Defining hierarchies of stemness in the intestine: Evidence from biomarkers and regulatory pathways

American Journal of Physiology - Gastrointestinal and Liver Physiology

Volumn 307, Issue 3, 2014, Pages

  Gracz, A D ^a   Magness, S T ^a,b  

^a UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

^b USA and North Carolina State University   (United States)

Author keywords

Bmp signaling; Cell fate; Differentiation; Intestinal stem cells; Wnt signaling

Indexed keywords

ACTIVATED LEUKOCYTE CELL ADHESION MOLECULE; BIOLOGICAL MARKER; CD24 ANTIGEN; HERMES ANTIGEN; NOTCH RECEPTOR;

CELL DIFFERENTIATION; CELL FATE; CELL PROLIFERATION; CELL RENEWAL; CLONAL CELL LINE; COLUMNAR EPITHELIUM; HUMAN; IN VITRO STUDY; INTESTINAL STEM CELL; INTESTINE CELL; INTESTINE EPITHELIUM; INTESTINE EPITHELIUM CELL; INTESTINE FUNCTION; NONHUMAN; PRIORITY JOURNAL; REGULATORY MECHANISM; REVIEW; STEM CELL; STEM CELL EXPANSION; STEM CELL NICHE; WNT SIGNALING PATHWAY;

BMP SIGNALING; CELL FATE; DIFFERENTIATION; INTESTINAL STEM CELLS; WNT SIGNALING;

ANIMALS; BIOLOGICAL MARKERS; CELL DIFFERENTIATION; CELL LINEAGE; CELL PROLIFERATION; GENE EXPRESSION REGULATION, DEVELOPMENTAL; HUMANS; INTESTINAL MUCOSA; INTESTINE, SMALL; SIGNAL TRANSDUCTION; STEM CELL NICHE; STEM CELLS;

EID: 84905234455     PISSN: 01931857     EISSN: 15221547     Source Type: Journal    
DOI: 10.1152/ajpgi.00066.2014     Document Type: Review

References (109)

