Improvement of Beta Cell Function in Intraportal Transplantation of Islet Cell Cluster Using Secretion Signal Peptide-Linked Exendin-4 Gene

Simmyung Yook; Jee-Heon Jeong; Youngro Byun

Macromolecular Research, Vol.22, No.8, 901-906, August, 2014

DOI10.1007/s13233-014-2120-z Export Citation

Improvement of Beta Cell Function in Intraportal Transplantation of Islet Cell Cluster Using Secretion Signal Peptide-Linked Exendin-4 Gene

Simmyung Yook¹, Jee-Heon Jeong², and Youngro Byun^{1, 3, †}

¹Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 151-742, Korea
²College of Pharmacy, Yeungnam University, Gyeongbuk, 712-749, Korea
³Departments of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 151-742, Korea

E-mail:

One of the major obstacles to successful intraportal islet transplantation is the early portal vein embolization elicited by the infused islets. Thus, reducing the size and the number of islets is an important process to alleviate the damage of liver after intraportal islet transplantation. In our previous studies, we developed a strategy to construct genetically modified islet cell clusters (ICCs) and demonstrated their superiority in maintaining better viability and functionality in vivo. In this study, signal-peptide linked exendin-4 transduced islet cell clusters (Sp-Ex-4 ICCs) were used to reverse diabetes after intraportal islet transplantation in hyperglycemic mouse model. Group of mice receiving 500 islet equivalent (IEQ) of unmodified ICCs failed to restore normoglycemia following transplantation. Although 500 IEQ of ICCs was insufficient to reverse hyperglycemia in diabetic mice, no significant acute liver damage or life-threatening liver embolization was observed. When 1000 IEQ ICCs were infused into the portal vein, all animals died within 24 h post-surgery. In order to clarify the effect of Sp-Ex-4 gene transduction in improving ICCs functionality, 500 IEQ of Sp-Ex-4 ICCs were infused into the portal vein of diabetic mice. Following transplantation, 75% of diabetic mice returned to normoglycemia and the survival fraction was 100%. In conclusion, intraportal transplantation of Sp-Ex-4 ICCs successfully reversed diabetes in hyperglycemic mice by reducing the mass required for the treatment. Therefore, intraportal transplantation of small islets (genetically engineered ICCs) can be proposed as a new strategy to overcome early graft embolization after intraportal transplantation.

Keywords:islet cell clusters (ICCs);exendin-4 (Sp-Ex-4);portal vein transplantation;gene transduction.

[References]

Robertson RP, N. Engl. J. Med., 350, 694 (2004)
Ryan EA, Lakey JR, Paty BW, Imes S, Korbutt GS, Kneteman NM, Bigam D, Rajotte RV, Shapiro AM, Diabetes, 51, 2148 (2002)
Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV, N. Engl. J. Med., 343, 230 (2000)
Yin D, Ding JW, Shen J, Ma L, Hara M, Chong AS, Am. J. Transplant., 6, 60 (2006)
Okaya T, Lentsch AB, J. Invest. Surg., 16, 141 (2003)
Hyon SH, Ceballos MC, Barbich M, Groppa R, Grosembacher L, Vieiro MM, Barcan L, Algranati S, Litwak L, Argibay PF, Cell Transplant., 13, 61 (2004)
Ozmen L, Ekdahl KN, Elgue G, Larsson R, Korsgren O, Nilsson B, Diabetes, 51, 1779 (2002)
Johansson H, Goto M, Dufrane D, Siegbahn A, Elgue G, Gianello P, Korsgren O, Nilsson B, Am. J. Transplant., 6, 305 (2006)
Jung YS, Jeong JH, Yook S, Im BH, Seo J, Hong SW, Park JB, Yang VC, Lee DY, Byun Y, Biomaterials, 33, 295 (2012)
Cabric S, Sanchez J, Lundgren T, Foss A, Felldin M, Kallen R, Salmela K, Tibell A, Tufveson G, Larsson R, Korsgren O, Nilsson B, Diabetes, 56, 2008 (2007)
Su Z, Xia J, Shao W, Cui Y, Tai S, Ekberg H, Corbascio M, Chen J, Qi Z, Scand. J. Immunol., 72, 504 (2010)
Yook S, Jeong JH, Jung YS, Hong SW, Im BH, Seo JW, Park JB, Lee M, Ahn CH, Lee H, Lee DY, Byun Y, Cell Transplant., 21, 1775 (2012)
Konstantinova I, Nikolova G, Ohara-Imaizumi M, Meda P, Kucera T, Zarbalis K, Wurst W, Nagamatsu S, Lammert E, Cell, 129, 359 (2007)
Jeong JH, Yook S, Jung Y, Im BH, Lee M, Ahn CH, Lee DY, Byun Y, J. Control. Release, 159, 368 (2012)
Lacy PE, Kostianovsky M, Diabetes, 16, 35 (1967)
Ricordi C, Pancreas, 6, 242 (1991)
Kim HI, Yu JE, Park CG, Kim SJ, J. Korean Medical. Sci., 25, 203 (2010)
Hara M, Yin D, Dizon RF, Shen J, Chong AS, Bindokas VP, Transplantation, 78, 615 (2004)
Rafael E, Ryan EA, Paty BW, Oberholzer J, Imes S, Senior P, McDonald C, Lakey JR, Shapiro AM, Transplantation, 76, 1280 (2003)
Barshes NR, Lee TC, Goodpastor SE, Balkrishnan R, Schock AP, Mote A, Brunicardi FC, Alejandro R, Ricordi C, Goss JA, J. Am. Coll. Surg., 200, 353 (2005)
van der Windt DJ, Bottino R, Casu A, Campanile N, Cooper DK, Xenotransplantation, 14, 288 (2007)
Walsh TJ, Eggleston JC, Cameron JL, Surgery, 91, 485 (1982)
Kojima A, Tsuyuzaki K, Ishizuka K, Shitijo K, Yamada T, Kaneko Y, Sato K, Nihon Naika Gakkai Zasshi, The Journal of the Japanese Society of Internal Medicine, 60, 638 (1971)
Farilla L, Hui H, Bertolotto C, Kang E, Bulotta A, Di Mario U, Perfetti R, Endocrinology, 143, 4397 (2002)
Ferdaoussi M, Abdelli S, Yang JY, Cornu M, Niederhauser G, Favre D, Widmann C, Regazzi R, Thorens B, Waeber G, Abderrahmani A, Diabetes, 57, 1205 (2008)

