Stem Cell Reviews

, Volume 2, Issue 3, pp 203–212 | Cite as

The gastrointestinal tract stem cell niche



The gastrointestinal epithelium is unique in that cell proliferation, differentiation, and apoptosis occur in an orderly fashion along the crypt-villus axis. The intestinal crypt is mainly a proliferative compartment, is monoclonal and is maintained by stem cells. The villus represents the differentiated compartment, and is polyclonal as it receives cells from multiple crypts. In the small intestine, cell migration begins near the base of the crypt, and cells migrate from here emerging onto the villi. The basal crypt cells at position 5 are candidate stem cells. As the function of stem cells is to maintain the integrity of the intestinal epithelium, it must self-renew, proliferate, and differentiate within a protective niche. This niche is made up of proliferating and differentiating epithelial cells and surrounding mesenchymal cells. These mesenchymal cells promote the epithelial-mesenchymal crosstalk required to maintain the niche. A stochastic model of cell division has been proposed to explain how a single common ancestral stem cell exists from which all stem cells in a niche are descended. Our group has argued that these crypts then clonally expand by crypt fission, forming two daughters’ crypts, and that this is the mechanism by which mutated stem cells or even cancer stem cell clones expand in the colon and in the entire gastrointestinal tract. Until recently, the differentiation potential of stem cells into adult tissues has been thought to be limited to cell lineages in the organ from which they were derived. Bone marrow cells are rare among adult stem cells regarding their abundance and role in the continuous, lifelong, physiological replenishment of circulating cells. In human and mice experiments, we have shown that bone marrow can contribute to the regeneration of intestinal myofibroblasts and thereby after epithelium following damage, through replacing the cells, which maintain the stem cells niche. Little is known about the markers characterizing the stem and transit amplifying populations of the gastrointestinal tract, although musashi-1 and hairy and enhancer of split homolog-1 have been proposed. As the mammalian gastrointestinal tract develops from the embryonic gut, it is made up of an endodermally-derived epithelium surrounded by cells of mesoderm origin. Cell signaling between these two tissue layers plays a critical role in coordinating patterning and organogenesis of the gut and its derivatives. Many lines of evidence have revealed that Wnt signaling is the most dominant force in controlling cell proliferation, differentiation, and apoptosis along the crypt-villus axis. We have found Wnt messenger RNAs expression in intestinal subepithelial myofibroblasts and frizzled messenger RNAs expression in both myofibroblasts and crypt epithelium. Moreover, there are many other factors, for example, bone morphogenetic protein, homeobox, forkhead, hedgehog, homeodomain, and platelet-derived growth factor that are also important to stem cell signaling in the gastrointestinal tract.

