert their function for a further 3–5 days as they continue their ascent. At the villus tip cells undergo apoptosis and are eventually shed. Paneth cells escape this upward motion and migrate down to the crypt base where they survive 6–8 weeks. (b) Flowchart depicting the generation of all epithelial lineages derived from the Lgr5+ CBC stem cell. (c) Under appropriate culture conditions, intestinal stem cells (ISCs) generate organoid structures organized into crypt‐villus‐like domains. Multiple crypts harboring Lgr5+ stem cells form around a central lumen and are connected by villus‐like epithelium. The epithelium is under constant renewal from the stem cells and apoptotic cells are shed into the lumen.

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Figure 2.

The two‐stem states of activation model. (a) Quiescent (+4) and active (crypt base columnar, CBC) stem cells coexist in the stem cell compartment. Upon division, CBC stem cells can choose to generate transit amplifying (TA) daughter cells (1), self‐renew (2), or to contribute to the quiescent stem cell reservoir (3). This reserve population can in turn be activated by stimulatory signals (e.g., injury) to replenish the active stem cell pool or presumably directly contribute to the TA compartment. (b) Separate activation states are maintained in adjacent zones by corresponding inhibitory and stimulatory signals. The CBC stem cell niche is established by signaling factors secreted by Paneth cells, and of these, Wnt‐signaling plays a prominent part. It is unclear what signals prevent the activation of ‘quiescent' intestinal stem cells (ISCs), but silencing of Wnt‐signaling via sFRP5 is a proposed mechanism.

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Figure 3.

Cellular architecture of the pyloric gland epithelium. (a) Epithelial homeostasis is driven by cycling Lgr5+ cells (green) located at the gland base. These generate rapidly cycling transit amplifying (TA) cells which differentiate into all gastric epithelial lineages. Short‐lived mucus cells migrate up the gland toward the pit, whereas the zymogenic chief cells descend to the gland base where they survive much longer. In contrast, parietal cells exhibit a bidirectional migration pattern. (b) Flowchart depicting the generation of all pyloric epithelial lineages derived from the Lgr5+ base stem cell.

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Figure 4.

Model of intestinal cancer initiation and progression. (a) Loss of adenomatous polyposis coli (APC) is known to be the initiating event behind adenoma formation in human colorectal cancer (CRC) and in the mouse model. Animal studies have identified the Wnt‐transformed Lgr5+ crypt base columnar (CBC) cell to be the adenoma cell of origin (red). Loss of APC results in accumulation of nuclear β‐catenin, leading to the constitutive activation of Wnt‐signaling. (b) The transformed Lgr5+ stem cell gives rise to β‐catenin^high progeny (red‐hued) that moves up the transit amplifying (TA) compartment. (c) Wnt‐activated TA cells are unable to exit the crypt unto the villus and start to expand sideways to form a benign adenoma. Scattered Lgr5+ cells associated with Paneth‐like cells can be observed in the benign tumor, implicating the Lgr5+ cell as a putative cancer stem cells (CSC). In human CRC, the transition from a dysplastic crypt to an early adenoma necessitates an additional Kras mutation. (d, e) The gradual accumulation of additional oncogenic hits (shown in italics) drives the progression from a benign adenoma to an invasive carcinoma in human CRC. The role of the Lgr5+ cell in cancer maintenance/progression is currently under study.

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References

1 Cunningham, D, Atkin, W, Lenz, HJ, Lynch, HT, Minsky, B, Nordlinger, B, Starling, N. Colorectal cancer. Lancet 2010, 375:1030–1047.
2 Sancho, E, Batlle, E, Clevers, H. Live and let die in the intestinal epithelium. Curr Opin Cell Biol 2003, 15:763–770.
3 Leblond, CP, Stevens, CE. The constant renewal of the intestinal epithelium in the albino rat. Anat Rec 1948, 100:357–377.
4 Heath, JP. Epithelial cell migration in the intestine. Cell Biol Int 1996, 20:139–146.
5 Ireland, H, Houghton, C, Howard, L, Winton, DJ. Cellular inheritance of a Cre‐activated reporter gene to determine Paneth cell longevity in the murine small intestine. Dev Dyn 2005, 233:1332–1336.