[1] Robertson RP, N. Engl. J. Med., 350, 694 (2004)

[2] Ryan EA, Lakey JR, Paty BW, Imes S, Korbutt GS, Kneteman NM, Bigam D, Rajotte RV, Shapiro AM, Diabetes, 51, 2148 (2002)

[3] Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV, N. Engl. J. Med., 343, 230 (2000)

[4] Yin D, Ding JW, Shen J, Ma L, Hara M, Chong AS, Am. J. Transplant., 6, 60 (2006)

[5] Okaya T, Lentsch AB, J. Invest. Surg., 16, 141 (2003)

[6] Hyon SH, Ceballos MC, Barbich M, Groppa R, Grosembacher L, Vieiro MM, Barcan L, Algranati S, Litwak L, Argibay PF, Cell Transplant., 13, 61 (2004)

[7] Ozmen L, Ekdahl KN, Elgue G, Larsson R, Korsgren O, Nilsson B, Diabetes, 51, 1779 (2002)

[8] Johansson H, Goto M, Dufrane D, Siegbahn A, Elgue G, Gianello P, Korsgren O, Nilsson B, Am. J. Transplant., 6, 305 (2006)

[9] Jung YS, Jeong JH, Yook S, Im BH, Seo J, Hong SW, Park JB, Yang VC, Lee DY, Byun Y, Biomaterials, 33, 295 (2012)

[10] Cabric S, Sanchez J, Lundgren T, Foss A, Felldin M, Kallen R, Salmela K, Tibell A, Tufveson G, Larsson R, Korsgren O, Nilsson B, Diabetes, 56, 2008 (2007)

[11] Su Z, Xia J, Shao W, Cui Y, Tai S, Ekberg H, Corbascio M, Chen J, Qi Z, Scand. J. Immunol., 72, 504 (2010)

[12] Yook S, Jeong JH, Jung YS, Hong SW, Im BH, Seo JW, Park JB, Lee M, Ahn CH, Lee H, Lee DY, Byun Y, Cell Transplant., 21, 1775 (2012)

[13] Konstantinova I, Nikolova G, Ohara-Imaizumi M, Meda P, Kucera T, Zarbalis K, Wurst W, Nagamatsu S, Lammert E, Cell, 129, 359 (2007)

[14] Jeong JH, Yook S, Jung Y, Im BH, Lee M, Ahn CH, Lee DY, Byun Y, J. Control. Release, 159, 368 (2012)

[15] Lacy PE, Kostianovsky M, Diabetes, 16, 35 (1967)

[16] Ricordi C, Pancreas, 6, 242 (1991)

[17] Kim HI, Yu JE, Park CG, Kim SJ, J. Korean Medical. Sci., 25, 203 (2010)

[18] Hara M, Yin D, Dizon RF, Shen J, Chong AS, Bindokas VP, Transplantation, 78, 615 (2004)

[19] Rafael E, Ryan EA, Paty BW, Oberholzer J, Imes S, Senior P, McDonald C, Lakey JR, Shapiro AM, Transplantation, 76, 1280 (2003)

[20] Barshes NR, Lee TC, Goodpastor SE, Balkrishnan R, Schock AP, Mote A, Brunicardi FC, Alejandro R, Ricordi C, Goss JA, J. Am. Coll. Surg., 200, 353 (2005)

[21] van der Windt DJ, Bottino R, Casu A, Campanile N, Cooper DK, Xenotransplantation, 14, 288 (2007)

[22] Walsh TJ, Eggleston JC, Cameron JL, Surgery, 91, 485 (1982)

[23] Kojima A, Tsuyuzaki K, Ishizuka K, Shitijo K, Yamada T, Kaneko Y, Sato K, Nihon Naika Gakkai Zasshi, The Journal of the Japanese Society of Internal Medicine, 60, 638 (1971)

[24] Farilla L, Hui H, Bertolotto C, Kang E, Bulotta A, Di Mario U, Perfetti R, Endocrinology, 143, 4397 (2002)

[25] Ferdaoussi M, Abdelli S, Yang JY, Cornu M, Niederhauser G, Favre D, Widmann C, Regazzi R, Thorens B, Waeber G, Abderrahmani A, Diabetes, 57, 1205 (2008)