TY - JOUR
T1 - Transplantation of Reversibly Immortalized Insulin-Secreting Human Hepatocytes Controls Diabetes in Pancreatectomized Pigs
AU - Okitsu, Teru
AU - Kobayashi, Naoya
AU - Jun, Hee Sook
AU - Shin, Seungjin
AU - Kim, Su Jin
AU - Han, Jaeseok
AU - Kwon, Hyokjoon
AU - Sakaguchi, Masakiyo
AU - Totsugawa, Toshinori
AU - Kohara, Michinori
AU - Westerman, Karen A.
AU - Tanaka, Noriaki
AU - Leboulch, Philippe
AU - Yoon, Ji Won
PY - 2004/1
Y1 - 2004/1
N2 - 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.
AB - 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.
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U2 - 10.2337/diabetes.53.1.105
DO - 10.2337/diabetes.53.1.105
M3 - Article
C2 - 14693704
AN - SCOPUS:9144237453
SN - 0012-1797
VL - 53
SP - 105
EP - 112
JO - Diabetes
JF - Diabetes
IS - 1
ER -