1. The North Carolina Central Cancer Registry, State Center for Health Statistics. Colon and Rectum Cancer. The North Carolina Central Cancer Registry, State Center for Health Statistics. Raleigh, NC: North Carolina Public Health http://www. schs. state. nc. us/schs/pdf/Colon_Rectum_Cancer_2011. pdf. [September 6, 2012, 2012].
2. Ahmad AA, Wang Y, Gracz AD, Sims CE, Magness ST, Allbritton NL. Optimization of 3-D organotypic primary colonic cultures for organ-on-chip applications. J Biol Eng 8: 9, 2014.
3. Auclair BA, Benoit YD, Rivard N, Mishina Y, Perreault N. Bone morphogenetic protein signaling is essential for terminal differentiation of the intestinal secretory cell lineage. Gastroenterology 133: 887-896, 2007.
4. Barker N, Clevers H. Leucine-rich repeat-containing G-protein-coupled receptors as markers of adult stem cells. Gastroenterology 138: 1681-1696, 2010.
5. Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449: 1003-1007, 2007.
6. Batlle E, Henderson JT, Beghtel H, van den Born MM, Sancho E, Huls G, Meeldijk J, Robertson J, van de Wetering M, Pawson T, Clevers H. Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell 111: 251-263, 2002.
7. Bjerknes M, Khandanpour C, Moroy T, Fujiyama T, Hoshino M, Klisch TJ, Ding Q, Gan L, Wang J, Martin MG, Cheng H. Origin of the brush cell lineage in the mouse intestinal epithelium. Dev Biol 362: 194-218, 2012.
8. Boron WF, Boulpaep EL. Medical Physiology: A Cellular and Molecular Approach. Philadelphia, PA: Saunders/Elsevier, 2009, p. xii, 1337 p.
9. Buczacki SJ, Zecchini HI, Nicholson AM, Russell R, Vermeulen L, Kemp R, Winton DJ. Intestinal label-retaining cells are secretory precursors expressing Lgr5. Nature 495: 65-69, 2013.
10. 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/beta-catenin signaling. Proc Natl Acad Sci USA 108: 11452-11457, 2011.
11. Cheng H. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. II. Mucous cells. Am J Anat 141: 481-501, 1974.
12. Cheng H. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. IV. Paneth cells. Am J Anat 141: 521-535, 1974.
13. Cheng H, Leblond CP. 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.
14. Cheng H, Leblond CP. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. III. Enteroendocrine cells. Am J Anat 141: 503-519, 1974.
15. 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 141: 537-561, 1974.
16. Clevers H. The intestinal crypt, a prototype stem cell compartment. Cell 154: 274-284, 2013.
17. Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell 149: 1192-1205, 2012.
18. Clevers HC, Bevins CL. Paneth cells: maestros of the small intestinal crypts. Annu Rev Physiol 75: 289-311, 2013.
19. Crosnier C, Stamataki D, Lewis J. Organizing cell renewal in the intestine: stem cells, signals and combinatorial control. Nat Rev Genet 7: 349-359, 2006.
20. de Lau W, Barker N, Low TY, Koo BK, Li VS, Teunissen H, Kujala P, Haegebarth A, Peters PJ, van de Wetering M, Stange DE, van Es JE, Guardavaccaro D, Schasfoort RB, Mohri Y, Nishimori K, Mohammed S, Heck AJ, Clevers H. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 476: 293-297, 2011.
21. Durand A, Donahue B, Peignon G, Letourneur F, Cagnard N, Slomianny C, Perret C, Shroyer NF, Romagnolo B. Functional intestinal stem cells after Paneth cell ablation induced by the loss of transcription factor Math1 (Atoh1). Proc Natl Acad Sci USA 109: 8965-8970, 2012.
22. Escobar M, Nicolas P, Sangar F, Laurent-Chabalier S, Clair P, Joubert D, Jay P, Legraverend C. Intestinal epithelial stem cells do not protect their genome by asymmetric chromosome segregation. Nat Commun 2: 258, 2011.
23. Fafilek B, Krausova M, Vojtechova M, Pospichalova V, Tumova L, Sloncova E, Huranova M, Stancikova J, Hlavata A, Svec J, Sedlacek R, Luksan O, Oliverius M, Voska L, Jirsa M, Paces J, Kolar M, Krivjanska M, Klimesova K, Tlaskalova-Hogenova H, Korinek V. Troy, a tumor necrosis factor receptor family member, interacts with lgr5 to inhibit wnt signaling in intestinal stem cells. Gastroenterology 144: 381-391, 2013.
