Cell Biochemistry and Biophysics

, Volume 48, Issue 2–3, pp 191–199 | Cite as

Improving islet transplantation by gene delivery of hepatocyte growth factor (HGF) and its downstream target, protein kinase B (PKB)/Akt

  • Nathalie Fiaschi-Taesch
  • Andrew F. Stewart
  • Adolfo Garcia-OcañaEmail author
Original Paper


Clinical studies have demonstrated that islet transplantation may be a useful procedure to replace beta cell function in patients with Type 1 diabetes. Islet transplantation faces many challenges, including complications associated with the procedure itself, the toxicity of immunosuppression regimens, and to the loss of islet function and insulin-independence with time. Despite the current successes, and residual challenges, these studies have pointed out an enormous scarcity of islet tissue that precludes the use of islet transplantation in a clinical setting on a wider scale. To address this problem, many research groups are trying to identify different islet growth factors and intracellular molecules capable of improving islet graft survival and function, therefore reducing the number of islets needed for successful transplantation. Among these growth factors, hepatocyte growth factor (HGF), a factor known to improve transplantation of a variety of organs/cells, has shown promising results in increasing islet graft survival and reducing the number of islets needed for successful transplantation in four different rodent models of islet transplantation. Protein kinase B (PKB)/Akt, a pro-survival intracellular signaling molecule is known to be activated in the beta cell by several different growth factors, including HGF. PKB/Akt has also shown promising results for improving human islet graft survival and function in a minimal islet mass model of islet transplantation in diabetic SCID mice. Increasing our knowledge on how HGF, PKB/Akt and other emerging molecules work for improving islet transplantation may provide substrate for future therapeutic approaches aimed at increasing the number of patients in which beta cell function can be successfully replaced.


Diabetes Gene therapy Pancreatic beta cell Hepatocyte growth factor Islet transplantation Protein kinase B Akt 



This work was supported by National Institutes of Health grants DK068836 and DK067351 to A.G.-O. and DK55023 and DK R33066127 to AFS.


  1. 1.
    Becker, B. N., Odorico, J. S., Becker, Y. T., Groshek, M., Werwinski, C., Pirsch, J. D., & Sollinger, H.W. (2001). Simultaneous pancreas-kidney and pancreas transplantation. Journal of the American Society of Nephrology, 12, 2517–2527.PubMedGoogle Scholar
  2. 2.
    Gaglia, J. L., Shapiro, A. M., & Weir, G. C. (2005). Islet transplantation: Progress and challenge. Archives of Medical Research, 36, 273–280.PubMedCrossRefGoogle Scholar
  3. 3.
    Shapiro, A. M., Lakey, J. R, Ryan, E. A., Korbutt, G. S., Toth, E., Warnock, G. L., Kneteman, N. M., & Rajotte, R. V. (2000). Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. New England Journal of Medicine, 343, 230–238.PubMedCrossRefGoogle Scholar
  4. 4.
    Ryan, E. A., Lakey, J. R., Rajotte, R. V., Korbutt, G. S., Kin, T., Imes, S., Rabinovitch, A., Elliott, J. F., Bigam, D., Kneteman, N. M., Warnock, G. L., Larsen, I., & Shapiro, A. M. (2001). Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes, 50, 710–719.PubMedCrossRefGoogle Scholar
  5. 5.
    Ryan, E. A., Lakey, J. R., Paty, B. W., Imes, S., Korbutt, G. S., Kneteman, N. M., Bigam, D., Rajotte, R. V., & Shapiro, A. M. (2002). Successful islet transplantation: Continued insulin reserve provides long-term glycemic control. Diabetes, 51, 2148–2157.PubMedCrossRefGoogle Scholar
  6. 6.
    Ryan, E. A., Paty, B. W., Senior, P. A., Bigam, D., Alfadhli, E., Kneteman, N. M., Lakey, J. R., & Shapiro, A. M. (2005). Five-year follow-up after clinical islet transplantation. Diabetes, 54, 2060–2069.PubMedCrossRefGoogle Scholar
  7. 7.
    Bretzel, R. G., Hering, B. J., & Federlin, K. F. (1995). Islet cell transplantation in diabetes mellitus – from bench to bedside. Experimental and Clinical Endocrinology and Diabetes, 103, 143–159.PubMedCrossRefGoogle Scholar
  8. 8.
    Ricordi, C., Inverardi, L., Kenyon, N. S., Goss, J., Bertuzzi, F., & Alejandro, R. (2005). Requirements for success in clinical islet transplantation. Transplantation, 79, 1298–1300.PubMedCrossRefGoogle Scholar
  9. 9.