Index Entries

Intestine stem cell niche, crypt bone marrow myofibroblast 


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  1. 1.
    Schofield R. Blood Cells 1978;4:7–25.PubMedGoogle Scholar
  2. 2.
    Lin H. Nat Rev Genet 2002;3:931–940.PubMedCrossRefGoogle Scholar
  3. 3.
    Spradling A, Drummond-Barbosa D, Kai T. Nature 2001;414:98–104.PubMedCrossRefGoogle Scholar
  4. 4.
    Xie T, Spradling AC. Science 2000;290:328–330.PubMedCrossRefGoogle Scholar
  5. 5.
    Brinster RL, Zimmermann JW. Proc Natl Acad Sci USA 1994;91:11,298–11,302.Google Scholar
  6. 6.
    Nishimura EK, Jordan SA, Oshima H, et al. Nature 2002;416:854–860.PubMedCrossRefGoogle Scholar
  7. 7.
    Oshima H, Rochat A, Kedzia C, Kobayashi K, Barrandon Y. Cell 2001;104:233–245.PubMedCrossRefGoogle Scholar
  8. 8.
    Wright NA. Int J Exp Pathol 2000;81:117–143.PubMedCrossRefGoogle Scholar
  9. 9.
    Andoh A, Bamba S, Fujiyama Y, Brittan M, Wright NA. J Gastroenterol 2005;40:1089–1099.PubMedCrossRefGoogle Scholar
  10. 10.
    Kim KM, Oh YL, Ko JS, Choe YH, Seo JK. J Gastroenterol 2004;39:231–237.PubMedCrossRefGoogle Scholar
  11. 11.
    Potten CS, Loeffler M. Development 1990;110:1001–1020.PubMedGoogle Scholar
  12. 12.
    Bjerknes M, Cheng H. Am J Anat 1981;160:51–63.PubMedCrossRefGoogle Scholar
  13. 13.
    Bjerknes M, Cheng H. Am J Anat 1981;160:77–91.PubMedCrossRefGoogle Scholar
  14. 14.
    Lee ER, Leblond CP. Am J Anat 1985;172:241–259.PubMedCrossRefGoogle Scholar
  15. 15.
    Karam SM, Leblond CP. Anat Rec 1993;236:259–279.PubMedCrossRefGoogle Scholar
  16. 16.
    Yamada K, Yoshitake K, Sato M, Ahnen DJ. Gastroenterology 1992;103:160–167.PubMedGoogle Scholar
  17. 17.
    Cheng H, Leblond CP. Am J Anat 1974;141:503–519.PubMedCrossRefGoogle Scholar
  18. 18.
    Cai WB, Roberts SA, Potten CS. Int J Radiat Biol 1997;71:573–579.PubMedCrossRefGoogle Scholar
  19. 19.
    Potten CS, Booth C, Pritchard DM. Int J Exp Pathol 1997;78:219–243.PubMedCrossRefGoogle Scholar
  20. 20.
    Potten CS. Philos Trans R Soc Lond B Biol Sci 1998;353:821–830.PubMedCrossRefGoogle Scholar
  21. 21.
    Watt FM, Hogan BL. Science 2000;287:1427–1430.PubMedCrossRefGoogle Scholar
  22. 22.
    Yatabe Y, Tavare S, Shibata D. Proc Natl Acad Sci USA 2001;98:10,839–10,844.CrossRefGoogle Scholar
  23. 23.
    Kim KM, Shibata D. Oncogene 2002;21:5441–5449.PubMedCrossRefGoogle Scholar
  24. 24.
    Potten CS, Li YQ, O’Connor PJ, Winton DJ. Carcinogenesis 1992;13:2305–2312.PubMedCrossRefGoogle Scholar
  25. 25.
    Cairns J. Nature 1975;255:197–200.PubMedCrossRefGoogle Scholar
  26. 26.
    Potten CS, Owen G, Booth D. J Cell Sci 2002;115:2381–2388.PubMedGoogle Scholar
  27. 27.
    Preston SL, Mandir N, Hunt T, Goodlad RA, Wright NA, Alison MR. Cell Prolif 2005;38:317.Google Scholar
  28. 28.
    Kim JY, Siegmund KD, Tavare S, Shibata D. BMC Med 2005;3:10.PubMedCrossRefGoogle Scholar
  29. 29.
    Park HS, Goodlad RA, Wright NA. Am J Pathol 1995;147:1416–1427.PubMedGoogle Scholar
  30. 30.
