Prevention of Diabetes Using Adenoviral Mediated Hepatocyte Growth Factor Gene Transfer in Mice

  • Lee, Hye-Jeong (Departments of Pharmacology, Dong-A University College of Medicine) ;
  • Kim, Hyun-Jeong (Departments of Pharmacology, Dong-A University College of Medicine) ;
  • Roh, Mee-Sook (Departments of Pathology, Dong-A University College of Medicine) ;
  • Lee, Jae-Ik (Departments of Thoracic and Cardiovascular Surgery, Dong-A University College of Medicine) ;
  • Lee, Sung-Won (Departments of Internal Medicine, Dong-A University College of Medicine) ;
  • Jung, Dong-Sik (Departments of Internal Medicine, Dong-A University College of Medicine) ;
  • Kim, Duk-Kyu (Departments of Internal Medicine, Dong-A University College of Medicine) ;
  • Park, Mi-Kyoung (Departments of Internal Medicine, Dong-A University College of Medicine)
  • Published : 2003.10.21

Abstract

Type 1 diabetes is an organ-specific autoimmune disease caused by the cytotoxic T cells-mediated destruction of the insulin-producing beta cells in the Langerhans pancreatic islets. Hepatocyte growth factor (HGF) is a potent mitogen and a promoter of proliferation of insulin producing beta cells of pancreatic islets. To study the role of HGF via viral vector in the development of streptozotocin (STZ)-induced diabetes in mice, we have developed an adenoviral vector genetically engineered to carry the gene for human HGF (hHGF) and evaluate the change of blood glucose, insulin level, and insulin-secreting beta cells of pancreatic islets. We demonstrate that the treatment with hHGF gene prevented the development of STZ-induced diabetes and increased serum insulin level to above normal range. Furthermore, it preserved pancreatic beta cells from destruction. These in vivo results may support previous findings that HGF is insulinotropic agent for beta cells and HGF treatment renders the cells to be resistant to the development of diabetes from STZ administration. We suggest that an adenoviral mediated hHGF gene therapy is a good candidate for the prevention and treatment of type 1 diabetes.

