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Diabetes 53:105-112, 2004
© 2004 by the American Diabetes Association, Inc.

Transplantation of Reversibly Immortalized Insulin-Secreting Human Hepatocytes Controls Diabetes in Pancreatectomized Pigs

Teru Okitsu1, Naoya Kobayashi1, Hee-Sook Jun2, Seungjin Shin2, Su-Jin Kim2, Jaeseok Han2, Hyokjoon Kwon2, Masakiyo Sakaguchi3, Toshinori Totsugawa1, Michinori Kohara4, Karen A. Westerman5, Noriaki Tanaka1, Philippe Leboulch5,6,7, and Ji-Won Yoon2

1 Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
2 Laboratory of Viral and Immunopathogenesis of Diabetes, Julia McFarlane Diabetes Research Centre, Faculty of Medicine, The University of Calgary, Calgary, Alberta, Canada
3 Department of Cell Biology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
4 Department of Microbiology and Cell Biology, The Tokyo Metropolitan Institute of Medical Science, Honkomagome, Bukyo-ku, Japan
5 Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts
6 Genetix Pharmaceuticals, Cambridge, Massachusetts
6 Department of Medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts

Type 1 diabetes results from the destruction of insulin-producing pancreatic ß-cells by a ß-cell–specific autoimmune process. Although converting other cell types into insulin-producing cells may compensate for the loss of the ß-cell mass while evading ß-cell–specific T-cell responses, proof-of-principle of this approach in large animal models is lacking. This investigation was initiated to determine whether an insulin-producing human hepatocyte line can control diabetes when transplanted into totally pancreatectomized diabetic pigs. We established a reversibly immortalized human hepatocyte line, YOCK-13, by transferring a human telomerase reverse transcriptase cDNA and a drug-inducible Cre recombinase cassette, followed by cDNA for a modified insulin under the control of the L-type pyruvate kinase (L-PK) promoter. YOCK-13 cells produced small amounts of modified insulin and no detectable endogenous L-PK at low glucose concentrations, whereas they produced large amounts of both modified insulin and L-PK in response to high glucose concentrations. Xenotransplantation of YOCK-13 cells via the portal vein into immunosuppressed, totally pancreatectomized pigs decreased hyperglycemia and prolonged survival without adverse effects such as portal thrombosis, liver necrosis, pulmonary embolism, and tumor development. We suggest that this reversibly immortalized, insulin-secreting human hepatocyte line may overcome the shortage of donor pancreata for islet transplantation into patients with type 1 diabetes.

Address correspondence and reprint requests to Dr. Ji-Won Yoon, Faculty of Medicine, The University of Calgary, Calgary, Alberta T2N 4N1, Canada. E-mail: yoon{at}ucalgary.ca. Dr. Naoya Kobayashi, E-mail: immortal{at}md.okayama-u.ac.jp or Dr. Philippe Leboulch, E-mail: pleboulch{at}mit.edu


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2004 by the American Diabetes Association.