6 Cheng, H, Leblond, CP. 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 1974, 141:537–561.
7 Bjerknes, M, Cheng, H. Clonal analysis of mouse intestinal epithelial progenitors. Gastroenterology 1999, 116:7–14.
8 Bjerknes, M, Cheng, H. The stem‐cell zone of the small intestinal epithelium. V. Evidence for controls over orientation of boundaries between the stem‐cell zone, proliferative zone, and the maturation zone. Am J Anat 1981, 160:105–112.
9 van der Flier, LG, Sabates‐Bellver, J, Oving, I, Haegebarth, A, De Palo, M, Anti, M, van Gijn, ME, Suijkerbuijk, S, Van de Wetering, M, Marra, G, et al. The intestinal Wnt/TCF signature. Gastroenterology 2007, 132:628–632.
10 Barker, N, van Es, JH, Kuipers, J, Kujala, P, van den Born, M, Cozijnsen, M, Haegebarth, A, Korving, J, Begthel, H, Peters, PJ , et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007, 449:1003–1007.
11 Snippert, HJ, van der Flier, LG, Sato, T, van Es, J, van den Born, M, Kroon‐Veenboer, C, Barker, N, Klein, AM, van Rheenen, J, Simons, BD ,et al. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 2010, 143:134–144.
12 Dignass, AU, Sturm, A. Peptide growth factors in the intestine. Eur J Gastroenterol Hepatol 2001, 13:763–770.
13 Haramis, AP, Begthel, H, van den Born, M, van Es, J, Jonkheer, S, Offerhaus, GJ, Clevers, H. De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. Science 2004, 303:1684–1686.
14 Kim, KA, Kakitani, M, Zhao, J, Oshima, T, Tang, T, Binnerts, M, Liu, Y, Boyle, B, Park, E, Emtage, P, et al. Mitogenic influence of human R‐spondin1 on the intestinal epithelium. Science 2005, 309:1256–1259.
15 Sato, T, Vries, RG, Snippert, HJ, Van de Wetering, M, Barker, N, Stange, DE, van Es, JH, Abo, A, Kujala, P, Peters, PJ, et al. Single Lgr5 stem cells build crypt‐villus structures in vitro without a mesenchymal niche. Nature 2009, 459:262–265.
16 Yui, S, Nakamura, T, Sato, T, Nemoto, Y, Mizutani, T, Zheng, X, Ichinose, S, Nagaishi, T, Okamoto, R, Tsuchiya, K, et al. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5(+) stem cell. Nat Med 2012, 18:618–623.
17 van der Flier, LG, van Gijn, ME, Hatzis, P, Kujala, P, Haegebarth, A, Stange, DE, Begthel, H, van den Born, M, Guryev, V, Oving, I, et al. Transcription factor achaete scute‐like 2 controls intestinal stem cell fate. Cell 2009, 136: 903–912 .
18 Ireland, H, Kemp, R, Houghton, C, Howard, L, Clarke, AR, Sansom, OJ, Winton, DJ. Inducible Cre‐mediated control of gene expression in the murine gastrointestinal tract: effect of loss of β‐catenin. Gastroenterology 2004, 126:1236–1246.
19 Kosinski, C, Li, VS, Chan, AS, Zhang, J, Ho, C, Tsui, WY, Chan, TL, Mifflin, RC, Powell, DW, Yuen, ST, et al. Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors. Proc Natl Acad Sci U S A 2007, 104:15418–15423.
20 van der Flier, LG, Haegebarth, A, Stange, DE, 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 2009, 137:15–17.
21 Powell, AE, Wang, Y, Li, Y, Poulin, EJ, Means, AL, Washington, MK, Higginbotham, JN, Juchheim, A, Prasad, N, Levy, SE, et al. The Pan‐ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell 2012, 149:146–158.
