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Published online 26 February 2001. doi:10.1083/jcb.152.5.911
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© The Rockefeller University Press, 0021-9525/2001/3/911/ $5.00
The Journal of Cell Biology, Volume 152, Number 5, March 5, 2001 911-922

Original Article

Autocrine Stimulation of Human Pancreatic Duct–like Development by Soluble Isoforms of Epimorphin In Vitro

Lasse Lehnerta, Markus M. Lerchc, Yohei Hiraid, Marie-Luise Kruseb, Wolff Schmiegele, and Holger Kalthoffa
a Molecular Oncology, Department of General and Thoracic Surgery
b First Department of Medicine, Laboratory for Molecular Gastroenterology and Hepatology, Christian-Albrechts University, Kiel 24105, Germany
c Department of Medicine B, Westfälische Wilhelms University, Münster 48149, Germany
d Sumitomo Industries, Yokohama 244-8588, Japan
e Medical Clinic, Knappschaftskrankenhaus, Ruhr, University of Bochum, Bochum 44780, Germany

Correspondence to: Holger Kalthoff, Molecular Oncology, Department of General and Thoracic Surgery, Christian-Albrechts-University, Kiel 24105, Germany. Tel:49-431-597-1938 Fax:49-431-597-1939 E-mail:hkalthoff{at}email.uni-kiel.de.

Epimorphin was recently described as a mesenchymal factor modulating morphogenesis of murine mammary ducts, skin, liver, and lung in vitro. In this study epimorphin was analyzed in a human, pancreatic adenocarcinoma cell line (A818-6) which develops single layer epithelial hollow spheres resembling normal pancreatic ductal structures in vitro. Soluble 34- and 31-kD isoforms of epimorphin were found in the culture supernatant of A818-6 cells. In lysates of A818-6 cells we detected the 34-and 31-kD isoforms and the dimers, and in lysates of fibroblasts the 150-kD tetramers of epimorphin additionally. A neutralizing monoclonal antibody against epimorphin (MC-1) efficiently blocked the development of hollow sphere structures from A818-6 cells. Coculture of A818-6 cells with fibroblasts stimulated the development of hollow sphere structures in general and increased differentiation in 5–6-d-old hollow spheres. A818-6 hollow sphere development in the presence of fibroblasts was also blocked by MC-1. In this novel system for human duct-like differentiation of pancreatic epithelial cells, we provide evidence for an autocrine and paracrine function of epimorphin as a major mediator for morphogenesis.

Key Words: epimorphin, pancreas, epithelial differentiation, spheres, duct structures


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