24. Farin HF, Van Es JH, Clevers H. Redundant sources of Wnt regulate intestinal stem cells and promote formation of Paneth cells. Gastroenterology 143: 1518-1529, 2012.
25. 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 296: G1108-G1118, 2009.
26. Fre S, Hannezo E, Sale S, Huyghe M, Lafkas D, Kissel H, Louvi A, Greve J, Louvard D, Artavanis-Tsakonas S. Notch lineages and activity in intestinal stem cells determined by a new set of knock-in mice. PLos One 6: e25785, 2011.
27. Furuyama K, Kawaguchi Y, Akiyama H, Horiguchi M, Kodama S, Kuhara T, Hosokawa S, Elbahrawy A, Soeda T, Koizumi M, Masui T, Kawaguchi M, Takaori K, Doi R, Nishi E, Kakinoki R, Deng JM, Behringer RR, Nakamura T, Uemoto S. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet 43: 34-41, 2011.
28. 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 137: 2179-2180; author reply 2180-2171, 2009.
29. Gerbe F, van Es JH, Makrini L, Brulin B, Mellitzer G, Robine S, Romagnolo B, Shroyer NF, Bourgaux JF, Pignodel C, Clevers H, Jay P. 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.
30. Gracz AD, Fuller MK, Wang F, Li L, Stelzner M, Dunn JC, Martin MG, Magness ST. CD24 and CD44 mark human intestinal epithelial cell populations with characteristics of active and facultative stem cells. Stem Cells 31: 2024-2030, 2013.
31. 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 298: G590-G600, 2010.
32. 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 303: 1684-1686, 2004.
33. He XC, Zhang J, Tong WG, Tawfik O, Ross J, Scoville DH, Tian Q, Zeng X, He X, Wiedemann LM, Mishina Y, Li L. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wntbeta-catenin signaling. Nat Genet 36: 1117-1121, 2004.
34. Holmberg J, Genander M, Halford MM, Anneren C, Sondell M, Chumley MJ, Silvany RE, Henkemeyer M, Frisen J. EphB receptors coordinate migration and proliferation in the intestinal stem cell niche. Cell 125: 1151-1163, 2006.
35. Howe JR, Bair JL, Sayed MG, Anderson ME, Mitros FA, Petersen GM, Velculescu VE, Traverso G, Vogelstein B. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet 28: 184-187, 2001.
36. Howe JR, Roth S, Ringold JC, Summers RW, Jarvinen HJ, Sistonen P, Tomlinson IP, Houlston RS, Bevan S, Mitros FA, Stone EM, Aaltonen LA. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280: 1086-1088, 1998.
37. Hua G, Thin TH, Feldman R, Haimovitz-Friedman A, Clevers H, Fuks Z, Kolesnick R. Crypt base columnar stem cells in small intestines of mice are radioresistant. Gastroenterology 143: 1266-1276, 2012.
38. Itasaki N, Hoppler S. Crosstalk between Wnt and bone morphogenic protein signaling: a turbulent relationship. Dev Dyn 239: 16-33, 2010.
39. Itoh S, Itoh F, Goumans MJ, Ten Dijke P. Signaling of transforming growth factor-beta family members through Smad proteins. Eur J Biochem 267: 6954-6967, 2000.
40. Jensen J, Pedersen EE, Galante P, Hald J, Heller RS, Ishibashi M, Kageyama R, Guillemot F, Serup P, Madsen OD. Control of endodermal endocrine development by Hes-1. Nat Genet 24: 36-44, 2000.
41. Jung P, Sato T, Merlos-Suarez A, Barriga FM, Iglesias M, Rossell D, Auer H, Gallardo M, Blasco MA, Sancho E, Clevers H, Batlle E. Isolation and in vitro expansion of human colonic stem cells. Nat Med 17: 1225-1227, 2011.
42. Kanaya T, Hase K, Takahashi D, Fukuda S, Hoshino K, Sasaki I, Hemmi H, Knoop KA, Kumar N, Sato M, Katsuno T, Yokosuka O, Toyooka K, Nakai K, Sakamoto A, Kitahara Y, Jinnohara T, Mc-Sorley SJ, Kaisho T, Williams IR, Ohno H. The Ets transcription factor Spi-B is essential for the differentiation of intestinal microfold cells. Nat Immunol 13: 729-736, 2012.
43. Kim TH, Escudero S, Shivdasani RA. Intact function of Lgr5 receptorexpressing intestinal stem cells in the absence of Paneth cells. Proc Natl Acad Sci USA 109: 3932-3937, 2012.