22 Wong, VW, Stange, DE, Page, ME, Buczacki, S, Wabik, A, Itami, S, Van de Wetering, M, Poulsom, R, Wright, NA, Trotter, MW et al. Lrig1 controls intestinal stem‐cell homeostasis by negative regulation of ErbB signalling. Nat Cell Biol 2012, 14:401–408.
23 Itzkovitz, S, Lyubimova, A, Blat, IC, Maynard, M, van Es, JH, Lees, J, Jacks, T, Clevers, H, van Oudenaarden, A. Single‐molecule transcript counting of stem‐cell markers in the mouse intestine. Nat Cell Biol 2012, 14:106–114.
24 Snippert, HJ, van Es, JH, van den Born, M, Begthel, H, Stange, DE, Barker, N, Clevers, H. Prominin‐1/CD133 marks stem cells and early progenitors in mouse small intestine. Gastroenterology 2009, 136:2187–2194.
25 Zhu, L, Gibson, P, Currle, DS, Tong, Y, Richardson, RJ, Bayazitov, IT, Poppleton, H, Zakharenko, S, Ellison, DW, Gilbertson, RJ. Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 2009, 457:603–607.
26 Formeister, EJ, Sionas, AL, Lorance, DK, Barkley, CL, Lee, GH, Magness, ST. Distinct SOX9 levels differentially mark stem/progenitor populations and enteroendocrine cells of the small intestine epithelium. Am J Physiol Gastrointest Liver Physiol 2009, 296:G1108–G1118.
27 Gracz, AD, Ramalingam, S, Magness, ST. Sox9 expression marks a subset of CD24‐expressing small intestine epithelial stem cells that form organoids in vitro. Am J Physiol Gastrointest Liver Physiol 2010, 298:G590–G600.
28 Mori‐Akiyama, Y, van den Born, M, van, Es JH, Hamilton, SR, Adams, HP, Zhang, J, Clevers, H, de Crombrugghe, B. SOX9 is required for the differentiation of paneth cells in the intestinal epithelium. Gastroenterology 2007, 133:539–546.
29 Potten, CS, Booth, C, Tudor, GL, Booth, D, Brady, G, Hurley, P, Ashton, G, Clarke, R, Sakakibara, S, Okano, H. Identification of a putative intestinal stem cell and early lineage marker; musashi‐1. Differentiation 2003, 71:28–41.
30 Breault, DT, Min, IM, Carlone, DL, Farilla, LG, Ambruzs, DM, Henderson, DE, Algra, S, Montgomery, RK, Wagers, AJ, Hole, N. Generation of mTert‐GFP mice as a model to identify and study tissue progenitor cells. Proc Natl Acad Sci U S A 2008, 105:10420–10425.
31 Schepers, AG, 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 2011, 30:1104–1109.
32 Montgomery, RK, Carlone, DL, Richmond, CA, Farilla, L, Kranendonk, ME, Henderson, DE, Baffour‐Awuah, NY, Ambruzs, DM, Fogli, LK, Algra, S et al. Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells. Proc Natl Acad Sci U S A 2011, 108:179–184.
33 Sangiorgi, E, Capecchi, MR. Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet 2008, 40:915–920.
34 Tian, H, Biehs, B, Warming, S, Leong, KG, Rangell, L, Klein, OD, de Sauvage, FJ. A reserve stem cell population in small intestine renders Lgr5‐positive cells dispensable. Nature 2011, 478:255–259.
35 Yan, KS, Chia, LA, Li, X, Ootani, A, Su, J, Lee, JY, Su, N, Luo, Y, Heilshorn, SC, Amieva, MR et al. The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. Proc Natl Acad Sci U S A 2012, 109:466–471.
36 Takeda, N, Jain, R, LeBoeuf, MR, Wang, Q, Lu, MM, Epstein, JA. Interconversion between intestinal stem cell populations in distinct niches. Science 2011, 334:1420–1424.
37 May, R, Sureban, SM, Hoang, N, Riehl, TE, Lightfoot, SA, Ramanujam, R, Wyche, JH, Anant, S, Houchen, CW. Doublecortin and CaM kinase‐like‐1 and leucine‐rich‐repeat‐containing G‐protein‐coupled receptor mark quiescent and cycling intestinal stem cells, respectively. Stem Cells 2009, 27:2571–2579.
