Intestinal Enteroendocrine Lineage Cells Possess Homeostatic and Injury-Inducible Stem Cell Activity

Cell Stem Cell

Volumn 21, Issue 1, 2017, Pages 78-90.e6

  Yan, Kelley S ^a,b   Gevaert, Olivier ^a   Zheng, Grace X Y ^c   Anchang, Benedict ^a   Probert, Christopher S ^a   Larkin, Kathryn A ^a   Davies, Paige S ^d   Cheng, Zhuan fen ^a   Kaddis, John S ^e   Han, Arnold ^a,b   Roelf, Kelly ^a   Calderon, Ruben I ^b   Cynn, Esther ^b   Hu, Xiaoyi ^b   Mandleywala, Komal ^b   Wilhelmy, Julie ^a   Grimes, Sue M ^a   Corney, David C ^a   Boutet, Stéphane C ^c   Terry, Jessica M ^c   Belgrader, Phillip ^c   Ziraldo, Solongo B ^c   Mikkelsen, Tarjei S ^c   Wang, Fengchao ^f   von Furstenberg, Richard J ^g   Smith, Nicholas R ^d   Chandrakesan, Parthasarathy ^l   May, Randal ^l   Chrissy, Mary Ann S ^h   Jain, Rajan ^h   Cartwright, Christine A ^a   Niland, Joyce C ^e   Hong, Young Kwon ⁱ   Carrington, Jill ^j   Breault, David T ^k   Epstein, Jonathan ^h   Houchen, Courtney W ^l   Lynch, John P ^h   Martin, Martin G ^m   Plevritis, Sylvia K ^a   Curtis, Christina ^a   Ji, Hanlee P ^a   Li, Linheng ^f   Henning, Susan J ^g   Wong, Melissa H ^d   Kuo, Calvin J ^a   more..

^a STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b Department of Medicine   (United States)

^c 10x Genomics Inc ^*  (United States)

^d OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

^e CITY OF HOPE NATIONAL MEDICAL CENTER   (United States)

^f STOWERS INSTITUTE FOR MEDICAL RESEARCH   (United States)

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

^h UNIVERSITY OF PENNSYLVANIA   (United States)

ⁱ UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^j NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES   (United States)

^k BOSTON CHILDREN S HOSPITAL   (United States)

^l UNIVERSITY OF OKLAHOMA COLLEGE OF MEDICINE   (United States)

^m UNIVERSITY OF CALIFORNIA   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

ASCL2 PROTEIN; BMI1 PROTEIN; CELL MARKER; GREEN FLUORESCENT PROTEIN; LGR5 PROTEIN; MESSENGER RNA; PEPTIDES AND PROTEINS; PROX1 PROTEIN; RNA; TRANSCRIPTOME; UNCLASSIFIED DRUG; DIFFERENTIATION ANTIGEN;

ANIMAL CELL; ARTICLE; CELL ACTIVITY; CELL CLONE; CELL GROWTH; CELL LINEAGE; CELL PLASTICITY; CLONOGENESIS; CONTROLLED STUDY; ENTEROENDOCRINE CELL; GENE EXPRESSION; HOMEOSTASIS; IN VITRO STUDY; IN VIVO STUDY; INTESTINAL STEM CELL; LGR5+ STEM CELL LINE; MOUSE; NONHUMAN; PRIORITY JOURNAL; RADIATION INJURY; RNA SEQUENCE; SINGLE CELL ANALYSIS; ANIMAL; GENE EXPRESSION REGULATION; GENETICS; INJURIES; INTESTINE MUCOSA; JEJUNUM; METABOLISM; PATHOLOGY; STEM CELL; TRANSGENIC MOUSE;

ANIMALS; ANTIGENS, DIFFERENTIATION; ENTEROENDOCRINE CELLS; GENE EXPRESSION REGULATION; INTESTINAL MUCOSA; JEJUNUM; MICE; MICE, TRANSGENIC; STEM CELLS;

EID: 85029219708     PISSN: 19345909     EISSN: 18759777     Source Type: Journal    
DOI: 10.1016/j.stem.2017.06.014     Document Type: Article

References (76)