44. Kim TH, Li F, Ferreiro-Neira I, Ho LL, Luyten A, Nalapareddy K, Long H, Verzi M, Shivdasani RA. Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity. Nature 506: 511-515, 2014.
45. Klein AM, Simons BD. Universal patterns of stem cell fate in cycling adult tissues. Development 138: 3103-3111, 2011.
46. Koo BK, Stange DE, Sato T, Karthaus W, Farin HF, Huch M, van Es JH, Clevers H. Controlled gene expression in primary Lgr5 organoid cultures. Nat Methods 9: 81-83, 2011.
47. 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 19: 379-383, 1998.
48. Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B, Clevers H. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/-colon carcinoma. Science 275: 1784-1787, 1997.
49. Kozar S, Morrissey E, Nicholson AM, van der Heijden M, Zecchini HI, Kemp R, Tavare S, Vermeulen L, Winton DJ. Continuous clonal labeling reveals small numbers of functional stem cells in intestinal crypts and adenomas. Cell Stem Cell 13: 626-633, 2013.
50. Kraehenbuhl JP, Neutra MR. Epithelial M cells: differentiation and function. Annu Rev Cell Dev Biol 16: 301-332, 2000.
51. Leblond CP, Messier B. Renewal of chief cells and goblet cells in the small intestine as shown by radioautography after injection of thymidine-H3 into mice. Anat Rec 132: 247-259, 1958.
52. Li L, Clevers H. Coexistence of quiescent and active adult stem cells in mammals. Science 327: 542-545, 2010.
53. 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 450: 56-62, 2007.
54. Lopez-Garcia C, Klein AM, Simons BD, Winton DJ. Intestinal stem cell replacement follows a pattern of neutral drift. Science 330: 822-825, 2010.
55. Markowitz SD, Bertagnolli MM. Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med 361: 2449-2460, 2009.
56. Metcalfe C, Kljavin NM, Ybarra R, de Sauvage FJ. Lgr5 stem cells are indispensable for radiation-induced intestinal regeneration. Cell Stem Cell 14: 149-159, 2014.
57. Montgomery RK, Carlone DL, Richmond CA, Farilla L, Kranendonk ME, Henderson DE, Baffour-Awuah NY, Ambruzs DM, Fogli LK, Algra S, Breault DT. Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells. Proc Natl Acad Sci USA 108: 179-184, 2011.
58. Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 275: 1787-1790, 1997.
59. Morrison SJ, Spradling AC. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132: 598-611, 2008.
60. Munoz J, Stange DE, Schepers AG, van de Wetering M, Koo BK, Itzkovitz S, Volckmann R, Kung KS, Koster J, Radulescu S, Myant K, Versteeg R, Sansom OJ, van Es JH, Barker N, van Oudenaarden A, Mohammed S, Heck AJ, Clevers H. The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent "+4" cell markers. EMBO J 31: 3079-3091, 2012.
61. Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A, Koyama K, Utsunomiya J, Baba S, Hedge P. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253: 665-669, 1991.
62. Noah TK, Shroyer NF. Notch in the intestine: regulation of homeostasis and pathogenesis. Annu Rev Physiol 75: 263-288, 2013.
63. Pellegrinet L, Rodilla V, Liu Z, Chen S, Koch U, Espinosa L, Kaestner KH, Kopan R, Lewis J, Radtke F. Dll1-and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells. Gastroenterology 140: 1230-1240 e1231-e1237, 2011.
64. Potten CS. Extreme sensitivity of some intestinal crypt cells to X and gamma irradiation. Nature 269: 518-521, 1977.
65. Potten CS, Booth C, Pritchard DM. The intestinal epithelial stem cell: the mucosal governor. Int J Exp Pathol 78: 219-243, 1997.
66. Potten CS, Hume WJ, Reid P, Cairns J. The segregation of DNA in epithelial stem cells. Cell 15: 899-906, 1978.
67. Potten CS, Loeffler M. Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development 110: 1001-1020, 1990.
68. Potten CS, Owen G, Booth D. Intestinal stem cells protect their genome by selective segregation of template DNA strands. J Cell Sci 115: 2381-2388, 2002.