    Park HS, Goodlad RA, Wright NA. Cancer Res 1997;57:4507–4510.PubMedGoogle Scholar
  31. 31.
    Park HS, Goodlad RA, Ahnen DJ, et al. Am J Pathol 1997;151:843–852.PubMedGoogle Scholar
  32. 32.
    Wong WM, Mandir N, Goodlad RA, et al. Gut 2002;50:212–217.PubMedCrossRefGoogle Scholar
  33. 33.
    Wright NA. Philos Trans R Soc Lond B Biol Sci 1998;353:925–933.PubMedCrossRefGoogle Scholar
  34. 34.
    Preston SL, Wong WM, Chan AO, et al. Cancer Res 2003;63:3819–3825.PubMedGoogle Scholar
  35. 35.
    Wasan HS, Park HS, Liu KC, et al. J Pathol 1998;185:246–255.PubMedCrossRefGoogle Scholar
  36. 36.
    Yen TH, Wright NA, Poulsom R. In Horizons in Medicine. Franklyn J, (ed), Royal College of Physicians of London, London: 2004 Vol. 16, pp. 249–257.Google Scholar
  37. 37.
    Ferrari G, Cusella-De Angelis G, Coletta M, et al. Science 1998;279:1528–1530.PubMedCrossRefGoogle Scholar
  38. 38.
    Eglitis MA, Mezey E. Proc Natl Acad Sci USA 1997;94:4080–4085.PubMedCrossRefGoogle Scholar
  39. 39.
    Poulsom R, Forbes SJ, Hodivala-Dilke K, et al. J Pathol 2001;195:229–235.PubMedCrossRefGoogle Scholar
  40. 40.
    Poulsom R, Alison MR, Forbes SJ, Wright NA. J Pathol 2002;197:441–456.PubMedCrossRefGoogle Scholar
  41. 41.
    Poulsom R, Alison MR, Cook T, et al. J Am Soc Nephrol 2003; 14(Suppl 1):S48-S54.PubMedCrossRefGoogle Scholar
  42. 42.
    Poulsom R. Nephron Exp Nephrol 2003;93:e53.Google Scholar
  43. 43.
    Fang TC, Alison MR, Cook HT, Jeffery R, Wright NA, Poulsom R. J Am Soc Nephrol 2005;16:1723–1732.PubMedCrossRefGoogle Scholar
  44. 44.
    Fang TC, Alison MR, Wright NA, Poulsom R. Int J Exp Pathol 2004;85:115–124.PubMedCrossRefGoogle Scholar
  45. 45.
    Fang TC, Poulsom R. Birth Defects Res C Embryo Today 2003;69:238–249.PubMedCrossRefGoogle Scholar
  46. 46.
    Roufosse C, Bou-Gharios G, Prodromidi E, et al. J Am Soc Nephrol 2006;17:775–782.PubMedCrossRefGoogle Scholar
  47. 47.
    Alison MR, Poulsom R, Jeffery R, et al. Nature 2000;406:257.PubMedCrossRefGoogle Scholar
  48. 48.
    Alison MR, Poulsom R, Forbes S, Wright NA. J Pathol 2002;197:419–423.PubMedCrossRefGoogle Scholar
  49. 49.
    Alison MR. Semin Liver Dis 2003;23:325–336.PubMedCrossRefGoogle Scholar
  50. 50.
    Alison MR, Poulsom R, Otto WR, et al. J Clin Pathol 2004;57:113–120.PubMedCrossRefGoogle Scholar
  51. 51.
    Alison MR, Poulsom R, Otto WR, et al. J Cell Sci 2003;116:599–603.PubMedCrossRefGoogle Scholar
  52. 52.
    Brittan M, Braun KM, Reynolds LE, et al. J Pathol 2005;205:1–13.PubMedCrossRefGoogle Scholar
  53. 53.
    Brittan M, Hunt T, Jeffery R, et al. Gut 2002;50:752–757.PubMedCrossRefGoogle Scholar
  54. 54.
    Brittan M, Chance V, Elia G, et al. Gastroenterology 2005;128:1984–1995.PubMedCrossRefGoogle Scholar
  55. 55.
    Brittan M, Wright NA. Gut 2004;53:899–910.PubMedCrossRefGoogle Scholar
  56. 56.
    Brittan M, Wright NA. Cell Prolif 2004;37:35–53.PubMedCrossRefGoogle Scholar
  57. 57.
    Brittan M, Wright NA. J Pathol 2002;197:492–509.PubMedCrossRefGoogle Scholar