1. Anchang, B., Hart, T.D., Bendall, S.C., Qiu, P., Bjornson, Z., Linderman, M., Nolan, G.P., Plevritis, S.K., Visualization and cellular hierarchy inference of single-cell data using SPADE. Nat. Protoc. 11 (2016), 1264–1279.
2. Barker, N., van Es, J.H., Kuipers, J., Kujala, P., van den Born, M., Cozijnsen, M., Haegebarth, A., Korving, J., Begthel, H., Peters, P.J., Clevers, H., Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449 (2007), 1003–1007.
3. Barriga, F.M., Montagni, E., Mana, M., Mendez-Lago, M., Hernando-Momblona, X., Sevillano, M., Guillaumet-Adkins, A., Rodriguez-Esteban, G., Buczacki, S.J., Gut, M., et al. Mex3a Marks a Slowly Dividing Subpopulation of Lgr5+ Intestinal Stem Cells. Cell Stem Cell 20 (2017), 801–816.e7.
4. Beucher, A., Gjernes, E., Collin, C., Courtney, M., Meunier, A., Collombat, P., Gradwohl, G., The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice. PLoS ONE, 7, 2012, e36449.
5. Bezençon, C., Fürholz, A., Raymond, F., Mansourian, R., Métairon, S., Le Coutre, J., Damak, S., Murine intestinal cells expressing Trpm5 are mostly brush cells and express markers of neuronal and inflammatory cells. J. Comp. Neurol. 509 (2008), 514–525.
6. Bjerknes, M., Cheng, H., The stem-cell zone of the small intestinal epithelium. III. Evidence from columnar, enteroendocrine, and mucous cells in the adult mouse. Am. J. Anat. 160 (1981), 77–91.
7. Bjerknes, M., Cheng, H., Neurogenin 3 and the enteroendocrine cell lineage in the adult mouse small intestinal epithelium. Dev. Biol. 300 (2006), 722–735.
8. Breault, D.T., Min, I.M., Carlone, D.L., Farilla, L.G., Ambruzs, D.M., Henderson, D.E., Algra, S., Montgomery, R.K., Wagers, A.J., Hole, N., Generation of mTert-GFP mice as a model to identify and study tissue progenitor cells. Proc. Natl. Acad. Sci. USA 105 (2008), 10420–10425.
9. Buczacki, S.J., Zecchini, H.I., Nicholson, A.M., Russell, R., Vermeulen, L., Kemp, R., Winton, D.J., Intestinal label-retaining cells are secretory precursors expressing Lgr5. Nature 495 (2013), 65–69.
10. Chandrakesan, P., May, R., Qu, D., Weygant, N., Taylor, V.E., Li, J.D., Ali, N., Sureban, S.M., Qante, M., Wang, T.C., et al. Dclk1+ small intestinal epithelial tuft cells display the hallmarks of quiescence and self-renewal. Oncotarget 6 (2015), 30876–30886.
11. 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 (1974), 461–479.
12. Choi, I., Chung, H.K., Ramu, S., Lee, H.N., Kim, K.E., Lee, S., Yoo, J., Choi, D., Lee, Y.S., Aguilar, B., Hong, Y.K., Visualization of lymphatic vessels by Prox1-promoter directed GFP reporter in a bacterial artificial chromosome-based transgenic mouse. Blood 117 (2011), 362–365.
13. Clevers, H., The intestinal crypt, a prototype stem cell compartment. Cell 154 (2013), 274–284.
14. Dalerba, P., Dylla, S.J., Park, I.K., Liu, R., Wang, X., Cho, R.W., Hoey, T., Gurney, A., Huang, E.H., Simeone, D.M., et al. Phenotypic characterization of human colorectal cancer stem cells. Proc. Natl. Acad. Sci. USA 104 (2007), 10158–10163.
15. Davies, P.S., Dismuke, A.D., Powell, A.E., Carroll, K.H., Wong, M.H., Wnt-reporter expression pattern in the mouse intestine during homeostasis. BMC Gastroenterol., 8, 2008, 57.
16. Du, A., McCracken, K.W., Walp, E.R., Terry, N.A., Klein, T.J., Han, A., Wells, J.M., May, C.L., Arx is required for normal enteroendocrine cell development in mice and humans. Dev. Biol. 365 (2012), 175–188.