69. Powell AE, Wang Y, Li Y, Poulin EJ, Means AL, Washington MK, Higginbotham JN, Juchheim A, Prasad N, Levy SE, Guo Y, Shyr Y, Aronow BJ, Haigis KM, Franklin JL, Coffey RJ. The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell 149: 146-158, 2012.
70. Quastler H, Sherman FG. Cell population kinetics in the intestinal epithelium of the mouse. Exp Cell Res 17: 420-438, 1959.
71. Riccio O, van Gijn ME, Bezdek AC, Pellegrinet L, van Es JH, Zimber-Strobl U, Strobl LJ, Honjo T, Clevers H, Radtke F. 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 9: 377-383, 2008.
72. Rompolas P, Mesa KR, Greco V. Spatial organization within a niche as a determinant of stem-cell fate. Nature 502: 513-518, 2013.
73. Sangiorgi E, Capecchi MR. Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet 40: 915-920, 2008.
74. Sato T, Stange DE, Ferrante M, Vries RG, van Es JH, van den Brink S, van Houdt WJ, Pronk A, van Gorp J, Siersema PD, Clevers H. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology 141: 1762-1772, 2011.
75. 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 469: 415-418, 2011.
76. Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ, Clevers H. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459: 262-265, 2009.
77. Schroder N, Gossler A. Expression of Notch pathway components in fetal and adult mouse small intestine. Gene Expr Patterns 2: 247-250, 2002.
78. Schwank G, Andersson-Rolf A, Koo BK, Sasaki N, Clevers H. Generation of BAC transgenic epithelial organoids. PLos One 8: e76871, 2013.
79. Schwank G, Koo BK, Sasselli V, Dekkers JF, Heo I, Demircan T, Sasaki N, Boymans S, Cuppen E, van der Ent CK, Nieuwenhuis EE, Beekman JM, Clevers H. Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell 13: 653-658, 2013.
80. Snippert HJ, Schepers AG, van Es JH, Simons BD, Clevers H. Biased competition between Lgr5 intestinal stem cells driven by oncogenic mutation induces clonal expansion. EMBO Rep 15: 62-69, 2014.
81. Snippert HJ, van der Flier LG, Sato T, van Es JH, van den Born M, Kroon-Veenboer C, Barker N, Klein AM, van Rheenen J, Simons BD, Clevers H. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143: 134-144, 2010.
82. Spradling A, Drummond-Barbosa D, Kai T. Stem cells find their niche. Nature 414: 98-104, 2001.
83. Stelzner M, Helmrath M, Dunn JC, Henning SJ, Houchen CW, Kuo C, Lynch J, Li L, Magness ST, Martin MG, Wong MH, Yu J. A nomenclature for intestinal in vitro cultures. Am J Physiol Gastrointest Liver Physiol 302: G1359-G1363, 2012.
84. Sugimura R, Li L. Noncanonical Wnt signaling in vertebrate development, stem cells, and diseases. Birth Defects Res C Embryo Today 90: 243-256, 2010.
85. Takeda N, Jain R, LeBoeuf MR, Wang Q, Lu MM, Epstein JA. Interconversion between intestinal stem cell populations in distinct niches. Science 334: 1420-1424, 2011.
86. 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 478: 255-259, 2011.
87. Ueo T, Imayoshi I, Kobayashi T, Ohtsuka T, Seno H, Nakase H, Chiba T, Kageyama R. The role of Hes genes in intestinal development, homeostasis and tumor formation. Development 139: 1071-1082, 2012.
88. van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A, van der Horn K, Batlle E, Coudreuse D, Haramis AP, Tjon-Pon-Fong M, Moerer P, van den Born M, Soete G, Pals S, Eilers M, Medema R, Clevers H. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111: 241-250, 2002.
89. 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 137: 15-17, 2009.
90. 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, Clevers H. The intestinal Wnt/TCF signature. Gastroenterology 132: 628-632, 2007.
91. 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, van Es JH, Barker N, Peters PJ, van de Wetering M, Clevers H. Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell 136: 903-912, 2009.
