Journal of Gastroenterology

, Volume 44, Issue 5, pp 372–379

The role of hedgehog signaling during gastric regeneration

  • Dae-Hwan Kang
  • Myoung-Eun Han
  • Moo-Ho Song
  • Young-Suk Lee
  • Eun-Hee Kim
  • Hyun-Jung Kim
  • Gwang-Ha Kim
  • Dong-Heon Kim
  • Sik Yoon
  • Sun-Yong Baek
  • Bong-Seon Kim
  • Jae-Bong Kim
  • Sae-Ock Oh
Original Article—Alimentary Tract

Abstract

Background

Hedgehog signaling plays critical roles during embryonic development. It is also involved in tissue regeneration and carcinogenesis in various adult tissues. Moreover, it regulates the maintenance of cancer stem cells and adult stem cells. Although hedgehog signaling is important in gastric carcinogenesis, its role in gastric regeneration has not been previously examined. In the present study, we evaluated the expression and roles of hedgehog signaling during gastric regeneration.

Methods

Gastric ulcers were induced by serosal application of an acetic acid solution in mice. Sham-operated mice served as controls. The proliferation of gastric progenitor cells was studied using bromodeoxyuridine (BrdU). The expression of hedgehog signaling molecules and the differentiation of gastric progenitor cells were examined by immunohistochemical staining and Western blotting.

Results

One day after the induction of gastric ulcer, the proliferation of gastric progenitor cells increased; however, the expression of hedgehog signaling molecules, including sonic hedgehog (Shh), Indian hedgehog (Ihh), desert hedgehog (Dhh), and patched (Ptch1) decreased at the ulcer margin. From 5 days after the induction of gastric ulcer, newly generated gastric glands and their differentiation were observed at the ulcer margin. The expression of hedgehog signaling molecules gradually increased in the newly generated gastric glands of the ulcer margin. Cyclopamine, a specific inhibitor of hedgehog signaling, significantly inhibited the differentiation of mucous cells and parietal cells during the gastric regeneration process.

Conclusion

The above results suggest that hedgehog signaling is involved in the differentiation of gastric progenitor cells during the gastric ulcer repair process.

Keywords

Hedgehog signaling Gastric regeneration Differentiation Parietal cells Mucous cells 

Supplementary material

535_2009_6_MOESM1_ESM.jpg (2.8 mb)
Supplementary Fig.1 (JPEG 2901 kb)

