Biology:List of intestinal stem cell marker genes

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The following is a list of intestinal stem cell marker genes, including their name and known function.

Intestinal stem cells

In the adult intestine, the crypts of Lieberkühn are the niche for epithelial stem cells and contain all proliferative stem and progenitor cells. Differentiating cells exit the cell cycle and migrate out of the crypts and onto the surface epithelium of the intestine, where they perform their physiological role (e.g., nutrient absorption by enterocytes; mucous secretion by goblet cells) and are eventually shed into the lumen.[1] Intestinal stem cells were first identified as such in the 1970s. Cheng and Leblond used autoradiography of phagosomes to track the fate of cells at the base of the crypts, and determined that slender cells interspersed among Paneth cells at the crypt base could give rise to all of the other cell types that constituted the intestinal epithelium.[2] Due to their narrow shape and location, these cells were called crypt base columnar cells (CBCs). Potten and colleagues used a combination of DNA labeling and assessment of the response of the epithelium to high-dose radiation to identify label-retaining cells (LRCs) as putative stem cells, which were typically located around four cell positions above the bottom of the crypt, and were therefore also called "+4 cells".[3][4] Later work suggested that these "+4 cells" may function as reserve or back-up stem cells, and further suggested that they divide slowly relative to the other progenitor cells in the crypt. Thus, these cells are also called quiescent stem cells.[5]

The stem cell zone model states that the CBC stem cells reside in a stem-cell-permissive environment. These cycling stem cells regularly generate progeny, which subsequently exit the niche and pass through the “common origin of differentiation” around position +5, where they commit toward the various individual lineages. Progenitors mature as they migrate upward onto the villus. Maturing Paneth cell progenitors migrate downward, with the oldest Paneth cells residing at the very base of the crypt.[6] In accordance with the stem cell zone model proposing that, during their upward migration, CBC stem cells would only gradually lose their self-renewal capacity, it was shown in vivo that transient amplifying cells can revert to Lgr5+ CBC stem cells after damage, presumably by direct contact with Paneth cells.[6]

Molecular markers of intestinal stem cells

More recently modern genetics techniques, primarily using transgenic mice, have been used to identify genes that are specifically expressed or highly enriched in the intestinal stem cells. Below, a table of intestinal stem cell "marker" genes is given, along with a notation if this marks active of CBC stem cells, or quiescent/reserve/+4 stem cells.

Gene Name Aliases Name Functional Description Active vs. Quiescent Reference (PMID)
ALCAM CD166, MEMD activated leukocyte cell adhesion molecule transmembrane glycoprotein Active 20826154[7]
ASCL2 ASH2, HASH2, MASH2, bHLHa45 achaete-scute family bHLH transcription factor 2 basic helix loop helix transcription factor Active 19269367[8]
BMI1 RP11-573G6.1, FLVI2/BMI1, PCGF4, RNF51 polycomb ring finger oncogene polycomb transcription repressor complex Quiescent 18536716[9] 22190486 [10] 21927002[11]
DCLK1 RP11-113P14.1, CL1, CLICK1, DCAMKL1, DCDC3A, DCLK Doublecortin and CaM kinase-like-1 microtubule-associated protein kinase Quiescent? 16464855[12] 18055444[13] 24487592[14]
EPHB2 CAPB, DRT, EK5, EPHT3, ERK, Hek5, PCBC, Tyro5 Ephrin type-B receptor 2 ephrin receptor Active 21419747[15]
HOPX CAMEO, HOD, HOP, LAGY, NECC1, OB1, SMAP31, TOTO Homeodomain-only protein atypical homeobox protein Quiescent 22075725[16]
Igfbp4 BP-4, HT29-IGFBP, IBP4, IGFBP-4 insulin-like growth factor binding protein 4 Inhibitor of the Igf pathway Active 21419747[15]
Itgb1 RP11-479G22.2, CD29, FNRB, GPIIA, MDF2, MSK12, VLA-BETA, VLAB β1 integrin fibronectin receptor beta Active 16285956[17]
LGR5 FEX, GPR49, GPR67, GRP49, HG38 Luciene-rich repeat containing G-protein-coupled receptor R-spondin receptor Active 17934449[18] 22473993[19]
Lrig1 LIG-1, LIG1 Leucine-rich repeats and immunoglobulin-like domains protein 1 ErbB inhibitor Active, Quiescent 22464327[20] 22388892 [21]
mTert CMM9, DKCA2, DKCB4, EST2, PFBMFT1, TCS1, TP2, TRT, hEST2, hTRT Mouse telomerase reverse transcriptase enzymatic catalytic subunit of mouse telomerase Quiescent 21173232[22]
Musashi-1 MSI1 Musashi RNA-binding protein 1 translational repressor and regulator Notch signaling Active 17122772[23]
OLFM4 UNQ362/PRO698, GC1, GW112, OLM4, OlfD, UNQ362, bA209J19.1, hGC-1, hOLfD Olfactomedin 4 glycoprotein Active 19450592[24]
PHLDA1 DT1P1B11, PHRIP, TDAG51 pleckstrin homology-like domain, family A, member 1 regulation of apoptosis Active, Quiescent 21558389[25]
Prom1 MSTP061, AC133, CD133, CORD12, MCDR2, PROML1, RP41, STGD4 Prominin1 glycoprotein Active 19092805[26]
PW1 PEG3, hCG_1685807, ZKSCAN22, ZNF904, ZSCAN24 Paternally expressed gene 3 unknown Active 21709251[27]
Smoc2 RP11-270C4__A.1, DTDP1, MST117, MSTP117, MSTP140, SMAP2, bA270C4A.1, bA37D8.1, dJ421D16.1 SPARC-related modular calcium-binding protein 2 BMP signaling inhibitor Active 21419747[15] 22692129[28]
Sox9 CMD1, CMPD1, SRA1 SRY (sex determining region Y)-box 9 transcription factor Active 19228882[29]
TNFRSF19 UNQ1888/PRO4333, TAJ, TAJ-alpha, TRADE, TROY tumor necrosis factor receptor family member transmembrane receptor Active 23142137[30]

