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Cystic cholangiomas after transplantation of pancreatic islets into the livers of diabetic rats

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Abstract

Islet transplantation is increasingly used as a therapy for human type 1 diabetes mellitus. In our study, we investigated the effect of the transplantation of a low number (n=350) of pancreatic islets into the right liver part on the neighboring portal bile ducts. Male streptozotocin- diabetic Lewis or autoimmune-diabetic BB/Pfd rats (n=1065) were subdivided into 11 experimental groups. A few days after low-number islet transplantation, cholangiocytes adjacent to the grafts showed an increase in proliferative activity. During the next 12–24 months, many peri-insular ductules progressed via tumor-like cystic lesions to large cystic cholangiomas, accompanied by a translocation of the insulin receptor into the cytoplasm and an increase in expression of insulin-related signaling proteins (Insulin-receptor-substrate-1, Raf-1, Mek-1). After 24 months, 53% of rats with low-number transplantation exhibited at least one cholangioma >10 mm, significantly outnumbering tumor development in the transplant-free left liver part and in any control group. No cholangiocarcinomas emerged. A graft cell origin of the tumors was excluded by Y chromosome in situ hybridization in cross-gender transplantations. Conclusively, low-number intrahepatic islet transplantation, most likely acting by permanent local hyperinsulinism, leads to prolonged cholangiocellular proliferation in streptozotocin- and in autoimmune-diabetic rats, resulting in the development of benign cystic cholangiomas.

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Acknowledgements

The authors wish to thank Gabriele Becker, Jörg Bedorf, Danuta Chrobok, Mariana Dombrowski, Mathilde Hau-Liersch, Kirsten Herrmanns, and Uta Schönborn for technical assistance, Yvonne Fischer and Kurt Rüdel for animal care, Thomas Jonczyk-Weber for photographic work, and Bernd Wüsthoff for editing the manuscript. We are indebted to Dr. Chantal Mathieu, University of Leuven, Belgium, for providing us with breeding pairs of the BB/Pfd rats.This work was supported by the Deutsche Forschungsgemeinschaft (grant numbers Do 622/1-3,1-4, and 1-5).

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  1. Institute for Pathology, Otto-von-Guericke-University Magdeburg, Leipziger Strasse 44, 39120, Magdeburg, Germany

    Matthias Evert, Regine Schneider-Stock & Frank Dombrowski

  2. Institute for Pathology, Rheinische Friedrich-Wilhelm-University, Sigmund-Freud-Strasse 25, 53105, Bonn, Germany

    Hans-Ulrich Schildhaus

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  1. Matthias Evert
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Correspondence to Frank Dombrowski.

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Evert, M., Schildhaus, HU., Schneider-Stock, R. et al. Cystic cholangiomas after transplantation of pancreatic islets into the livers of diabetic rats. Virchows Arch 448, 776–787 (2006). https://doi.org/10.1007/s00428-006-0196-3

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