Digestive Diseases and Sciences

, Volume 50, Supplement 1, pp S34–S38

Cellular and Molecular Mechanisms of the Epithelial Repair in IBD

Article

Abstract

Inflammatory bowel diseases such as ulcerative colitis or Crohn's disease frequently cause epithelial damage in the intestine. In general, the intestinal epithelium is able to rapidly repair itself by the restitution, proliferation, and differentiation of epithelial cells when such tissue damage occurs. However, severe and continuous inflammation could disturb the intrinsic repair system, resulting in refractory ulcers in the intestine. In this review, we will describe the recent findings of the cellular and molecular mechanisms regulating the regeneration process of the intestinal epithelium. Furthermore, we will propose bone marrow cells as a novel source of cells to regenerate the damaged intestinal epithelium. Bone marrow cells are the only cells of extra-gastrointestinal origin that are shown to contribute to the regeneration of the intestinal epithelium. Further studies of these cells and molecules may lead to a novel therapy for the repair of damaged intestinal epithelium.

Key Words

inflammatory bowel disease epithelial cells Wnt notch bone marrow derived cells 

References

  1. 1.
    Podolsky DK: Inflammatory bowel disease. N Engl J Med 347(6):417–429, 2003CrossRefGoogle Scholar
  2. 2.
    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(4):537–561, 1974.Google Scholar
  3. 3.
    Marshman E, Booth C, Potten CS: The intestinal epithelial stem cell. Bioessays 24(1):91–98.Google Scholar
  4. 4.
    Wong WM, Playford RJ, Wright NA: Peptide gene expression in gastrointestinal mucosal ulceration: ordered sequence or redundancy? Gut 46(2):286–292, 2000CrossRefPubMedGoogle Scholar
  5. 5.
    Taupin D, Podolsky DK: Trefoil factors: initiators of mucosal healing. Nat Rev Mol Cell Biol 4(9):721–732, 2003CrossRefPubMedGoogle Scholar
  6. 6.
    Mammen JM, Matthews JB: Mucosal repair in the gastrointestinal tract. Crit Care Med 31(8 Suppl):S532–S537, 2003CrossRefPubMedGoogle Scholar
  7. 7.
    Dignass AU, Podolsky DK: Interleukin 2 modulates intestinal epithelial cell function in vitro. Exp Cell Res 225(2):422–429, 1996CrossRefPubMedGoogle Scholar
  8. 8.
    McKaig BC, Makh SS, Hawkey CJ, Podolsky DK, Mahida YR: Normal human colonic subepithelial myofibroblasts enhance epithelial migration (restitution) via TGF-beta3. Am J Physiol 276(5 Pt 1):G1087–G1093, 1999PubMedGoogle Scholar
  9. 9.
    Sasaki H, Hirai K, Yamamoto H, Tanooka H, Sakamoto H, Iwamoto T, Takahashi T, Terada M, Ochiya T: HST-1/FGF-4 plays a critical role in crypt cell survival and facilitates epithelial cell restitution and proliferation. Oncogene 23(20):3681–3688, 2004CrossRefPubMedGoogle Scholar
  10. 10.
    Ramsanahie AP, Perez A, Duensing AU, Zinner MJ, Ashley SW, Whang EE: Glucagon-like peptide 2 enhances intestinal epithelial restitution. J Surg Res 107(1):44–49, 2002PubMedGoogle Scholar
  11. 11.
    Goke MN, Schneider M, Beil W, Manns MP: Differential glucocorticoid effects on repair mechanisms and NF-kappaB activity in the intestinal epithelium. Regulat Pept 105(3):203–214, 2002CrossRefGoogle Scholar
  12. 12.
    Nishimura S, Takahashi M, Ota S, Hirano M, Hiraishi H: Hepatocyte growth factor accelerates restitution of intestinal epithelial cells. J Gastroenterol 33(2):172–178, 1998CrossRefPubMedGoogle Scholar
  13. 13.
    Zbar AP, Simopoulos C, Karayiannakis AJ: Cadherins: an integral role in inflammatory bowel disease and mucosal restitution. J Gastroenterol 39(5):413–421, 2004CrossRefPubMedGoogle Scholar
  14. 14.
    Strauch ED, Yamaguchi J, Bass BL, Wang JY: Bile salts regulate intestinal epithelial cell migration by nuclear factor-kappa B-induced expression of transforming growth factor-beta. J Am Coll Surg 197(6):974–984, 2003CrossRefPubMedGoogle Scholar
  15. 15.
    Rao JN, Li J, Li L, Bass BL, Wang JY: Differentiated intestinal epithelial cells exhibit increased migration through polyamines and myosin II. Am J Physiol 277(6 Pt 1):G1149–G1158, 1999PubMedGoogle Scholar
