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

Teru Okitsu, Naoya Kobayashi, Hee Sook Jun, Seungjin Shin, Su Jin Kim, Jaeseok Han, Hyokjoon Kwon, Masakiyo Sakaguchi, Toshinori Totsugawa, Michinori Kohara, Karen A. Westerman, Noriaki Tanaka, Philippe Leboulch, Ji Won Yoon

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Type 1 diabetes results from the destruction of insulin-producing pancreatic β-cells by a β-cell-specific autoimmune process. Although converting other cell types into insulin-producing cells may compensate for the loss of the β-cell mass while evading β-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.

Original languageEnglish
Pages (from-to)105-112
Number of pages8
JournalDiabetes
Volume53
Issue number1
DOIs
Publication statusPublished - Jan 2004

Fingerprint

Hepatocytes
Swine
Transplantation
Insulin
Pyruvate Kinase
Type 1 Diabetes Mellitus
Complementary DNA
Glucose
Pancreas Transplantation
Islets of Langerhans Transplantation
Heterologous Transplantation
Portal Vein
Pulmonary Embolism
Hyperglycemia
Thrombosis
Necrosis
Animal Models
Tissue Donors
T-Lymphocytes
Survival

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Okitsu, T., Kobayashi, N., Jun, H. S., Shin, S., Kim, S. J., Han, J., ... Yoon, J. W. (2004). Transplantation of Reversibly Immortalized Insulin-Secreting Human Hepatocytes Controls Diabetes in Pancreatectomized Pigs. Diabetes, 53(1), 105-112. https://doi.org/10.2337/diabetes.53.1.105

Transplantation of Reversibly Immortalized Insulin-Secreting Human Hepatocytes Controls Diabetes in Pancreatectomized Pigs. / Okitsu, Teru; Kobayashi, Naoya; Jun, Hee Sook; Shin, Seungjin; Kim, Su Jin; Han, Jaeseok; Kwon, Hyokjoon; Sakaguchi, Masakiyo; Totsugawa, Toshinori; Kohara, Michinori; Westerman, Karen A.; Tanaka, Noriaki; Leboulch, Philippe; Yoon, Ji Won.

In: Diabetes, Vol. 53, No. 1, 01.2004, p. 105-112.

Research output: Contribution to journalArticle

Okitsu, T, Kobayashi, N, Jun, HS, Shin, S, Kim, SJ, Han, J, Kwon, H, Sakaguchi, M, Totsugawa, T, Kohara, M, Westerman, KA, Tanaka, N, Leboulch, P & Yoon, JW 2004, 'Transplantation of Reversibly Immortalized Insulin-Secreting Human Hepatocytes Controls Diabetes in Pancreatectomized Pigs', Diabetes, vol. 53, no. 1, pp. 105-112. https://doi.org/10.2337/diabetes.53.1.105
Okitsu, Teru ; Kobayashi, Naoya ; Jun, Hee Sook ; Shin, Seungjin ; Kim, Su Jin ; Han, Jaeseok ; Kwon, Hyokjoon ; Sakaguchi, Masakiyo ; Totsugawa, Toshinori ; Kohara, Michinori ; Westerman, Karen A. ; Tanaka, Noriaki ; Leboulch, Philippe ; Yoon, Ji Won. / Transplantation of Reversibly Immortalized Insulin-Secreting Human Hepatocytes Controls Diabetes in Pancreatectomized Pigs. In: Diabetes. 2004 ; Vol. 53, No. 1. pp. 105-112.
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