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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 295/6/G1182    most recent 90294.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kalabis, J. Articles by Herlyn, M. PubMed PubMed Citation Articles by Kalabis, J. Articles by Herlyn, M.

MUCOSAL BIOLOGY

Endothelin-3 stimulates survival of goblet cells in organotypic cultures of fetal human colonic epithelium

¹Molecular and Cellular Oncogenesis Program, The Wistar Institute; and ²Division of Gastroenterology, ³Department of Medicine, ⁴Department of Genetics, and ⁵Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania

Submitted 16 April 2008 ; accepted in final form 25 September 2008

Cells within the normal human colonic epithelium undergo a dynamic cycle of growth, differentiation, and death. The organotypic culture system of human fetal colonic epithelial cells seeded on top of collagen gels with embedded colonic fibroblasts allowed prolonged culture of the colonic epithelial cells (Kalabis J, Patterson MJ, Enders GM, Marian B, Iozzo RV, Rogler G, Gimotty PA, Herlyn M. FASEB J 17: 1115–1117, 2003). Herein, we have evaluated the role of endothelin-3 (ET3) and both cognate endothelin receptors (ETRA, ETRB) for human colonic epithelial cell growth and survival. ET3 was produced continuously by the fibroblasts as a result of adenovirus-mediated gene transfer. The presence and function of the endothelin receptors (ETRs) in epithelial cells was evaluated by [³H]thymidine incorporation using primary epithelial cells in monoculture and by immunohistochemistry on human fetal and adult paraffin-embedded tissues. In organotypic culture, ET3 increased the number of goblet cells but not of enteroendocrine cells. The increase in goblet cells was caused by prolonged cell survival and differentiation. The inhibition of both ETRA and ETRB significantly decreased the number of goblet cells and proliferation in epithelial cells, whereas the number of enteroendocrine cells remained unchanged. ET3 induced activation of IB and MAPK in the epithelial cells, suggesting that these signaling pathways mediate its proproliferation and prosurvival activities. Our results demonstrate that ET3 is involved in regulating human colonic epithelial cell proliferation and survival, particularly for goblet cells, and may be an important component of colonic homeostasis.

endothelin; proliferation; survival