  16. 16.
    Thompson JS, Saxena SK, Sharp JG: Regulation of intestinal regeneration: New insights. Microsc Res Tech 51(2):129–137, 2000CrossRefPubMedGoogle Scholar
  17. 17.
    Wong WM, Wright NA: Epidermal growth factor, epidermal growth factor receptors, intestinal growth, and adaptation. JPEN J Parenter Enteral Nut 23(5 Suppl):S83–S88, 1999Google Scholar
  18. 18.
    Bjerknes M, Cheng H: Modulation of specific intestinal epithelial progenitors by enteric neurons. Proc Natl Acad Sci USA 98(22):12497–12502, 2001CrossRefPubMedGoogle Scholar
  19. 19.
    Brauchle M, Madlener M, Wagner AD, Angermeyer K, Lauer U, Hofschneider PH, Gregor M, Werner S: Keratinocyte growth factor is highly overexpressed in inflammatory bowel disease. Am J Pathol 149(2):521–529, 1996PubMedGoogle Scholar
  20. 20.
    Gohda E, Tsubouchi H, Nakayama H, Hirono S, Sakiyama O, Takahashi K, Miyazaki H, Hashimoto S, Daikuhara Y: Purification and partial characterization of hepatocyte growth factor from plasma of a patient with fulminant hepatic failure. J Clin Invest 81(2):414–419, 1988PubMedGoogle Scholar
  21. 21.
    Bienz M, Clevers H, Brauchle M, Madlener M, Wagner AD, Angermeyer K, Lauer U, Hofschneider PH, Gregor M, Werner S: Linking colorectal cancer to Wnt signaling. Cell 103(2):311–320, 2000CrossRefPubMedGoogle Scholar
  22. 22.
    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(4):379–383, 1998CrossRefPubMedGoogle Scholar
  23. 23.
    Pinto D, Gregorieff A, Begthel H, Clevers H: Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev 17(14):1709–1713, 2003CrossRefPubMedGoogle Scholar
  24. 24.
    Lu Z, Hunter T: Wnt-independent beta-catenin transactivation in tumor development. Cell Cycle 3(5):571–573, 2004PubMedGoogle Scholar
  25. 25.
    Monga SP, Mars WM, Pediaditakis P, Bell A, Mule K, Bowen WC, Wang X, Zarnegar R, Michalopoulos GK: Hepatocyte growth factor induces Wnt-independent nuclear translocation of beta-catenin after Met-beta-catenin dissociation in hepatocytes. Cancer Res 262(7):2064–2071, 2002Google Scholar
  26. 26.
    Yang Q, Bermingham NA, Finegold MJ, Zoghbi HY: Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 294(5549):2155–2158, 2001CrossRefPubMedGoogle Scholar
  27. 27.
    van Den Brink GR, de Santa Barbara P, Roberts DJ: Development. Epithelial cell differentiation–A matter of choice. Science 294(5549):2115–2116, 2001Google Scholar
  28. 28.
    Okamoto R, Watanabe M: Molecular and clinical basis for the regeneration of human gastrointestinal epithelia. J Gastroenterol 39(1):1–6, 2004CrossRefPubMedGoogle Scholar
  29. 29.
    Naya FJ, Huang HP, Qiu Y, Mutoh H, DeMayo FJ, Leiter AB, Tsai MJ: Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev 11(18):2323–2334, 1997PubMedGoogle Scholar
  30. 30.
    Jensen J, Pedersen EE, Galante P, et al.: Control of endodermal endocrine development by Hes-1. Nat Genet 24(1):36–44, 2000CrossRefPubMedGoogle Scholar
  31. 31.
    Searfoss GH, Jordan WH, Calligaro DO, Galbreath EJ, Schirtzinger LM, Berridge BR, Gao H, Higgins MA, May PC, Ryan TP: Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. J Biol Chem 278(46):46107–46116, 2003CrossRefPubMedGoogle Scholar
  32. 32.
    Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, Engstrom L, Pinzon-Ortiz M, Fine JS, Lee HJ, Zhang L, Higgins GA, Parker EM: Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 279(13):12876–12882, 2004CrossRefPubMedGoogle Scholar
  33. 33.
    Verfaillie CM: Adult stem cells: Assessing the case for pluripotency. Trends Cell Biol 12(11):502–508, 2002CrossRefPubMedGoogle Scholar
  34. 34.
    Okamoto R, Yajima T, Yamazaki M, Kanai T, Mukai M, Okamoto S, Ikeda Y, Hibi T, Inazawa J, Watanabe M: Damaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tract. Nat Med 8(9):1011–1017, 2002CrossRefPubMedGoogle Scholar
  35. 35.
    Brittan M, Hunt T, Jeffery R, Poulsom R, Forbes SJ, Hodivala-Dilke K, Goldman J, Alison MR, Wright NA: Bone marrow derivation of pericryptal myofibroblasts in the mouse and human small intestine and colon. Gut 50(6):752–757, 2002CrossRefPubMedGoogle Scholar