Keywords

References

  1. Beattie GM, Cirulli V, Lopez AD, Hayek A. Ex vivo expansion of human pancreatic endocrine cells. J Clin Endocrinol Metab 82(6): 1852 1856, 1997 https://doi.org/10.1210/jc.82.6.1852
  2. Bonner-Weir S. Islet growth and development in the adult. J Mol Endocrinol 24(3): 297 302, 2000 https://doi.org/10.1677/jme.0.0240297
  3. Brelje TC, Scharp DW, Lacy PE, Ogren L, Talamantes F, Robertson M, Friesen HG, Sorenson RL. Effect of homologous placental lactogens, prolactins, and growth hormones on islet Beta-cell division and insulin secretion in rat, mouse, and human islets: implication for placental lactogen regulation of islet function during pregnancy. Endocrinology 132(2): 879 887, 1993 https://doi.org/10.1210/en.132.2.879
  4. Calvo EL, Boucher C, Pelletier G, Morisset J. Ontogeny of hepatocyte growth factor and c-met/hgf receptor in rat pancreas. Biochem Biophys Res Commun 4;229(1): 257 263, 1996
  5. Dai C, Li Y, Yang J, Liu Y. Hepatocyte growth factor preserves beta cell mass and mitigates hyperglycemia in streptozotocininduced diabetic mice. J Biol Chem 18;278(29): 27080 27087, 2003
  6. Eizirik DL, Sandler S, Ahnstrom G, Welsh M. Exposure of pancreatic islets to different alkylating agents decreases mitochondrial DNA content but only streptozotocin induces longlasting functional impairment of B-cells. Biochem Pharmacol 27; 42(12): 2275 2282, 1991
  7. Garcia-Ocana A, Takane KK, Reddy VT, Lopez-Talavera JC, Vasavada RC, Stewart AF. Adenovirus-mediated hepatocyte growth factor expression in mouse islets improves pancreatic islet transplant performance and reduces beta cell death. J Biol Chem 3;278(1): 343 351, 2003
  8. Garcia-Ocana A, Takane KK, Syed MA, Philbrick WM, Vasavada RC, Stewart AF. Hepatocyte growth factor overexpression in the islet of transgenic mice increases beta cell proliferation, enhances islet mass, and induces mild hypoglycemia. J Biol Chem 14;275(2): 1226 1232, 2000
  9. Garcia-Ocana A, Vasavada RC, Cebrian A, Reddy V, Takane KK, Lopez-Talavera JC, Stewart AF. Transgenic overexpression of hepatocyte growth factor in the beta-cell markedly improves islet function and islet transplant outcomes in mice. Diabetes 50(12): 2752 2762, 2001. https://doi.org/10.2337/diabetes.50.12.2752
  10. Garcia-Ocana A, Vasavada RC, Takane KK, Cebrian A, Lopez- Talavera JC, Stewart AF. Using beta-cell growth factors to enhance human pancreatic Islet transplantation. J Clin Endocrinol Metab 86(3): 984 988, 2001 https://doi.org/10.1210/jc.86.3.984
  11. Hayek A, Beattie GM, Cirulli V, Lopez AD, Ricordi C, Rubin JS. Growth factor/matrix-induced proliferation of human adult betacells. Diabetes 44(12): 1458 1460, 1995 https://doi.org/10.2337/diabetes.44.12.1458
  12. Hayek A, Beattie GM. Experimental transplantation of human fetal and adult pancreatic islets. J Clin Endocrinol Metab 82(8): 2471 2475, 1997 https://doi.org/10.1210/jc.82.8.2471
  13. Lefebvre VH, Otonkoski T, Ustinov J, Huotari MA, Pipeleers DG, Bouwens L. Culture of adult human islet preparations with hepatocyte growth factor and 804G matrix is mitogenic for duct cells but not for beta-cells. Diabetes 47(1): 134 137, 1998 https://doi.org/10.2337/diabetes.47.1.134
  14. Leibowitz G, Beattie GM, Kafri T, Cirulli V, Lopez AD, Hayek A, Levine F. Gene transfer to human pancreatic endocrine cells using viral vectors. Diabetes 48(4): 745 753, 1999 https://doi.org/10.2337/diabetes.48.4.745
  15. Liu KX, Kato Y, Narukawa M, Kim DC, Hanano M, Higuchi O, Nakamura T, Sugiyama Y. Importance of the liver in plasma clearance of hepatocyte growth factors in rats. Am J Physiol 263(5 Pt 1): G642 649, 1992 https://doi.org/10.1152/ajpcell.1992.263.3.C642
  16. Marx J. Unraveling the causes of diabetes. Science 26;296(5568): 686 689, 2002
  17. Mashima H, Shibata H, Mine T, Kojima I. Formation of insulinproducing cells from pancreatic acinar AR42J cells by hepatocyte growth factor. Endocrinology 137(9): 3969 3976, 1996