38 Gerbe, F, Brulin, B, Makrini, L, Legraverend, C, Jay, P. DCAMKL‐1 expression identifies Tuft cells rather than stem cells in the adult mouse intestinal epithelium. Gastroenterology 2009, 137:2179–2180.
39 Demidov, ON, Timofeev, O, Lwin, HN, Kek, C, Appella, E, Bulavin, DV. Wip1 phosphatase regulates p53‐dependent apoptosis of stem cells and tumorigenesis in the mouse intestine. Cell Stem Cell 2007, 1:180–190.
40 Gregorieff, A, Pinto, D, Begthel, H, Destree, O, Kielman, M, Clevers, H. Expression pattern of Wnt signaling components in the adult intestine. Gastroenterology 2005, 129:626–638.
41 von Furstenberg, RJ, Gulati, AS, Baxi, A, Doherty, JM, Stappenbeck, TS, Gracz, AD, Magness, ST, Henning, SJ. Sorting mouse jejunal epithelial cells with CD24 yields a population with characteristics of intestinal stem cells. Am J Physiol Gastrointest Liver Physiol 2011, 300:G409–G417.
42 Sato, T, van Es, JH, Snippert, HJ, Stange, DE, Vries, RG, van den Born, M, Barker, N, Shroyer, NF, Van de Wetering, M, Clevers, H. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 2011, 469:415–418.
43 Snippert, HJ, Clevers, H. Tracking adult stem cells. EMBO Rep 2011, 12:113–122.
44 Livet, J, Weissman, TA, Kang, H, Draft, RW, Lu, J, Bennis, RA, Sanes, JR, Lichtman, JW. Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature 2007, 450:56–62.
45 Neumuller, RA, Knoblich, JA. Dividing cellular asymmetry: asymmetric cell division and its implications for stem cells and cancer. Genes Dev 2009, 23:2675–2699.
46 Lopez‐Garcia, C, Klein, AM, Simons, BD, Winton, DJ. Intestinal stem cell replacement follows a pattern of neutral drift. Science 2010, 330:822–825.
47 Cairnie, AB, Lamerton, LF, Steel, GG. Cell proliferation studies in the intestinal epithelium of the rat. I. Determination of the kinetic parameters. Exp Cell Res 1965, 39:528–538.
48 Potten, CS. Extreme sensitivity of some intestinal crypt cells to X and γ irradiation. Nature 1977, 269:518–521.
49 Potten, CS, Kovacs, L, Hamilton, E. Continuous labelling studies on mouse skin and intestine. Cell Tissue Kinet 1974, 7:271–283.
50 Potten, CS, Owen, G, Booth, D. Intestinal stem cells protect their genome by selective segregation of template DNA strands. J Cell Sci 2002, 115:2381–2388.
51 Cairns, J. Mutation selection and the natural history of cancer. Nature 1975, 255:197–200.
52 Lin, SA, Barker, N. Gastrointestinal stem cells in self‐renewal and cancer. J Gastroenterol 2011, 46:1039–1055.
53 Park, IK, Morrison, SJ, Clarke, MF. Bmi1, stem cells, and senescence regulation. J Clin Invest 2004, 113:175–179.
54 Barker, N, Bartfeld, S, Clevers, H. Tissue‐resident adult stem cell populations of rapidly self‐renewing organs. Cell Stem Cell 2010, 7:656–670.
55 Li, L, Clevers, H. Coexistence of quiescent and active adult stem cells in mammals. Science 2010, 327:542–545.
56 Shibata, H, Toyama, K, Shioya, H, Ito, M, Hirota, M, Hasegawa, S, Matsumoto, H, Takano, H, Akiyama, T, Toyoshima, K et al. Rapid colorectal adenoma formation initiated by conditional targeting of the Apc gene. Science 1997, 278:120–123.
57 Korinek, V, Barker, N, Moerer, P, van Donselaar, E, Huls, G, Peters, PJ, Clevers, H. Depletion of epithelial stem‐cell compartments in the small intestine of mice lacking Tcf‐4. Nat Genet 1998, 19:379–383.