17. Egerod, K.L., Engelstoft, M.S., Grunddal, K.V., Nøhr, M.K., Secher, A., Sakata, I., Pedersen, J., Windeløv, J.A., Füchtbauer, E.M., Olsen, J., et al. A major lineage of enteroendocrine cells coexpress CCK, secretin, GIP, GLP-1, PYY, and neurotensin but not somatostatin. Endocrinology 153 (2012), 5782–5795.
18. Engelstoft, M.S., Egerod, K.L., Lund, M.L., Schwartz, T.W., Enteroendocrine cell types revisited. Curr. Opin. Pharmacol. 13 (2013), 912–921.
19. Formeister, E.J., Sionas, A.L., Lorance, D.K., Barkley, C.L., Lee, G.H., Magness, S.T., Distinct SOX9 Levels Differentially Mark Stem/Progenitor Populations and Enteroendocrine Cells of the Small Intestine Epithelium. Am. J Physiol. Gastrointest. Liver Physiol. 296 (2009), G1108–G1118.
20. Gross, S., Balderes, D., Liu, J., Asfaha, S., Gu, G., Wang, T.C., Sussel, L., Nkx2.2 is expressed in a subset of enteroendocrine cells with expanded lineage potential. Am. J. Physiol. Gastrointest. Liver Physiol. 309 (2015), G975–G987.
21. Grün, D., Lyubimova, A., Kester, L., Wiebrands, K., Basak, O., Sasaki, N., Clevers, H., van Oudenaarden, A., Single-cell messenger RNA sequencing reveals rare intestinal cell types. Nature 525 (2015), 251–255.
22. Guo, Z., Ohlstein, B., Stem cell regulation. Bidirectional Notch signaling regulates Drosophila intestinal stem cell multipotency. Science, 350, 2015, 350.
23. Habib, A.M., Richards, P., Cairns, L.S., Rogers, G.J., Bannon, C.A., Parker, H.E., Morley, T.C., Yeo, G.S., Reimann, F., Gribble, F.M., Overlap of endocrine hormone expression in the mouse intestine revealed by transcriptional profiling and flow cytometry. Endocrinology 153 (2012), 3054–3065.
24. Hosen, N., Yamane, T., Muijtjens, M., Pham, K., Clarke, M.F., Weissman, I.L., Bmi-1-green fluorescent protein-knock-in mice reveal the dynamic regulation of bmi-1 expression in normal and leukemic hematopoietic cells. Stem Cells 25 (2007), 1635–1644.
25. Itzkovitz, S., Lyubimova, A., Blat, I.C., Maynard, M., van Es, J., Lees, J., Jacks, T., Clevers, H., van Oudenaarden, A., Single-molecule transcript counting of stem-cell markers in the mouse intestine. Nat. Cell Biol. 14 (2011), 106–114.
26. Jadhav, U., Saxena, M., O'Neill, N.K., Saadatpour, A., Yuan, G.-C., Herbert, Z., Murata, K., Shivdasani, R.A., Dynamic reorganization of chromatin accessibility signatures during dedifferentiation of secretory precursors into Lgr5+ intestinal stem cells. Cell Stem Cell 21 (2017), 65–77 this issue.
27. Kim, D., Pertea, G., Trapnell, C., Pimentel, H., Kelley, R., Salzberg, S.L., TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol., 14, 2013, R36.
28. Kokrashvili, Z., Rodriguez, D., Yevshayeva, V., Zhou, H., Margolskee, R.F., Mosinger, B., Release of endogenous opioids from duodenal enteroendocrine cells requires Trpm5. Gastroenterology 137 (2009), 598–606 606 e591–592.
29. Koo, B.K., Spit, M., Jordens, I., Low, T.Y., Stange, D.E., van de Wetering, M., van Es, J.H., Mohammed, S., Heck, A.J., Maurice, M.M., Clevers, H., Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature 488 (2012), 665–669.
30. Kozar, S., Morrissey, E., Nicholson, A.M., van der Heijden, M., Zecchini, H.I., Kemp, R., Tavaré, S., Vermeulen, L., Winton, D.J., Continuous clonal labeling reveals small numbers of functional stem cells in intestinal crypts and adenomas. Cell Stem Cell 13 (2013), 626–633.
31. Langmead, B., Trapnell, C., Pop, M., Salzberg, S.L., Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol., 10, 2009, R25.