    Rother, K. I., & Harlan, D. M. (2004). Challenges facing islet transplantation for the treatment of type 1 diabetes mellitus. Journal of Clinical Investigation, 114, 877–883.PubMedCrossRefGoogle Scholar
  10. 10.
    Hering, B. J., Kandaswamy, R., Ansite, J. D., Eckman, P. M., Nakano, M., Sawada, T., Matsumoto, I., Ihm, S. H., Zhang, H. J., Parkey, J., Hunter, D. W., & Sutherland, D. E. (2005). Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes. JAMA, 293, 830–835.PubMedCrossRefGoogle Scholar
  11. 11.
    Matsumoto, S., Okitsu, T., Iwanaga, Y., Noguchi, H., Nagata, H., Yonekawa, Y., Yamada, Y., Fukuda, K., Tsukiyama, K., Suzuki, H., Kawasaki, Y., Shimodaira, M., Matsuoka, K., Shibata, T., Kasai, Y., Maekawa, T., Shapiro, J., & Tanaka, K. (2005). Insulin independence after living-donor distal pancreatectomy and islet allotransplantation. Lancet, 365, 1642–1644.PubMedCrossRefGoogle Scholar
  12. 12.
    Garcia-Ocana, A., Vasavada, R. C., Takane, K. K., Cebrian, A., Lopez-Talavera, J. C., & Stewart, A. F. (2001). Using beta-cell growth factors to enhance human pancreatic Islet transplantation. Journal of Clinical Endocrinology and Metabolism, 86, 984–988.PubMedCrossRefGoogle Scholar
  13. 13.
    Hayek, A., & Beattie, G. M. (2002). Alternatives to unmodified human islets for transplantation. Current Diabetes Reports, 2, 371–376.PubMedCrossRefGoogle Scholar
  14. 14.
    Stuart, K. A., Riordan, S. M., Lidder, S., Crostella, L., Williams, R., & Skouteris, G. G. (2000). Hepatocyte growth factor/scatter factor-induced intracellular signalling. International Journal of Experimental Pathology, 81, 17–30.PubMedCrossRefGoogle Scholar
  15. 15.
    Furge, K. A., Zhang, Y. W., & Vande Woude, G. F. (2000). Met receptor tyrosine kinase: Enhanced signaling through adapter proteins. Oncogene, 19, 5582–5589.PubMedCrossRefGoogle Scholar
  16. 16.
    Kataoka, H., Miyata, S., Uchinokura, S., & Itoh, H. (2003). Roles of hepatocyte growth factor (HGF) activator and HGF activator inhibitor in the pericellular activation of HGF/scatter factor. Cancer Metastasis Reviews, 22, 223–236.PubMedCrossRefGoogle Scholar
  17. 17.
    Isaka, Y., Yamada, K., Takabatake, Y., Mizui, M., Miura-Tsujie, M., Ichimaru, N., Yazawa, K., Utsugi, R., Okuyama, A., Hori, M., Imai, E., & Takahara, S. (2005). Electroporation-mediated HGF gene transfection protected the kidney against graft injury. Gene Therapy, 12, 815–820.PubMedCrossRefGoogle Scholar
  18. 18.
    Tambara, K., Premaratne, G. U., Sakaguchi, G., Kanemitsu, N., Lin, X., Nakajima, H., Sakakibara, Y., Kimura, Y., Yamamoto, M., Tabata, Y., Ikeda, T., & Komeda, M. (2005). Administration of control-released hepatocyte growth factor enhances the efficacy of skeletal myoblast transplantation in rat infarcted hearts by greatly increasing both quantity and quality of the graft. Circulation, 112, 129–134.Google Scholar
  19. 19.
    Yamaura, K., Ito, K., Tsukioka, K., Wada, Y., Makiuchi, A., Sakaguchi, M., Akashima, T., Fujimori, M., Sawa, Y., Morishita, R., Matsumoto, K., Nakamura, T., Suzuki, J., Amano, J., & Isobe, M. (2004). Suppression of acute and chronic rejection by hepatocyte growth factor in a murine model of cardiac transplantation: Induction of tolerance and prevention of cardiac allograft vasculopathy. Circulation, 110, 1650–1657.PubMedCrossRefGoogle Scholar
  20. 20.