  36. 36.
    Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, Meyer EM, Morel L, Petersen BE, Scott EW: Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416(6880):542–545, 2002CrossRefPubMedGoogle Scholar
  37. 37.
    Wang X, Willenbring H, Akkari Y, et al.: Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 422(6934):897–901, 2003CrossRefPubMedGoogle Scholar
  38. 38.
    Vassilopoulos G, Wang PR, Russell DW: Transplanted bone marrow regenerates liver by cell fusion. Nature 422(6934):901–904, 2003CrossRefPubMedGoogle Scholar
  39. 39.
    Wagers AJ, Sherwood RI, Christensen JL, Weissman IL: Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 297(5590):2256–2259, 2002CrossRefPubMedGoogle Scholar
  40. 40.
    Sinha A, Nightingale J, West KP, Berlanga-Acosta J, Playford RJ: Epidermal growth factor enemas with oral mesalamine for mild-to-moderate left-sided ulcerative colitis or proctitis. N Engl J Med 349(4):350–357, 2003CrossRefPubMedGoogle Scholar
  41. 41.
    Zeeh JM, Procaccino F, Hoffmann P, et al.: Keratinocyte growth factor ameliorates mucosal injury in an experimental model of colitis in rats. Gastroenterology 110(4):1077–1083, 1996CrossRefPubMedGoogle Scholar
  42. 42.
    Greenwood-Van Meerveld B, Venkova K, Connolly K: Efficacy of repifermin (keratinocyte growth factor-2) against abnormalities in gastrointestinal mucosal transport in a murine model of colitis. J Pharm Pharmacol 55(1):67–75, 2003PubMedGoogle Scholar
  43. 43.
    Farrell CL, Rex KL, Chen JN, Bready JV, DiPalma CR, Kaufman SA, Rattan A, Scully S, Lacey DL: The effects of keratinocyte growth factor in preclinical models of mucositis. Cell Prolif 35(Suppl 1):78–85, 2002CrossRefPubMedGoogle Scholar
  44. 44.
    Kitamura S, Kondo S, Shinomura Y, Isozaki K, Kanayama S, Higashimoto Y, Minami T, Kiyohara T, Yasunaga Y, Ishikawa H, Ohtani T, Ishiguro S, Matsuzawa Y: Expression of hepatocyte growth factor and c-met in ulcerative colitis. Inflamm Res 49(7):320–324, 2000PubMedGoogle Scholar
  45. 45.
    Tahara Y, Ido A, Yamamoto S, Miyata Y, Uto H, Hori T, Hayashi K, Tsubouchi H: Hepatocyte growth factor facilitates colonic mucosal repair in experimental ulcerative colitis in rats. J Pharmacol Exp Ther 307(1):146–151, 2003CrossRefPubMedGoogle Scholar
  46. 46.
    Drucker DJ: Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology 122(2):531–544, 2002PubMedGoogle Scholar
  47. 47.
    L'Heureux MC, Brubaker PL: Glucagon-like peptide-2 and common therapeutics in a murine model of ulcerative colitis. J Pharmacol Exp Ther 306(1):347–354, 2003CrossRefPubMedGoogle Scholar
  48. 48.
    Dieckgraefe BK, Korzenik JR: Treatment of active Crohn's disease with recombinant human granulocyte-macrophage colony-stimulating factor. Lancet 360(9344):1478–1480, 2002CrossRefPubMedGoogle Scholar
  49. 49.
    Egi H, Hayamizu K, Yoshimitsu M, Shimamoto F, Oishi K, Ohmori I, Okajima M, Asahara T: Regulation of T helper type-1 immunity in hapten-induced colitis by host pretreatment with granulocyte colony-stimulating factor. Cytokine 23(1–2):23–30, 2003CrossRefPubMedGoogle Scholar
  50. 50.
    Okamoto R, Watanabe M: Prospects for regeneration of gastrointestinal epithelia using bone-marrow cells. Trends Mol Med 9(7):286–290, 2003CrossRefPubMedGoogle Scholar
  51. 51.
    Burt RK, Traynor A, Oyama Y, Craig R: High-dose immune suppression and autologous hematopoietic stem cell transplantation in refractory Crohn disease. Blood 101(5):2064–2066, 2003CrossRefPubMedGoogle Scholar
  52. 52.
    Thulesen J, Hartmann B, Hare KJ, Kissow H, Orskov C, Holst JJ, Poulsen SS: Glucagon-like peptide 2 (GLP-2) accelerates the growth of colonic neoplasms in mice. Gut 53(8):1145–1150, 2004CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  1. 1.Department of Gastroenterology and Hepatology, Graduate SchoolTokyo Medical and Dental UniversityTokyoJapan

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