  58. 58.
    Direkze NC, Hodivala-Dilke K, Jeffery R, et al. Cancer Res 2004;64:8492–8495.PubMedCrossRefGoogle Scholar
  59. 59.
    Direkze NC, Forbes SJ, Brittan M, et al. Stem Cells 2003;21:514–520.PubMedCrossRefGoogle Scholar
  60. 60.
    Direkze NC, Jeffery R, Hodivala-Dilke K, et al. Cancer Res 2006;66:1265–1269.PubMedCrossRefGoogle Scholar
  61. 61.
    Bamba S, Lee CY, Brittan M, et al. J Pathol 2006;209:265–273.PubMedCrossRefGoogle Scholar
  62. 62.
    Vig P, Russo FP, Edwards RJ, et al. Hepatology 2006;43:316–324.PubMedCrossRefGoogle Scholar
  63. 63.
    Forbes SJ, Russo FP, Rey V, et al. Gastroenterology 2004;126:955–963.PubMedCrossRefGoogle Scholar
  64. 64.
    Brodie JC, Humes HD. Pharmacol Rev 2005;57:299–313.PubMedCrossRefGoogle Scholar
  65. 65.
    Herzog EL, Chai L, Krause DS. Blood 2003;102:3483–3493.PubMedCrossRefGoogle Scholar
  66. 66.
    Kucia M, Reca R, Jala VR, Dawn B, Ratajczak J, Ratajczak MZ. Leukemia 2005;19:1118–1127.PubMedCrossRefGoogle Scholar
  67. 67.
    Jones PH, Harper S, Watt FM. Cell 1995;80:83–93.PubMedCrossRefGoogle Scholar
  68. 68.
    Berardi AC, Wang A, Levine JD, Lopez P, Scadden DT. Science 1995;267:104–108.PubMedCrossRefGoogle Scholar
  69. 69.
    Kaneko Y, Sakakibara S, Imai T, et al. Dev Neurosci 2000;22:139–153.PubMedCrossRefGoogle Scholar
  70. 70.
    Sakakibara S, Imai T, Hamaguchi K, et al. Dev Biol 1996;176:230–242.PubMedCrossRefGoogle Scholar
  71. 71.
    Nakamura M, Okano H, Blendy JA, Montell C. Neuron 1994;13:67–81.CrossRefGoogle Scholar
  72. 72.
    Okabe M, Imai T, Kurusu M, Hiromi Y, Okano H. Nature 2001;411:94–98.PubMedCrossRefGoogle Scholar
  73. 73.
    Sakakibara S, Okano H. J Neurosci 1997;17:8300–8312.PubMedGoogle Scholar
  74. 74.
    Okano H, Imai T, Okabe M. J Cell Sci 2002;115:1355–1359.PubMedGoogle Scholar
  75. 75.
    Sakakibara S, Nakamura Y, Yoshida T, et al. Proc Natl Acad Sci USA 2002;99:15,194–15,199.CrossRefGoogle Scholar
  76. 76.
    Akazawa C, Sasai Y, Nakanishi S, Kageyama R. J Biol Chem 1992;267:21,879–21,885.Google Scholar
  77. 77.
    Sasai Y, Kageyama R, Tagawa Y, Shigemoto R, Nakanishi S. Genes Dev 1992;6:2620–2634.PubMedGoogle Scholar
  78. 78.
    Nakamura Y, Sakakibara S, Miyata T, et al. J Neurosci 2000;20:283–293.PubMedGoogle Scholar
  79. 79.
    Imai T, Tokunaga A, Yoshida T, et al. Mol Cell Biol 2001;21:3888–3890.PubMedCrossRefGoogle Scholar
  80. 80.
    Jensen J, Pedersen EE, Galante P, et al. Nat Genet 2000;24:36–44.PubMedCrossRefGoogle Scholar
  81. 81.
    Kayahara T, Sawada M, Takaishi S, et al. FEBS Lett 2003;535:131–135.PubMedCrossRefGoogle Scholar
  82. 82.
    Teufel A, Wong EA, Mukhopadhyay M, Malik N, Westphal H. Biochim Biophys Acta 2003;1627:147–152.PubMedGoogle Scholar
  83. 83.
    Stappenbeck TS, Mills JC, Gordon JI. Proc Natl Acad Sci USA 2003;100:1004–1009.PubMedCrossRefGoogle Scholar
  84. 84.
    Giannakis M, Stappenbeck TS, Mills JC, et al. J Biol Chem 2006;281:11,292–11,300.CrossRefGoogle Scholar