References

  1. 1.
    Marigo V, Tabin CJ. Regulation of patched by sonic hedgehog in the developing neural tube. Proc Natl Acad Sci USA. 1996;93:9346–51.PubMedCrossRefGoogle Scholar
  2. 2.
    Bellusci S, Furuta Y, Rush MG, Henderson R, Winnier G, Hogan BL. Involvement of sonic hedgehog (shh) in mouse embryonic lung growth and morphogenesis. Development. 1997;124:53–63.PubMedGoogle Scholar
  3. 3.
    Chiang C, Swan RZ, Grachtchouk M, Bolinger M, Litingtung Y, Robertson EK, et al. Essential role for sonic hedgehog during hair follicle morphogenesis. Dev Biol. 1999;205:1–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, Westphal H, et al. Cyclopia and defective axial patterning in mice lacking sonic hedgehog gene function. Nature. 1996;383:407–13.PubMedCrossRefGoogle Scholar
  5. 5.
    Vortkamp A, Lee K, Lanske B, Segre GV, Kronenberg HM, Tabin CJ. Regulation of rate of cartilage differentiation by Indian hedgehog and pth-related protein. Science. 1996;273:613–22.PubMedCrossRefGoogle Scholar
  6. 6.
    Litingtung Y, Lei L, Westphal H, Chiang C. Sonic hedgehog is essential to foregut development. Nat Genet. 1998;20:58–61.PubMedCrossRefGoogle Scholar
  7. 7.
    Motoyama J, Liu J, Mo R, Ding Q, Post M, Hui CC. Essential function of gli2 and gli3 in the formation of lung, trachea and oesophagus. Nat Genet. 1998;20:54–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Ramalho-Santos M, Melton DA, McMahon AP. Hedgehog signals regulate multiple aspects of gastrointestinal development. Development. 2000;127:2763–72.PubMedGoogle Scholar
  9. 9.
    Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature. 2004;432:324–31.PubMedCrossRefGoogle Scholar
  10. 10.
    Ahn S, Joyner AL. In vivo analysis of quiescent adult neural stem cells responding to sonic hedgehog. Nature. 2005;437:894–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Athar M, Tang X, Lee JL, Kopelovich L, Kim AL. Hedgehog signalling in skin development and cancer. Exp Dermatol. 2006;15:667–77.PubMedCrossRefGoogle Scholar
  12. 12.
    Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X, et al. Mutations in sufu predispose to medulloblastoma. Nat Genet. 2002;31:306–10.PubMedCrossRefGoogle Scholar
  13. 13.
    Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, et al. Activating smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998;391:90–2.PubMedCrossRefGoogle Scholar
  14. 14.
    Watkins DN, Berman DM, Burkholder SG, Wang B, Beachy PA, Baylin SB. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature. 2003;422:313–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Kubo M, Nakamura M, Tasaki A, Yamanaka N, Nakashima H, Nomura M, et al. Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer. Cancer Res. 2004;64:6071–4.PubMedCrossRefGoogle Scholar
  16. 16.
    Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003;425:851–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Berman DM, Karhadkar SS, Maitra A, Montes De Oca R, Gerstenblith MR, Briggs K, et al. Widespread requirement for hedgehog ligand stimulation in growth of digestive tract tumours. Nature. 2003;425:846–51.PubMedCrossRefGoogle Scholar
  18. 18.
    Cooper MK, Porter JA, Young KE, Beachy PA. Teratogen-mediated inhibition of target tissue response to shh signaling. Science. 1998;280:1603–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Chen JK, Taipale J, Cooper MK, Beachy PA. Inhibition of hedgehog signaling by direct binding of cyclopamine to smoothened. Genes Dev. 2002;16:2743–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Bayne K. Revised guide for the care and use of laboratory animals. American physiological society. Physiologist. 1996;39(199):208–11.Google Scholar
  21. 21.
    Okabe S, Amagase K. An overview of acetic acid ulcer models—the history and state of the art of peptic ulcer research. Biol Pharm Bull. 2005;28:1321–41.PubMedCrossRefGoogle Scholar
  22. 22.
    Tarnawski AS. Cellular and molecular mechanisms of gastrointestinal ulcer healing. Dig Dis Sci. 2005;50(Suppl 1):S24–33.PubMedCrossRefGoogle Scholar
  23. 23.
    van den Brink GR, Hardwick JC, Tytgat GN, Brink MA, Ten Kate FJ, Van Deventer SJ, et al. Sonic hedgehog regulates gastric gland morphogenesis in man and mouse. Gastroenterology. 2001;121:317–28.PubMedCrossRefGoogle Scholar
  24. 24.
    Tarnawski A. Molecular mechanisms of ulcer healing. Drug News Perspect. 2000;13:158–68.PubMedCrossRefGoogle Scholar
  25. 25.
    Imokawa Y, Yoshizato K. Expression of sonic hedgehog gene in regenerating newt limb blastemas recapitulates that in developing limb buds. Proc Natl Acad Sci USA. 1997;94:9159–64.PubMedCrossRefGoogle Scholar
  26. 26.
    Akazawa C, Tsuzuki H, Nakamura Y, Sasaki Y, Ohsaki K, Nakamura S, et al. The upregulated expression of sonic hedgehog in motor neurons after rat facial nerve axotomy. J Neurosci. 2004;24:7923–30.PubMedCrossRefGoogle Scholar
  27. 27.
    Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, et al. Cancer stem cells—perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Res. 2006;66:9339–44.PubMedCrossRefGoogle Scholar
  28. 28.
    Peacock CD, Wang Q, Gesell GS, Corcoran-Schwartz IM, Jones E, Kim J, et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci USA. 2007;104:4048–53.PubMedCrossRefGoogle Scholar
  29. 29.
    Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D, Maitra A, et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature. 2004;431:707–12.PubMedCrossRefGoogle Scholar
  30. 30.
    Stepan V, Ramamoorthy S, Nitsche H, Zavros Y, Merchant JL, Todisco A. Regulation and function of the sonic hedgehog signal transduction pathway in isolated gastric parietal cells. J Biol Chem. 2005;280:15700–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Fukaya M, Isohata N, Ohta H, Aoyagi K, Ochiya T, Saeki N, et al. Hedgehog signal activation in gastric pit cell and in diffuse-type gastric cancer. Gastroenterology. 2006;131:14–29.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2009

Authors and Affiliations

  • Dae-Hwan Kang
    • 1
  • Myoung-Eun Han
    • 2
    • 3
  • Moo-Ho Song
    • 2
  • Young-Suk Lee
    • 2
  • Eun-Hee Kim
    • 2
  • Hyun-Jung Kim
    • 2
  • Gwang-Ha Kim
    • 1
  • Dong-Heon Kim
    • 4
  • Sik Yoon
    • 2
    • 3
  • Sun-Yong Baek
    • 2
  • Bong-Seon Kim
    • 2
  • Jae-Bong Kim
    • 2
  • Sae-Ock Oh
    • 2
    • 3
  1. 1.Department of Internal Medicine, School of MedicinePusan National UniversityYangsanSouth Korea
  2. 2.Department of Anatomy, School of MedicinePusan National UniversityYangsanSouth Korea
  3. 3.Medical Research Center for Ischemic Tissue RegenerationPusan National UniversityYangsanSouth Korea
  4. 4.Department of Surgery, School of MedicinePusan National UniversityYangsanSouth Korea

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