Additional possible markers: CD24 CD44v6 Active beta-catenin Pcdh8 21419747

References

  1. ↑ Noah, T. K.; Donahue, B.; Shroyer, N. F. (2011). "Intestinal development and differentiation". Experimental Cell Research 317 (19): 2702–10. doi:10.1016/j.yexcr.2011.09.006. PMID 21978911. 
  2. ↑ Cheng, H; Leblond, C. P. (1974). "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". The American Journal of Anatomy 141 (4): 537–61. doi:10.1002/aja.1001410407. PMID 4440635. 
  3. ↑ Potten, C. S.; Hume, W. J.; Reid, P; Cairns, J (1978). "The segregation of DNA in epithelial stem cells". Cell 15 (3): 899–906. doi:10.1016/0092-8674(78)90274-x. PMID 728994. 
  4. ↑ Potten, C. S.; Owen, G; Booth, D (2002). "Intestinal stem cells protect their genome by selective segregation of template DNA strands". Journal of Cell Science 115 (Pt 11): 2381–8. doi:10.1242/jcs.115.11.2381. PMID 12006622. 
  5. ↑ May, R; Sureban, S. M.; Hoang, N; Riehl, T. E.; Lightfoot, S. A.; Ramanujam, R; Wyche, J. H.; Anant, S et al. (2009). "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 (10): 2571–9. doi:10.1002/stem.193. PMID 19676123. 
  6. ↑ 6.0 6.1 Barker, Nick; Oudenaarden, Alexander van; Clevers, Hans (2012). "Identifying the Stem Cell of the Intestinal Crypt: Strategies and Pitfalls". Cell Stem Cell 11 (4): 452–460. doi:10.1016/j.stem.2012.09.009. PMID 23040474. 
  7. ↑ Levin, T. G.; Powell, A. E.; Davies, P. S.; Silk, A. D.; Dismuke, A. D.; Anderson, E. C.; Swain, J. R.; Wong, M. H. (2010). "Characterization of the Intestinal Cancer Stem Cell Marker CD166 in the Human and Mouse Gastrointestinal Tract". Gastroenterology 139 (6): 2072–2082.e5. doi:10.1053/j.gastro.2010.08.053. PMID 20826154. 
  8. ↑ Van Der Flier, L. G.; Van Gijn, M. E.; Hatzis, P.; Kujala, P.; Haegebarth, A.; Stange, D. E.; Begthel, H.; Van Den Born, M. et al. (2009). "Transcription Factor Achaete Scute-Like 2 Controls Intestinal Stem Cell Fate". Cell 136 (5): 903–912. doi:10.1016/j.cell.2009.01.031. PMID 19269367. 
  9. ↑ Sangiorgi, E.; Capecchi, M. R. (2008). "Bmi1 is expressed in vivo in intestinal stem cells". Nature Genetics 40 (7): 915–920. doi:10.1038/ng.165. PMID 18536716. 
  10. ↑ Yan, K. S.; Chia, L. A.; Li, X.; Ootani, A.; Su, J.; Lee, J. Y.; Su, N.; Luo, Y. et al. (2011). "The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations". Proceedings of the National Academy of Sciences 109 (2): 466–471. doi:10.1073/pnas.1118857109. PMID 22190486. 
  11. ↑ Tian, H; Biehs, B; Warming, S; Leong, K. G.; Rangell, L; Klein, O. D.; De Sauvage, F. J. (2011). "A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable". Nature 478 (7368): 255–9. doi:10.1038/nature10408. PMID 21927002. Bibcode: 2011Natur.478..255T. 
  12. ↑ Giannakis, M; Stappenbeck, T. S.; Mills, J. C.; Leip, D. G.; Lovett, M; Clifton, S. W.; Ippolito, J. E.; Glasscock, J. I. et al. (2006). "Molecular properties of adult mouse gastric and intestinal epithelial progenitors in their niches". Journal of Biological Chemistry 281 (16): 11292–300. doi:10.1074/jbc.M512118200. PMID 16464855. 