92. van Es JH, Haegebarth A, Kujala P, Itzkovitz S, Koo BK, Boj SF, Korving J, van den Born M, van Oudenaarden A, Robine S, Clevers H. A critical role for the Wnt effector Tcf4 in adult intestinal homeostatic self-renewal. Mol Cell Biol 32: 1918-1927, 2012.
93. van Es JH, Jay P, Gregorieff A, van Gijn ME, Jonkheer S, Hatzis P, Thiele A, van den Born M, Begthel H, Brabletz T, Taketo MM, Clevers H. Wnt signalling induces maturation of Paneth cells in intestinal crypts. Nat Cell Biol 7: 381-386, 2005.
94. van Es JH, Sato T, van de Wetering M, Lyubimova A, Yee Nee AN, Gregorieff A, Sasaki N, Zeinstra L, van den Born M, Korving J, Martens AC, Barker N, van Oudenaarden A, Clevers H. Dll1(+) secretory progenitor cells revert to stem cells upon crypt damage. Nat Cell Biol 14: 1099-1104, 2012.
95. van Es JH, van Gijn ME, Riccio O, van den Born M, Vooijs M, Begthel H, Cozijnsen M, Robine S, Winton DJ, Radtke F, Clevers H. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435: 959-963, 2005.
96. Van Landeghem L, Santoro MA, Krebs AE, Mah AT, Dehmer JJ, Gracz AD, Scull BP, McNaughton K, Magness ST, Lund PK. Activation of two distinct Sox9-EGFP expressing intestinal stem cell populations during crypt regeneration after irradiation. Am J Physiol Gastrointest Liver Physiol 302: G1111-G1132, 2012.
97. VanDussen KL, Carulli AJ, Keeley TM, Patel SR, Puthoff BJ, Magness ST, Tran IT, Maillard I, Siebel C, Kolterud A, Grosse AS, Gumucio DL, Ernst SA, Tsai YH, Dempsey PJ, Samuelson LC. Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells. Development 139: 488-497, 2012.
98. Vermeulen L, Morrissey E, van der Heijden M, Nicholson AM, Sottoriva A, Buczacki S, Kemp R, Tavare S, Winton DJ. Defining stem cell dynamics in models of intestinal tumor initiation. Science 342: 995-998, 2013.
99. 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 300: G409-G417, 2011.
100. Walker BE, Leblond CP. Sites of nucleic acid synthesis in the mouse visualized by radioautography after administration of C14-labelled adenine and thymidine. Exp Cell Res 14: 510-531, 1958.
101. Wang F, Scoville D, He XC, Mahe MM, Box A, Perry JM, Smith NR, Lei NY, Davies PS, Fuller MK, Haug JS, McClain M, Gracz AD, Ding S, Stelzner M, Dunn JC, Magness ST, Wong MH, Martin MG, Helmrath M, Li L. Isolation and characterization of intestinal stem cells based on surface marker combinations and colony-formation assay. Gastroenterology 145: 383-395, 2013.
102. Wang Y, Ahmad AA, Shah PK, Sims CE, Magness ST, Allbritton NL. Capture and 3D culture of colonic crypts and colonoids in a microarray platform. Lab Chip 13: 4625-4634, 2013.
103. Wang Y, Ahmad AA, Sims CE, Magness ST, Allbritton NL. In vitro generation of colonic epithelium from primary cells guided by microstructures. Lab Chip 14: 1622-1631, 2014.
104. Wong VW, Stange DE, Page ME, Buczacki S, Wabik A, Itami S, van de Wetering M, Poulsom R, Wright NA, Trotter MW, Watt FM, Winton DJ, Clevers H, Jensen KB. Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling. Nat Cell Biol 14: 401-408, 2012.
105. Wright N, Allison M. The Biology of Epithelial Cell Populations. Oxford: Clarindon, 1984.
106. Yan KS, Chia LA, Li X, Ootani A, Su J, Lee JY, Su N, Luo Y, Heilshorn SC, Amieva MR, Sangiorgi E, Capecchi MR, Kuo CJ. The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. Proc Natl Acad Sci USA 109: 466-471, 2012.
107. Yang Q, Bermingham NA, Finegold MJ, Zoghbi HY. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 294: 2155-2158, 2001.
108. Yilmaz OH, Katajisto P, Lamming DW, Gultekin Y, Bauer-Rowe KE, Sengupta S, Birsoy K, Dursun A, Yilmaz VO, Selig M, Nielsen GP, Mino-Kenudson M, Zukerberg LR, Bhan AK, Deshpande V, Sabatini DM. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486: 490-495, 2012.
109. Yui S, Nakamura T, Sato T, Nemoto Y, Mizutani T, Zheng X, Ichinose S, Nagaishi T, Okamoto R, Tsuchiya K, Clevers H, Watanabe M. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5(+) stem cell. Nat Med 18: 618-623, 2012.