32. Levin, T.G., Powell, A.E., Davies, P.S., Silk, A.D., Dismuke, A.D., Anderson, E.C., Swain, J.R., Wong, M.H., Characterization of the intestinal cancer stem cell marker CD166 in the human and mouse gastrointestinal tract. Gastroenterology 139 (2010), 2072–2082 e2075.
33. Lopez-Garcia, C., Klein, A.M., Simons, B.D., Winton, D.J., Intestinal stem cell replacement follows a pattern of neutral drift. Science 330 (2010), 822–825.
34. Macosko, E.Z., Basu, A., Satija, R., Nemesh, J., Shekhar, K., Goldman, M., Tirosh, I., Bialas, A.R., Kamitaki, N., Martersteck, E.M., et al. Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. Cell 161 (2015), 1202–1214.
35. Magness, S.T., Puthoff, B.J., Crissey, M.A., Dunn, J., Henning, S.J., Houchen, C., Kaddis, J.S., Kuo, C.J., Li, L., Lynch, J., et al. A multicenter study to standardize reporting and analyses of fluorescence-activated cell-sorted murine intestinal epithelial cells. Am. J. Physiol. Gastrointest. Liver Physiol. 305 (2013), G542–G551.
36. Marshman, E., Booth, C., Potten, C.S., The intestinal epithelial stem cell. BioEssays 24 (2002), 91–98.
37. May, R., Sureban, S.M., Hoang, N., Riehl, T.E., Lightfoot, S.A., Ramanujam, R., Wyche, J.H., Anant, S., Houchen, C.W., 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 27 (2009), 2571–2579.
38. McCarthy, D.J., Chen, Y., Smyth, G.K., Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation. Nucleic Acids Res. 40 (2012), 4288–4297.
39. Montgomery, R.K., Carlone, D.L., Richmond, C.A., Farilla, L., Kranendonk, M.E., Henderson, D.E., Baffour-Awuah, N.Y., Ambruzs, D.M., Fogli, L.K., Algra, S., Breault, D.T., Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells. Proc. Natl. Acad. Sci. USA 108 (2011), 179–184.
40. Muñoz, J., Stange, D.E., Schepers, A.G., van de Wetering, M., Koo, B.K., Itzkovitz, S., Volckmann, R., Kung, K.S., Koster, J., Radulescu, S., et al. The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent ‘+4′ cell markers. EMBO J. 31 (2012), 3079–3091.
41. Nakanishi, Y., Seno, H., Fukuoka, A., Ueo, T., Yamaga, Y., Maruno, T., Nakanishi, N., Kanda, K., Komekado, H., Kawada, M., et al. Dclk1 distinguishes between tumor and normal stem cells in the intestine. Nat. Genet. 45 (2013), 98–103.
42. Ootani, A., Li, X., Sangiorgi, E., Ho, Q.T., Ueno, H., Toda, S., Sugihara, H., Fujimoto, K., Weissman, I.L., Capecchi, M.R., Kuo, C.J., Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat. Med. 15 (2009), 701–706.
43. Petrova, T.V., Nykänen, A., Norrmén, C., Ivanov, K.I., Andersson, L.C., Haglund, C., Puolakkainen, P., Wempe, F., von Melchner, H., Gradwohl, G., et al. Transcription factor PROX1 induces colon cancer progression by promoting the transition from benign to highly dysplastic phenotype. Cancer Cell 13 (2008), 407–419.
44. Powell, A.E., Wang, Y., Li, Y., Poulin, E.J., Means, A.L., Washington, M.K., Higginbotham, J.N., Juchheim, A., Prasad, N., Levy, S.E., et al. The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell 149 (2012), 146–158.
45. Qiu, P., Simonds, E.F., Bendall, S.C., Gibbs, K.D. Jr., Bruggner, R.V., Linderman, M.D., Sachs, K., Nolan, G.P., Plevritis, S.K., Extracting a cellular hierarchy from high-dimensional cytometry data with SPADE. Nat. Biotechnol. 29 (2011), 886–891.