    Chen, Y., Kobayashi, N., Suzuki, S., Soto-Gutierrez, A., Rivas-Carrillo, J. D., Tanaka, K., Navarro-Alvarez, N., Fukazawa, T., Narushima, M., Miki, A., Okitsu, T., Amemiya, H., & Tanaka, N. (2005). Transplantation of human hepatocytes cultured with deleted variant of hepatocyte growth factor prolongs the survival of mice with acute liver failure. Transplantation, 79, 1378–1385.PubMedCrossRefGoogle Scholar
  21. 21.
    Tashiro, H., Fudaba, Y., Itoh, H., Mizunuma, K., Ohdan, H., Itamoto, T., & Asahara, T. (2003). Hepatocyte growth factor prevents chronic allograft dysfunction in liver-transplanted rats. Transplantation, 76, 761–765.PubMedCrossRefGoogle Scholar
  22. 22.
    Imado, T., Iwasaki, T., Kataoka, Y., Kuroiwa, T., Hara, H., Fujimoto, J., & Sano, H. (2004). Hepatocyte growth factor preserves graft-versus-leukemia effect and T-cell reconstitution after marrow transplantation. Blood, 104, 1542–1549.PubMedCrossRefGoogle Scholar
  23. 23.
    Fiaschi-Taesch, N. M., Santos, S., Reddy, V., Van Why, S., Phillbrick, W. F., Ortega, A., Esbrit, P., Orloff, J. J., & Garcia-Ocaña, A. (2004). Prevention of acute ischemic renal failure by targeted delivery of growth factors to the proximal tubule in transgenic mice: The efficacy of HGF and PTHrP. Journal of the American Society of Nephrology, 15, 112–125.PubMedCrossRefGoogle Scholar
  24. 24.
    Igawa, T., Matsumoto, K., Kanda, S., Saito, Y., & Nakamura, T. (1993). Hepatocyte growth factor may function as a renotropic factor for regeneration in rats with acute renal injury. American Journal of Physiology, 265, F61–F69.PubMedGoogle Scholar
  25. 25.
    Davalli, A. M., Scaglia, L., Zangen, D. H., Hollister, J., Bonner-Weir, S., & Weir, G. C. (1996). Vulnerability of islets in the immediate posttransplantation period. Dynamic changes in structure and function. Diabetes, 45, 1161–1167.PubMedCrossRefGoogle Scholar
  26. 26.
    Calvo, E. L., Boucher, C., Pelletier, G., & Morisset, J. (1996). Ontogeny of hepatocyte growth factor and c-met/hgf receptor in rat pancreas. Biochemical and Biophysical Research Communication, 229, 257–263.CrossRefGoogle Scholar
  27. 27.
    Otonkoski, T., Cirulli, V., Beattie, M., Mally, M. I., Soto, G., Rubin, J. S., & Hayek, A. (1996). A role for hepatocyte growth factor/scatter factor in fetal mesenchyme-induced pancreatic beta-cell growth. Endocrinology, 137, 3131–3139.PubMedCrossRefGoogle Scholar
  28. 28.
    Beattie, G. M., Rubin J. S., Mally, M. I., Otonkoski, T., & Hayek, A. (1996). Regulation of proliferation and differentiation of human fetal pancreatic islet cells by extracellular matrix, hepatocyte growth factor, and cell-cell contact. Diabetes, 45, 1223–1228.PubMedCrossRefGoogle Scholar
  29. 29.
    Hayek, A., Beattie, G. M., Cirulli, V., Lopez, A. D., Ricordi, C., & Rubin, J. S. (1995). Growth factor/matrix-induced proliferation of human adult beta-cells. Diabetes, 44, 1458–1460.PubMedCrossRefGoogle Scholar
  30. 30.
    Otonkoski, T., Beattie, G. M., Rubin, J. S., Lopez, A. D., Baird, A., & Hayek, A. (1994). Hepatocyte growth factor/scatter factor has insulinotropic activity in human fetal pancreatic cells. Diabetes, 43, 947–953.PubMedCrossRefGoogle Scholar
  31. 31.
    Beattie, G. M., Montgomery, A. M., Lopez, A. D., Hao, E., Perez, B., Just, M. L., Lakey, J. R., Hart, M. E., & Hayek, A. (2002). A novel approach to increase human islet cell mass while preserving beta-cell function. Diabetes, 51, 3435–3439.PubMedCrossRefGoogle Scholar
  32. 32.
    Garcia-Ocana, A., Takane, K. K., Syed, M. A., Philbrick, W. M., Vasavada, R. C., & Stewart, A. F. (2000). Hepatocyte growth factor overexpression in the islet of transgenic mice increases beta cell proliferation, enhances islet mass, and induces mild hypoglycemia. Journal of Biological Chemistry, 275, 1226–1232.PubMedCrossRefGoogle Scholar
  33. 33.