  18. Mathis D, Vence L, Benoist C. beta-Cell death during progression to diabetes. Nature 13;414(6865): 792 798, 2001
  19. Nakagami H, Morishita R, Yamamoto K, Taniyama Y, Aoki M, Yamasaki K, Matsumoto K, Nakamura T, Kaneda Y, Ogihara T. Hepatocyte growth factor prevents endothelial cell death through inhibition of bax translocation from cytosol to mitochondrial membrane. Diabetes 51(8): 2604 2611, 2002 https://doi.org/10.2337/diabetes.51.8.2604
  20. Nakano M, Yasunami Y, Maki T, Kodama S, Ikehara Y, Nakamura T, Tanaka M, Ikeda S. Hepatocyte growth factor is essential for amelioration of hyperglycemia in streptozotocin-induced diabetic mice receiving a marginal mass of intrahepatic islet grafts. Transplantation 27;69(2): 214 221, 2000
  21. Nielsen JH, Galsgaard ED, Moldrup A, Friedrichsen BN, Billestrup N, Hansen JA, Lee YC, Carlsson C. Regulation of beta-cell mass by hormones and growth factors. Diabetes 50 Suppl 1: S25-29, 2001 https://doi.org/10.2337/diabetes.50.2007.S25
  22. O'Brien BA, Cameron DC, Harmon BH, Allan DJ. Apotosis is the mode of beta-cello death responsible for the development of IDDM in the nonobese diabetic (NOD) mouse. Diabetes 46: 750 757, 1997. https://doi.org/10.2337/diabetes.46.5.750
  23. O'Brien BA, Cameron DC, Harmon BH, Allan DJ. Beta cell apoptosis is responsible for the development of IDDM in the multiple low0dose streptozotocin model. J Pathol 178: 176-181, 1996 https://doi.org/10.1002/(SICI)1096-9896(199602)178:2<176::AID-PATH433>3.0.CO;2-8
  24. Otonkoski T, Beattie GM, Rubin JS, Lopez AD, Baird A, Hayek A. Hepatocyte growth factor/scatter factor has insulinotropic activity in human fetal pancreatic cells. Diabetes 43(7): 947 953, 1994 https://doi.org/10.2337/diabetes.43.7.947
  25. Otonkoski T, Cirulli V, Beattie M, Mally MI, Soto G, Rubin JS, Hayek A. A role for hepatocyte growth factor/scatter factor in fetal mesenchyme-induced pancreatic beta-cell growth. Endocrinology 137(7): 3131 3139, 1996 https://doi.org/10.1210/en.137.7.3131
  26. Ryan EA, Lakey JR, Rajotte RV, Korbutt GS, Kin T, Imes S, Rabinovitch A, Elliott JF, Bigam D, Kneteman NM, Warnock GL, Larsen I, Shapiro AM. Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes 50(4): 710 719, 2001 https://doi.org/10.2337/diabetes.50.4.710
  27. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 27;343(4): 230 238, 2000
  28. Shapiro AM, Ryan EA, Lakey JR. Diabetes. Islet cell transplantation. Lancet 358 Suppl:S21, 2001 https://doi.org/10.1016/S0140-6736(01)07034-9
  29. Sonnenberg E, Meyer D, Weidner KM, Birchmeier C. Scatter factor/ hepatocyte growth factor and its receptor, the c-met tyrosine kinase, can mediate a signal exchange between mesenchyme and epithelia during mouse development. J Cell Biol 123(1): 223 235, 1993 https://doi.org/10.1083/jcb.123.1.223
  30. Stone D, David A, Bolognani F, Lowenstein PR, Castro MG. Viral vectors for gene delivery and gene therapy within the endocrine system. J Endocrinol 164(2): 103 118, 2000 https://doi.org/10.1677/joe.0.1640103
  31. Stratford-Perricaudet LD, Makeh I, Perricaudet M, Briand P. Widespread long-term gene transfer to mouse skeletal muscles and heart. J Clin Invest 90(2): 626 630, 1992 https://doi.org/10.1172/JCI115902
  32. Tyrberg B, Ustinov J, Otonkoski T, Andersson A. Stimulated endocrine cell proliferation and differentiation in transplanted human pancreatic islets: effects of the ob gene and compensatory growth of the implantation organ. Diabetes 50(2): 301 307, 2001 https://doi.org/10.2337/diabetes.50.2.301
  33. Vila MR, Nakamura T, Real FX. Hepatocyte growth factor is a potent mitogen for normal human pancreas cells in vitro. Diabetes 73(3): 409 418, 1995
  34. Zarnegar R, Michalopoulos GK. The many faces of hepatocyte growth factor: from hepatopoiesis to hematopoiesis. J Cell Biol 129(5): 1177 1180, 1995 https://doi.org/10.1083/jcb.129.5.1177