46. Rindi, G., Ratineau, C., Ronco, A., Candusso, M.E., Tsai, M., Leiter, A.B., Targeted ablation of secretin-producing cells in transgenic mice reveals a common differentiation pathway with multiple enteroendocrine cell lineages in the small intestine. Development 126 (1999), 4149–4156.
47. Roth, K.A., Kim, S., Gordon, J.I., Immunocytochemical studies suggest two pathways for enteroendocrine cell differentiation in the colon. Am. J. Physiol. 263 (1992), G174–G180.
48. Rousseeuw, P.J., Croux, C., Alternatives to the Median Absolute Deviation. J. Am. Stat. Assoc. 88 (1993), 1273–1283.
49. Sangiorgi, E., Capecchi, M.R., Bmi1 is expressed in vivo in intestinal stem cells. Nat. Genet. 40 (2008), 915–920.
50. Satija, R., Farrell, J.A., Gennert, D., Schier, A.F., Regev, A., Spatial reconstruction of single-cell gene expression data. Nat. Biotechnol. 33 (2015), 495–502.
51. Sato, T., Vries, R.G., Snippert, H.J., van de Wetering, M., Barker, N., Stange, D.E., van Es, J.H., Abo, A., Kujala, P., Peters, P.J., Clevers, H., Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459 (2009), 262–265.
52. Schonhoff, S.E., Giel-Moloney, M., Leiter, A.B., Neurogenin 3-expressing progenitor cells in the gastrointestinal tract differentiate into both endocrine and non-endocrine cell types. Dev. Biol. 270 (2004), 443–454.
53. Sei, Y., Lu, X., Liou, A., Zhao, X., Wank, S.A., A stem cell marker-expressing subset of enteroendocrine cells resides at the crypt base in the small intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 300 (2011), G345–G356.
54. Snippert, H.J., van der Flier, L.G., Sato, T., van Es, J.H., van den Born, M., Kroon-Veenboer, C., Barker, N., Klein, A.M., van Rheenen, J., Simons, B.D., Clevers, H., Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143 (2010), 134–144.
55. Sonoshita, M., Aoki, M., Fuwa, H., Aoki, K., Hosogi, H., Sakai, Y., Hashida, H., Takabayashi, A., Sasaki, M., Robine, S., et al. Suppression of colon cancer metastasis by Aes through inhibition of Notch signaling. Cancer Cell 19 (2011), 125–137.
56. Srinivasan, R.S., Dillard, M.E., Lagutin, O.V., Lin, F.J., Tsai, S., Tsai, M.J., Samokhvalov, I.M., Oliver, G., Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev. 21 (2007), 2422–2432.
57. Takeda, N., Jain, R., LeBoeuf, M.R., Wang, Q., Lu, M.M., Epstein, J.A., Interconversion between intestinal stem cell populations in distinct niches. Science 334 (2011), 1420–1424.
58. Tetteh, P.W., Basak, O., Farin, H.F., Wiebrands, K., Kretzschmar, K., Begthel, H., van den Born, M., Korving, J., de Sauvage, F., van Es, J.H., et al. Replacement of Lost Lgr5-Positive Stem Cells through Plasticity of Their Enterocyte-Lineage Daughters. Cell Stem Cell 18 (2016), 203–213.
59. Tian, H., Biehs, B., Warming, S., Leong, K.G., Rangell, L., Klein, O.D., de Sauvage, F.J., A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478 (2011), 255–259.
60. Trapnell, C., Hendrickson, D.G., Sauvageau, M., Goff, L., Rinn, J.L., Pachter, L., Differential analysis of gene regulation at transcript resolution with RNA-seq. Nat. Biotechnol. 31 (2013), 46–53.
61. van der Flier, L.G., van Gijn, M.E., Hatzis, P., Kujala, P., Haegebarth, A., Stange, D.E., Begthel, H., van den Born, M., Guryev, V., Oving, I., et al. Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell 136 (2009), 903–912.
62. van der Maaten, L.J.P., Hinton, G.E., Visualizing High-Dimensional Data Using t-SNE. J. Mach. Learn. Res. 9 (2008), 2579–2605.