    Garcia-Ocana, A., Vasavada, R. C., Cebrian, A., Reddy, V., Takane, K. K., Lopez-Talavera, J. C., & Stewart, A. F. (2001). Transgenic overexpression of hepatocyte growth factor in the beta-cell markedly improves islet function and islet transplant outcomes in mice. Diabetes, 50, 2752–2762.PubMedCrossRefGoogle Scholar
  34. 34.
    Garcia-Ocana, A., Takane, K. K., Reddy, V. T., Lopez-Talavera, J. -C., Vasavada, R. C., & Stewart, A. F. (2003). Adenovirus-mediated hepatocyte growth factor expression in mouse islets improves pancreatic islet transplant performance and reduces beta cell death. Journal of Biological Chemistry, 278, 343–351.PubMedCrossRefGoogle Scholar
  35. 35.
    Gahr, S., Merger, M., Bollheimer, L. C., Hammerschmied, C. G., Scholmerich, J., & Hugl, S. R. (2002). Hepatocyte growth factor stimulates proliferation of pancreatic beta-cells particularly in the presence of subphysiological glucose concentrations. Journal of Molecular Endocrinology, 28, 99–110.PubMedCrossRefGoogle Scholar
  36. 36.
    Mashima, H., Shibata, H., Mine, T., & Kojima, I. (1996). Formation of insulin-producing cells from pancreatic acinar AR42J cells by hepatocyte growth factor. Endocrinology, 137, 3969–3976.PubMedCrossRefGoogle Scholar
  37. 37.
    Wang, R., Yashpal, N., Bacchus, F., & Li, J. (2004). Hepatocyte growth factor regulates proliferation and differentiation of epithelial monolayers derived from islets of postnatal rat pancreas. Journal of Endocrinology, 183, 163–171.PubMedCrossRefGoogle Scholar
  38. 38.
    Kato, Y., Yu, D., & Schwartz, M. Z. (1998). Hepatocyte growth factor up-regulates SGLT1 and GLUT5 gene expression after massive small bowel resection. Journal of Pediatric Surgery, 33, 13–15.PubMedCrossRefGoogle Scholar
  39. 39.
    Nakano, M., Yasunami, Y., Maki, T., Kodama, S., Ikehara, Y., Nakamura, T., Tanaka, M., & Ikeda, S. (2000). Hepatocyte growth factor is essential for amelioration of hyperglycemia in streptozotocin-induced diabetic mice receiving a marginal mass of intrahepatic islet grafts. Transplantation, 69, 214–221.PubMedCrossRefGoogle Scholar
  40. 40.
    Zioncheck, T. F., Richardson, L., Liu, J., Chang, L., King, K. L., Bennett, G. L., Fugedi, P., Chamow, S. M., Schwall, R. H., & Stack, R. J. (1995). Sulfated oligosaccharides promote hepatocyte growth factor association and govern its mitogenic activity. Journal of Biological Chemistry, 270, 16871–16878.PubMedCrossRefGoogle Scholar
  41. 41.
    Takayama, H., LaRochelle, W. J., Sharp, R., Otsuka, T., Kriebel, P., Anver, M., Aaronson, S. A., Merlino, G. (1997). Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor. Proceedings of the National Academy of Sciences of the United States of America, 94, 701–706.PubMedCrossRefGoogle Scholar
  42. 42.
    Lopez-Talavera, J. C., Garcia-Ocana, A., Sipula, I., Takane, K. K., Cozar-Castellano, I., & Stewart, A. F. (2004). Hepatocyte growth factor gene therapy for pancreatic islets in diabetes: Reducing the minimal islet transplant mass required in a glucocorticoid-free rat model of allogeneic portal vein islet transplantation. Endocrinology, 145, 467–474.PubMedCrossRefGoogle Scholar
  43. 43.
    Accili, D. (2001). A kinase in the life of the beta cell. Journal of Clinical Investigation, 108, 1575–1576.PubMedCrossRefGoogle Scholar
  44. 44.
    Brazil, D. P., & Hemmings, B. A. (2001). Ten years of protein kinase B signaling: a hard Akt to follow. Trends in Biochemical Sciences, 26, 657–664.PubMedCrossRefGoogle Scholar
  45. 45.