  85. 85.
    Pascal RR, Kaye GI, Lane N. Gastroenterology 1968;54:835–851.PubMedGoogle Scholar
  86. 86.
    Marsh MN, Trier JS. Gastroenterology 1974;67:636–645.PubMedGoogle Scholar
  87. 87.
    Giles RH, van Es JH, Clevers H. Biochim Biophys Acta 2003;1653:1–24.PubMedGoogle Scholar
  88. 88.
    Willert K, Nusse R. Curr Opin Genet Dev 1998;8:95–102.PubMedCrossRefGoogle Scholar
  89. 89.
    Bienz M, Clevers H. Cell 2000;103:311–320.PubMedCrossRefGoogle Scholar
  90. 90.
    Pinto D, Clevers H. Biol Cell 2005;97:185–196.PubMedCrossRefGoogle Scholar
  91. 91.
    Smith K, Bui TD, Poulsom R, Kaklamanis L, Williams G, Harris AL. Br J Cancer 1999;81:496–502.PubMedCrossRefGoogle Scholar
  92. 92.
    Korinek V, Barker N, Moerer P, et al. Nat Genet 1998;19:379–383.PubMedCrossRefGoogle Scholar
  93. 93.
    Pinto D, Gregorieff A, Begthel H, Clevers H. Genes Dev 2003;17:1709–1713.PubMedCrossRefGoogle Scholar
  94. 94.
    Gregorieff A, Pinto D, Begthel H, Destree O, Kielman M, Clevers H. Gastroenterology 2005;129:626–638.PubMedCrossRefGoogle Scholar
  95. 95.
    Haramis AP, Begthel H, van den Born M, et al. Science 2004;303:1684–1686.PubMedCrossRefGoogle Scholar
  96. 96.
    He XC, Zhang J, Tong WG, et al. Nat Genet 2004;36:1117–1121.PubMedCrossRefGoogle Scholar
  97. 97.
    Subramanian V, Meyer B, Evans GS. Differentiation 1998;64:11–18.PubMedCrossRefGoogle Scholar
  98. 98.
    Chawengsaksophak K, James R, Hammond VE, Kontgen F, Beck F. Nature 1997;386:84–87.PubMedCrossRefGoogle Scholar
  99. 99.
    Beck F, Chawengsaksophak K, Waring P, Playford RJ, Furness JB. Proc Natl Acad Sci USA 1999;96:7318–7323.PubMedCrossRefGoogle Scholar
  100. 100.
    Beck F, Chawengsaksophak K, Luckett J, et al. Dev Biol 2003;255:399–406.PubMedCrossRefGoogle Scholar
  101. 101.
    Lickert H, Domon C, Huls G, et al. Development 2000;127:3805–3813.PubMedGoogle Scholar
  102. 102.
    Kaestner KH, Silberg DG, Traber PG, Schutz G. Genes Dev 1997;11:1583–1595.PubMedGoogle Scholar
  103. 103.
    Ramalho-Santos M, Melton DA, McMahon AP. Development 2000;127:2763–2772.PubMedGoogle Scholar
  104. 104.
    Madison BB, Braunstein K, Kuizon E, Portman K, Qiao XT, Gumucio DL. Development 2005;132:279–289.PubMedCrossRefGoogle Scholar
  105. 105.
    Pabst O, Zweigerdt R, Arnold HH. Development 1999;126:2215–2225.PubMedGoogle Scholar
  106. 106.
    Karlsson L, Lindahl P, Heath JK, Betsholtz C. Development 2000;127:3457–3466.PubMedGoogle Scholar
  107. 107.
    Moore KA, Lemischka IR. Science 2006;311:1880–1885.PubMedCrossRefGoogle Scholar
  108. 108.
    Batts LE, Polk DB, Dubois RN, Kulessa H. Dev Dyn 2006;235:1563–1570.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2006

Authors and Affiliations

  1. 1.Histopathology Unit, Cancer Research UKLondon Research InstituteLondonUK
  2. 2.Barts and The LondonQueen Mary’s School of Medicine and DentistryLondonUK
  3. 3.Chang Gung Memorial Hospital and Chang Gung UniversityTaiwan

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