58 Gregorieff, A, Clevers, H. Wnt signaling in the intestinal epithelium: from endoderm to cancer. Genes Dev 2005, 19:877–890.
59 Pinto, D, Gregorieff, A, Begthel, H, Clevers, H. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev 2003, 17:1709–1713.
60 van Es, JH, Haegebarth, A, Kujala, P, Itzkovitz, S, Koo, BK, Boj, SF, Korving, J, van den Born, M, van Oudenaarden, A, Robine, S et al. A critical role for the wnt effector tcf4 in adult intestinal homeostatic self‐renewal. Mol Cell Biol 2012, 32:1918–1927.
61 Kuhnert, F, Davis, CR, Wang, HT, Chu, P, Lee, M, Yuan, J, Nusse, R, Kuo, CJ. Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf‐1. Proc Natl Acad Sci U S A 2004, 101:266–271.
62 Angus‐Hill, ML, Elbert, KM, Hidalgo, J, Capecchi, MR. T‐cell factor 4 functions as a tumor suppressor whose disruption modulates colon cell proliferation and tumorigenesis. Proc Natl Acad Sci U S A 2011, 108:4914–4919.
63 Korinek, V, Barker, N, Morin, PJ, van Wichen, D, de Weger, R, Kinzler, KW, Vogelstein, B, Clevers, H. Constitutive transcriptional activation by a β‐catenin‐Tcf complex in APC‐/‐ colon carcinoma. Science 1997, 275:1784–1787.
64 Rothenberg, ME, Nusse, Y, Kalisky, T, Lee, JJ, Dalerba, P, Scheeren, F, Lobo, N, Kulkarni, S, Sim, S, Qian, D et al. Identification of a Ckit+ colonic crypt base secretory cell that supports Lgr5+ stem cells in mice. Gastroenterology 2012, 142:1195–1205.
65 Shroyer, NF, Wallis, D, Venken, KJ, Bellen, HJ, Zoghbi, HY. Gfi1 functions downstream of Math1 to control intestinal secretory cell subtype allocation and differentiation. Genes Dev 2005, 19:2412–2417.
66 Garabedian, EM, Roberts, LJ, McNevin, MS, Gordon, JI. Examining the role of Paneth cells in the small intestine by lineage ablation in transgenic mice. J Biol Chem 1997, 272:23729–23740.
67 Bastide, P, Darido, C, Pannequin, J, Kist, R, Robine, S, Marty‐Double, C, Bibeau, F, Scherer, G, Joubert, D, Hollande, F et al. Sox9 regulates cell proliferation and is required for Paneth cell differentiation in the intestinal epithelium. J Cell Biol 2007, 178:635–648.
68 Shroyer, NF, Helmrath, MA, Wang, VY, Antalffy, B, Henning, SJ, Zoghbi, HY. Intestine‐specific ablation of mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis. Gastroenterology 2007, 132:2478–2488.
69 Kim, TH, Escudero, S, Shivdasani, RA. Intact function of Lgr5 receptor‐expressing intestinal stem cells in the absence of Paneth cells. Proc Natl Acad Sci U S A 2012, 109:3932–3937.
70 van Es, JH, de Geest, N, van den Born, M, Clevers, H, Hassan, BA. Intestinal stem cells lacking the Math1 tumour suppressor are refractory to Notch inhibitors. Nat Commun 2010, 1:18.
71 de Lau, W, Barker, N, Low, TY, Koo, BK, Li, VS, Teunissen, H, Kujala, P, Haegebarth, A, Peters, PJ, Van de Wetering, M, et al. Lgr5 homologues associate with Wnt receptors and mediate R‐spondin signalling. Nature 2011, 476:293–297.
72 Barker, N, Huch, M, Kujala, P, Van de Wetering, M, Snippert, HJ, van Es, JH, Sato, T, Stange, DE, Begthel, H, van den Born, M et al. Lgr5(+ve) stem cells drive self‐renewal in the stomach and build long‐lived gastric units in vitro. Cell Stem Cell 2010, 6:25–36.