63. van Es, J.H., Sato, T., van de Wetering, M., Lyubimova, A., Nee, A.N., Gregorieff, A., Sasaki, N., Zeinstra, L., van den Born, M., Korving, J., et al. Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nat. Cell Biol. 14 (2012), 1099–1104.
64. Van Landeghem, L., Santoro, M.A., Krebs, A.E., Mah, A.T., Dehmer, J.J., Gracz, A.D., Scull, B.P., McNaughton, K., Magness, S.T., Lund, P.K., Activation of two distinct Sox9-EGFP-expressing intestinal stem cell populations during crypt regeneration after irradiation. Am. J. Physiol. Gastrointest. Liver Physiol. 302 (2012), G1111–G1132.
65. von Furstenberg, R.J., Gulati, A.S., Baxi, A., Doherty, J.M., Stappenbeck, T.S., Gracz, A.D., Magness, S.T., Henning, S.J., Sorting mouse jejunal epithelial cells with CD24 yields a population with characteristics of intestinal stem cells. Am. J. Physiol. Gastrointest. Liver Physiol. 300 (2011), G409–G417.
66. von Furstenberg, R.J., Buczacki, S.J., Smith, B.J., Seiler, K.M., Winton, D.J., Henning, S.J., Side population sorting separates subfractions of cycling and non-cycling intestinal stem cells. Stem Cell Res. (Amst.) 12 (2014), 364–375.
67. Wang, F., Scoville, D., He, X.C., Mahe, M.M., Box, A., Perry, J.M., Smith, N.R., Lei, N.Y., Davies, P.S., Fuller, M.K., et al. Isolation and characterization of intestinal stem cells based on surface marker combinations and colony-formation assay. Gastroenterology, 145, 2013 383–395 e381–321.
68. Westphalen, C.B., Asfaha, S., Hayakawa, Y., Takemoto, Y., Lukin, D.J., Nuber, A.H., Brandtner, A., Setlik, W., Remotti, H., Muley, A., et al. Long-lived intestinal tuft cells serve as colon cancer-initiating cells. J. Clin. Invest. 124 (2014), 1283–1295.
69. Wong, V.W., Stange, D.E., Page, M.E., Buczacki, S., Wabik, A., Itami, S., van de Wetering, M., Poulsom, R., Wright, N.A., Trotter, M.W., et al. Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling. Nat. Cell Biol. 14 (2012), 401–408.
70. Yan, K.S., Chia, L.A., Li, X., Ootani, A., Su, J., Lee, J.Y., Su, N., Luo, Y., Heilshorn, S.C., Amieva, M.R., et al. The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. Proc. Natl. Acad. Sci. USA 109 (2012), 466–471.
71. Yan, K.S., Janda, C.Y., Chang, J., Zheng, G.X.Y., Larkin, K.A., Luca, V.C., Chia, L.A., Mah, A.T., Han, A., Terry, J.M., et al. Non-equivalence of Wnt and R-spondin ligands during Lgr5(+) intestinal stem-cell self-renewal. Nature 545 (2017), 238–242.
72. Yu, D., Huber, W., Vitek, O., Shrinkage estimation of dispersion in Negative Binomial models for RNA-seq experiments with small sample size. Bioinformatics 29 (2013), 1275–1282.
73. Zeng, X., Hou, S.X., Enteroendocrine cells are generated from stem cells through a distinct progenitor in the adult Drosophila posterior midgut. Development 142 (2015), 644–653.
74. Zheng, G.X.Y., Terry, J.M., Belgrader, P., Ryvkin, P., Bent, Z.W., Wilson, R., Ziraldo, S.B., Wheeler, T.D., McDermott, G.P., Zhu, J., et al. Massively parallel digital transcriptional profiling of single cells. bioRxiv, 2016, 10.1101/06591.
75. Zheng, G.X., Terry, J.M., Belgrader, P., Ryvkin, P., Bent, Z.W., Wilson, R., Ziraldo, S.B., Wheeler, T.D., McDermott, G.P., Zhu, J., et al. Massively parallel digital transcriptional profiling of single cells. Nat. Commun., 8, 2017, 14049.
76. Zhu, L., Gibson, P., Currle, D.S., Tong, Y., Richardson, R.J., Bayazitov, I.T., Poppleton, H., Zakharenko, S., Ellison, D.W., Gilbertson, R.J., Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 457 (2009), 603–607.