  13. ↑ May, R; Riehl, T. E.; Hunt, C; Sureban, S. M.; Anant, S; Houchen, C. W. (2008). "Identification of a novel putative gastrointestinal stem cell and adenoma stem cell marker, doublecortin and CaM kinase-like-1, following radiation injury and in adenomatous polyposis coli/multiple intestinal neoplasia mice". Stem Cells 26 (3): 630–7. doi:10.1634/stemcells.2007-0621. PMID 18055444. 
  14. ↑ Westphalen, C. B.; Asfaha, S; Hayakawa, Y; Takemoto, Y; Lukin, D. J.; Nuber, A. H.; Brandtner, A; Setlik, W et al. (2014). "Long-lived intestinal tuft cells serve as colon cancer-initiating cells". Journal of Clinical Investigation 124 (3): 1283–95. doi:10.1172/JCI73434. PMID 24487592. 
  15. ↑ 15.0 15.1 15.2 Merlos-Suárez, A.; Barriga, F. M.; Jung, P.; Iglesias, M.; Céspedes, M. A. V.; Rossell, D.; Sevillano, M.; Hernando-Momblona, X. et al. (2011). "The Intestinal Stem Cell Signature Identifies Colorectal Cancer Stem Cells and Predicts Disease Relapse". Cell Stem Cell 8 (5): 511–524. doi:10.1016/j.stem.2011.02.020. PMID 21419747. 
  16. ↑ Takeda, N.; Jain, R.; Leboeuf, M. R.; Wang, Q.; Lu, M. M.; Epstein, J. A. (2011). "Interconversion Between Intestinal Stem Cell Populations in Distinct Niches". Science 334 (6061): 1420–1424. doi:10.1126/science.1213214. PMID 22075725. Bibcode: 2011Sci...334.1420T. 
  17. ↑ Dekaney, C. M.; Rodriguez, J. M.; Graul, M. C.; Henning, S. J. (2005). "Isolation and characterization of a putative intestinal stem cell fraction from mouse jejunum". Gastroenterology 129 (5): 1567–80. doi:10.1053/j.gastro.2005.08.011. PMID 16285956. 
  18. ↑ Barker, N.; Van Es, J. H.; Kuipers, J.; Kujala, P.; Van Den Born, M.; Cozijnsen, M.; Haegebarth, A.; Korving, J. et al. (2007). "Identification of stem cells in small intestine and colon by marker gene Lgr5". Nature 449 (7165): 1003–1007. doi:10.1038/nature06196. PMID 17934449. Bibcode: 2007Natur.449.1003B. 
  19. ↑ Carmon, K. S.; Lin, Q; Gong, X; Thomas, A; Liu, Q (2012). "LGR5 interacts and cointernalizes with Wnt receptors to modulate Wnt/β-catenin signaling". Molecular and Cellular Biology 32 (11): 2054–64. doi:10.1128/MCB.00272-12. PMID 22473993. 
  20. ↑ Powell, A. E.; Wang, Y.; Li, Y.; Poulin, E. J.; Means, A. L.; Washington, M. K.; Higginbotham, J. N.; Juchheim, A. et al. (2012). "The Pan-ErbB Negative Regulator Lrig1 is an Intestinal Stem Cell Marker that Functions as a Tumor Suppressor". Cell 149 (1): 146–158. doi:10.1016/j.cell.2012.02.042. PMID 22464327. 
  21. ↑ Wong, V. W. Y.; Stange, D. E.; Page, M. E.; Buczacki, S.; Wabik, A.; Itami, S.; Van De Wetering, M.; Poulsom, R. et al. (2012). "Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling". Nature Cell Biology 14 (4): 401–408. doi:10.1038/ncb2464. PMID 22388892. 