73 Jaks, V, Barker, N, Kasper, M, van Es, JH, Snippert, HJ, Clevers, H, Toftgard, R. Lgr5 marks cycling, yet long‐lived, hair follicle stem cells. Nat Genet 2008, 40:1291–1299.
74 Snippert, HJ, Haegebarth, A, Kasper, M, Jaks, V, van Es, JH, Barker, N, Van de Wetering, M, van den Born, M, Begthel, H, Vries, RG, et al. Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin. Science 2010, 327:1385–1389.
75 Van Schoore, G, Mendive, F, Pochet, R, Vassart, G. Expression pattern of the orphan receptor LGR4/GPR48 gene in the mouse. Histochem Cell Biol 2005, 124:35–50.
76 Mustata, RC, Van Lov, T, Lefort, A, Libert, F, Strollo, S, Vassart, G, Garcia, MI. Lgr4 is required for Paneth cell differentiation and maintenance of intestinal stem cells ex vivo. EMBO Rep 2011, 12:558–564.
77 Mazerbourg, S, Bouley, DM, Sudo, S, Klein, CA, Zhang, JV, Kawamura, K, Goodrich, LV, Rayburn, H, Tessier‐Lavigne, M, Hsueh, AJ. Leucine‐rich repeat‐containing, G protein‐coupled receptor 4 mice exhibit intrauterine growth retardation associated with embryonic and perinatal lethality. Mol Endocrinol 2004, 18:2241–2254.
78 Morita, H, Mazerbourg, S, Bouley, DM, Luo, CW, Kawamura, K, Kuwabara, Y, Baribault, H, Tian, H, Hsueh, AJ. Neonatal lethality of LGR5 mice is associated with ankyloglossia and gastrointestinal distension. Mol Cell Biol 2004, 24:9736–9743.
79 de Lau, W, Barker, N, Clevers, H. WNT signaling in the normal intestine and colorectal cancer. Front Biosci 2007, 12:471–491.
80 Carmon, KS, Gong, X, Lin, Q, Thomas, A, Liu, Q. R‐spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/β‐catenin signaling. Proc Natl Acad Sci U S A 2011, 108:11452–11457.
81 Glinka, A, Dolde, C, Kirsch, N, Huang, YL, Kazanskaya, O, Ingelfinger, D, Boutros, M, Cruciat, CM, Niehrs, C. LGR4 and LGR5 are R‐spondin receptors mediating Wnt/β‐catenin and Wnt/PCP signalling. EMBO Rep 2011, 12:1055–1061.
82 Kim, KA, Wagle, M, Tran, K, Zhan, X, Dixon, MA, Liu, S, Gros, D, Korver, W, Yonkovich, S, Tomasevic, N et al. R‐Spondin family members regulate the Wnt pathway by a common mechanism. Mol Biol Cell 2008, 19:2588–2596.
83 Carmon, KS, Lin, Q, Gong, X, Thomas, A, Liu, Q. LGR5 interacts and co‐internalizes with Wnt receptors to modulate Wnt/β‐catenin signaling. Mol Cell Biol 2012. [epub ahead of print].
84 Leushacke, M, Barker, N. Lgr5 and Lgr6 as markers to study adult stem cell roles in self‐renewal and cancer. Oncogene 2011. [epub ahead of print].
85 Uchida, H, Yamazaki, K, Fukuma, M, Yamada, T, Hayashida, T, Hasegawa, H, Kitajima, M, Kitagawa, Y, Sakamoto, M. Overexpression of leucine‐rich repeat‐containing G protein‐coupled receptor 5 in colorectal cancer. Cancer Sci 2010, 101:1731–1737.
86 Sato, T, Stange, DE, Ferrante, M, Vries, RG, van Es, JH, van den Born, M, Van Houdt, WJ, Pronk, A, Van Gorp, J, Siersema, PD et al. Long‐term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett`s epithelium. Gastroenterology 2011, 141:1762–1772.