    Trumper, A., Trumper, K., & Horsch, D. (2002). Mechanisms of mitogenic and antiapoptotic signaling by glucose-dependent insulinotropic polypeptide in beta (INS-1)-cells. Journal of Endocrinology, 174, 233–246.PubMedCrossRefGoogle Scholar
  46. 46.
    Srinivasan, S., Bernal-Mizrachi, E., Ohsugi, M., & Permutt, M. A. (2002). Glucose promotes pancreatic islet beta cell survival through a PI 3-kinase/Akt signaling pathway. American Journal of Physiology Endocrinology and Metabolism, 283, E784–E793.PubMedGoogle Scholar
  47. 47.
    Brubaker, P. L., & Drucker, D. J. (2004). Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut and central nervous system. Endocrinology, 14, 2653–2659.CrossRefGoogle Scholar
  48. 48.
    Dickson, L. M., Lingohr, M. K., McCuaig, J., Hugl, S. R., Snow, L., Kahn, B. B., Myers, M. G. Jr., & Rhodes, C. J. (2001). Differential activation of protein kinase B and p70(S6)K by glucose and insulin-like growth factor 1 in pancreatic beta-cells (INS-1). Journal of Biological Chemistry, 276, 21110–21120.PubMedCrossRefGoogle Scholar
  49. 49.
    Holst, L. S., Mulder, H., Manganiello, V., Sundler, F., Ahren, B., Holm, C., & Degerman, E. (1998). Protein kinase B is expressed in pancreatic beta cells and activated upon stimulation with insulin-like growth factor I. Biochemical and Biophysical Research Communication, 250, 181–186.CrossRefGoogle Scholar
  50. 50.
    Aikin, R., Maysinger, D., & Rosenberg, L. (2004). Cross-talk between phosphatidylinositiol 3-kinase/Akt and c-Jun NH2-terminal kinase mediates survival of isolated human islets. Endocrinology, 145, 4522–4531.PubMedCrossRefGoogle Scholar
  51. 51.
    Tuttle, R. L., Gill, N. S., Pugh, W., Lee, J. P., Koeberlein, B., Furth, E. E., Polonsky, K. S., Naji, A., Birnbaum, M. J. (2001). Regulation of pancreatic beta-cell growth and survival by the serine/threonine protein kinase Akt1/PKBα. Nature Medicine, 7, 1133–1137.PubMedCrossRefGoogle Scholar
  52. 52.
    Bernal-Mizrachi, E., Wen, W., Stahlhut, S., Welling, C. M., & Permutt M. A. (2001). Islet beta cell expression of constitutively active Akt1/PKB alpha induces striking hypertrophy, hyperplasia, and hyperinsulinemia. Journal of Clinical Investigation, 108, 1631–1638.PubMedCrossRefGoogle Scholar
  53. 53.
    Wrede, C. E., Dickson, L. M., Lingohr, M. K., Briaud, I., & Rhodes, C. J. (2002). Protein kinase B/Akt prevents fatty acid-induced apoptosis in pancreatic beta-cells (INS-1). Journal of Biological Chemistry, 277, 49676–49684.PubMedCrossRefGoogle Scholar
  54. 54.
    Mangi, A. A., Noiseux, N., Kong, D., He, H., Rezvani, M., Ingwall, J. S., & Dzau, V. J. (2003). Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nature Medicine, 9, 1195–1201.PubMedCrossRefGoogle Scholar
  55. 55.
    Contreras, J. L., Smyth, C. A., Bilbao, G., Young, C. J., Thompson, J. A., & Eckhoff, D. E. (2002). Simvastatin induces activation of the serine-threonine protein kinase Akt and increases survival of isolated human pancreatic islets. Transplantation, 74, 1063–1069.PubMedCrossRefGoogle Scholar
  56. 56.
    Rao, P., Roccisana, J., Takane, K. K., Bottino, R., Zhao, A., Trucco, M., & Garcia-Ocana, A. (2005). Gene transfer of constitutively active Akt markedly improves human islet transplant outcomes in diabetic severe combined immunodeficient mice. Diabetes, 54, 1664–1675.PubMedCrossRefGoogle Scholar
  57. 57.
    Plesner, A., Liston, P., Tan, R., Korneluk, R. G., & Verchere, C. B. (2005). The x-linked inhibitor of apoptosis protein enhances survival of murine islet allografts. Diabetes, 54, 2533–2540.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Nathalie Fiaschi-Taesch
    • 1
  • Andrew F. Stewart
    • 1
  • Adolfo Garcia-Ocaña
    • 1
    Email author
  1. 1.Division of EndocrinologyUniversity of PittsburghPittsburghUSA

Personalised recommendations