  22. ↑ Montgomery, R. K.; Carlone, D. L.; Richmond, C. A.; Farilla, L.; Kranendonk, M. E. G.; Henderson, D. E.; Baffour-Awuah, N. Y.; Ambruzs, D. M. et al. (2010). "Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells". Proceedings of the National Academy of Sciences 108 (1): 179–184. doi:10.1073/pnas.1013004108. PMID 21173232. 
  23. ↑ o’Brien, C. A.; Pollett, A.; Gallinger, S.; Dick, J. E. (2006). "A human colon cancer cell capable of initiating tumour growth in immunodeficient mice". Nature 445 (7123): 106–10. doi:10.1038/nature05372. PMID 17122772. 
  24. ↑ Van Der Flier, L. G.; Haegebarth, A.; Stange, D. E.; Van De Wetering, M.; Clevers, H. (2009). "OLFM4 is a Robust Marker for Stem Cells in Human Intestine and Marks a Subset of Colorectal Cancer Cells". Gastroenterology 137 (1): 15–17. doi:10.1053/j.gastro.2009.05.035. PMID 19450592. 
  25. ↑ Sakthianandeswaren, A.; Christie, M.; d'Andreti, C.; Tsui, C.; Jorissen, R. N.; Li, S.; Fleming, N. I.; Gibbs, P. et al. (2011). "PHLDA1 Expression Marks the Putative Epithelial Stem Cells and Contributes to Intestinal Tumorigenesis". Cancer Research 71 (10): 3709–3719. doi:10.1158/0008-5472.CAN-10-2342. PMID 21558389. 
  26. ↑ Zhu, L.; Gibson, P.; Currle, D. S.; Tong, Y.; Richardson, R. J.; Bayazitov, I. T.; Poppleton, H.; Zakharenko, S. et al. (2008). "Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation". Nature 457 (7229): 603–607. doi:10.1038/nature07589. PMID 19092805. 
  27. ↑ Besson, V.; Smeriglio, P.; Wegener, A.; Relaix, F.; Nait Oumesmar, B.; Sassoon, D. A.; Marazzi, G. (2011). "PW1 gene/paternally expressed gene 3 (PW1/Peg3) identifies multiple adult stem and progenitor cell populations". Proceedings of the National Academy of Sciences 108 (28): 11470–11475. doi:10.1073/pnas.1103873108. PMID 21709251. Bibcode: 2011PNAS..10811470B. 
  28. ↑ Muñoz, J; Stange, D. E.; Schepers, A. G.; Van De Wetering, M; Koo, B. K.; Itzkovitz, S; Volckmann, R; Kung, K. S. et al. (2012). "The Lgr5 intestinal stem cell signature: Robust expression of proposed quiescent '+4' cell markers". The EMBO Journal 31 (14): 3079–91. doi:10.1038/emboj.2012.166. PMID 22692129. 
  29. ↑ Formeister, E. J.; Sionas, A. L.; Lorance, D. K.; Barkley, C. L.; Lee, G. H.; Magness, S. T. (2009). "Distinct SOX9 levels differentially mark stem/progenitor populations and enteroendocrine cells of the small intestine epithelium". AJP: Gastrointestinal and Liver Physiology 296 (5): G1108–18. doi:10.1152/ajpgi.00004.2009. PMID 19228882. 
  30. ↑ Fafilek, B; Krausova, M; Vojtechova, M; Pospichalova, V; Tumova, L; Sloncova, E; Huranova, M; Stancikova, J et al. (2013). "Troy, a tumor necrosis factor receptor family member, interacts with lgr5 to inhibit wnt signaling in intestinal stem cells". Gastroenterology 144 (2): 381–91. doi:10.1053/j.gastro.2012.10.048. PMID 23142137. 



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