87 Karam, SM. Lineage commitment and maturation of epithelial cells in the gut. Front Biosci 1999, 4:D286–D298.
88 Karam, SM, Leblond, CP. Dynamics of epithelial cells in the corpus of the mouse stomach. I. Identification of proliferative cell types and pinpointing of the stem cell. Anat Rec 1993, 236:259–279.
89 Lee, ER, Leblond, CP. Dynamic histology of the antral epithelium in the mouse stomach: IV. Ultrastructure and renewal of gland cells. Am J Anat 1985, 172:241–259.
90 Lee, ER, Leblond, CP. Dynamic histology of the antral epithelium in the mouse stomach: II. Ultrastructure and renewal of isthmal cells. Am J Anat 1985, 172:205–224.
91 Bjerknes, M, Cheng, H. Multipotential stem cells in adult mouse gastric epithelium. Am J Physiol Gastrointest Liver Physiol 2002, 283:G767–G777.
92 Qiao, XT, Ziel, JW, McKimpson, W, Madison, BB, Todisco, A, Merchant, JL, Samuelson, LC, Gumucio, DL. Prospective identification of a multilineage progenitor in murine stomach epithelium. Gastroenterology 2007, 133:1989–1998.
93 Visvader, JE. Cells of origin in cancer. Nature 2011, 469:314–322.
94 Jamieson, CH, Ailles, LE, Dylla, SJ, Muijtjens, M, Jones, C, Zehnder, JL, Gotlib, J, Li, K, Manz, MG, Keating, A et al. Granulocyte‐macrophage progenitors as candidate leukemic stem cells in blast‐crisis CML. N Engl J Med 2004, 351:657–667.
95 Fearon, ER, Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 1990, 61:759–767.
96 Sancho, E, Batlle, E, Clevers, H. Signaling pathways in intestinal development and cancer. Annu Rev Cell Dev Biol 2004, 20:695–723.
97 Morin, PJ, Sparks, AB, Korinek, V, Barker, N, Clevers, H, Vogelstein, B, Kinzler, KW. Activation of β‐catenin‐Tcf signaling in colon cancer by mutations in β‐catenin or APC. Science 1997, 275:1787–1790.
98 Groden, J, Thliveris, A, Samowitz, W, Carlson, M, Gelbert, L, Albertsen, H, Joslyn, G, Stevens, J, Spirio, L, Robertson, M, et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 1991, 66:589–600.
99 Kinzler, KW, Nilbert, MC, Vogelstein, B, Bryan, TM, Levy, DB, Smith, KJ, Preisinger, AC, Hamilton, SR, Hedge, P, Markham, A, et al. Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science 1991, 251:1366–1370.
100 Ilyas, M, Tomlinson, IP, Rowan, A, Pignatelli, M, Bodmer, WF. β‐catenin mutations in cell lines established from human colorectal cancers. Proc Natl Acad Sci U S A 1997, 94:10330–10334.
101 Barker, N, Ridgway, RA, van Es, JH, Van de Wetering, M, Begthel, H, van den Born, M, Danenberg, E, Clarke, AR, Sansom, OJ, Clevers, H. Crypt stem cells as the cells‐of‐origin of intestinal cancer. Nature 2009, 457:608–611.
102 Sangiorgi, E, Capecchi, MR. Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet 2008, 40:915–920.
103 Merlos‐Suarez, A, Barriga, FM, Jung, P, Iglesias, M, Cespedes, MV, Rossell, D, Sevillano, M, Hernando‐Momblona, X, da Silva‐Diz, V, Munoz, P, et al. The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell 2011, 8:511–524.
104 Park, WS, Oh, RR, Park, JY, Lee, SH, Shin, MS, Kim, YS, Kim, SY, Lee, HK, Kim, PJ, Oh, ST, et al. Frequent somatic mutations of the β‐catenin gene in intestinal‐type gastric cancer. Cancer Res 1999, 59:4257–4260.
105 Clements, WM, Wang, J, Sarnaik, A, Kim, OJ, MacDonald, J, Fenoglio‐Preiser, C, Groden, J, Lowy, AM. β‐Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Cancer Res 2002, 62:3503–3506.
106 Offerhaus, GJ, Entius, MM, Giardiello, FM. Upper gastrointestinal polyps in familial adenomatous polyposis. Hepatogastroenterology 1999, 46:667–669.
107 O’Brien, CA, Pollett, A, Gallinger, S, Dick, JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007, 445:106–110.
108 Ricci‐Vitiani, L, Lombardi, DG, Pilozzi, E, Biffoni, M, Todaro, M, Peschle, C, De Maria, R. Identification and expansion of human colon‐cancer‐initiating cells. Nature 2007, 445:111–115.
109 Shmelkov, SV, Butler, JM, Hooper, AT, Hormigo, A, Kushner, J, Milde, T, St, CR, Baljevic, M, White, I, Jin, DK, et al. CD133 expression is not restricted to stem cells, and both CD133+ and CD133‐ metastatic colon cancer cells initiate tumors. J Clin Invest 2008, 118:2111–2120.
110 Dalerba, P, Dylla, SJ, Park, IK, Liu, R, Wang, X, Cho, RW, Hoey, T, Gurney, A, Huang, EH, Simeone, DM, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A 2007, 104:10158–10163.
111 Ng, A, Barker, N. Stem cells in epithelial renewal and cancer of the intestine. Eur Gastroenterol Hepatol 2011, 7:154–159.
112 Batlle, E, Henderson, JT, Beghtel, H, van den Born, M, Sancho, E, Huls, G, Meeldijk, J, Robertson, J, Van de Wetering, M, Pawson, T, et al. β‐catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell 2002, 111:251–263.
113 Takahashi, H, Ishii, H, Nishida, N, Takemasa, I, Mizushima, T, Ikeda, M, Yokobori, T, Mimori, K, Yamamoto, H, Sekimoto, M et al. Significance of Lgr5(+ve) cancer stem cells in the colon and rectum. Ann Surg Oncol 2011, 18:1166–1174.
114 de Sousa, E Melo, Colak, S, Buikhuisen, J, Koster, J, Cameron, K, de Jong, JH, Tuynman, JB, Prasetyanti, PR, Fessler, E, van den Bergh, SP, et al. Methylation of cancer‐stem‐cell‐associated Wnt target genes predicts poor prognosis in colorectal cancer patients. Cell Stem Cell 2011, 9:476–485.
115 Walker, F, Zhang, HH, Odorizzi, A, Burgess, AW. LGR5 is a negative regulator of tumourigenicity, antagonizes Wnt signalling and regulates cell adhesion in colorectal cancer cell lines. PLoS One 2011, 6:e22733.
116 Barker, N, Clevers, H. Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov 2006, 5:997–1014.
117 Takahashi‐Yanaga, F, Kahn, M. Targeting Wnt signaling: can we safely eradicate cancer stem cells? Clin Cancer Res 2010, 16:3153–3162.
118 de Sousa, EM, Vermeulen, L, Richel, D, Medema, JP. Targeting Wnt signaling in colon cancer stem cells. Clin Cancer Res 2011, 17:647–653.
119 Vermeulen, L, de Sousa e Melo, F, Richel, DJ, Medema, JP. The developing cancer stem‐cell model: clinical challenges and opportunities. Lancet Oncol 2012, 13:e83–e89.
120 Jung, P, Sato, T, Merlos‐Suarez, A, Barriga, FM, Iglesias, M, Rossell, D, Auer, H, Gallardo, M, Blasco, MA, Sancho, E, et al. Isolation and in vitro expansion of human colonic stem cells. Nat Med 2011, 17:1225–1227.

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Philip Benfey

Is intrigued by one of the key questions in developmental biology: how cells acquire their identities. This is an important question in human development, where stem cells divide and differentiate into skin, muscle, fat etc. It is equally central to plant development, where most organs and cells are formed from stem cell populations known as meristems. The Benfey lab addresses this question using a combination of genetics, molecular biology, and genomics to identify and characterize the genes that regulate formation of the root in the plant model system, Arabidopsis thaliana. The choice of the root as a model was based on the simplicity of its organization and its stereotyped developmental program.

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