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Differential Expression Patterns of Gangliosides in the Liver and Heart of NIH-miniature Pigs

NIH-미니돼지의 간과 심장에서 갱글리오시드의 서로 다른 발현 패턴

  • Ryu, Jae-Sung (Department of Biological Science, College of Natural Sciences, Wonkwang University) ;
  • Chang, Kyu-Tae (National Primate Research Center (NPRC), Korea Research Institute of Bioscience & Biotechnology (KRIBB)) ;
  • Kim, Ji-Su (National Primate Research Center (NPRC), Korea Research Institute of Bioscience & Biotechnology (KRIBB)) ;
  • Kwak, Dong-Hoon (Department of Biological Science, College of Natural Sciences, Wonkwang University) ;
  • Lee, Young-Choon (Department of Biotechnology, College of Natural Resources and Life Sciences, Dong-A University) ;
  • Oh, Keon-Bong (Animal Biotechnology Division, National Institute of Animal Science, Rural Development Administration) ;
  • Choo, Young-Kug (Department of Biological Science, College of Natural Sciences, Wonkwang University)
  • 유재성 (원광대학교 자연과학대학 생명과학부) ;
  • 장규태 (한국생명공학연구원 국가영장류센터) ;
  • 김지수 (한국생명공학연구원 국가영장류센터) ;
  • 곽동훈 (원광대학교 자연과학대학 생명과학부) ;
  • 이영춘 (동아대학교 생명자원과학대학 생명공학과) ;
  • 오건봉 (농촌진흥청 국립축산과학원 축산생명환경부 동물바이오공학과) ;
  • 추영국 (원광대학교 자연과학대학 생명과학부)
  • Received : 2009.12.02
  • Accepted : 2010.02.22
  • Published : 2010.04.30

Abstract

Gangliosides are a major component of the plasma membrane of mammalian cells, which are directly involved in a variety of immunological events, including cell-to cell or cell-to-protein interactions. In this study, we investigated whether gangliosides, sialic acid-containing glycosphingolipids, are related to rejection during the xenotransplantation of NIH-miniature pig livers and hearts to humans. Both high performance thin-layer chromatography and immunohistochemistry analyses revealed that the expression of gangliosides in the liver tissue of NIH-miniature pigs was higher than that in the heart. Gangliosides GD3, GD1a, GD1b, GT1b and GQ1b were observed in both the liver and heart, whereas GQ1b was detected only in the liver, indicating that the ganglioside expression profiles are tissue specific. Moreover, other ganglio-series gangliosides, including GM3, were not detected in the livers and hearts of NIH-miniature pigs. Taken together, these results suggest that gangliosides may play important roles in immune responses in clinical xenotransplants of pig livers and hearts.

갱글리오시드는 포유동물 세포막의 중요한 구성요소로서 세포와 세포 혹은 세포와 단백질간의 상호작용을 포함한 다양한 면역학적 역할을 수행하고 있다. 이 연구는 NIH-미니돼지의 간과 심장을 인간에게 이식할려고 할 때 예측되어지는 거부 반응과 관련된 구성성분들 중 시알산을 함유하고 있는 스핑고당지질인 갱글리오시드에 대해 조사하였다. 얇은막크로마토그래피와 면역조직화학적분석을 실시한 결과 NIH-미니돼지의 간은 갱글리오시드의 발현이 심장보다 높게 나타났다. 갱글리오시드 GD3, GD1a, GD1b, GT1b는 간과 심장의 두 기관에서 발견되었다. 그러나 GQ1b는 간에서만 발견되었고 심장에서는 검출되지 않았다. 이러한 결과는 갱글리오시드의 발현양상은 간과 심장에서 조직특이적이라는 것을 의미한다. 한편, GM3를 포함한 다른 갱글리오 시리즈인 갱글리오시드들은 NIH-미니돼지의 간과 심장에서 검출되어지지 않았다. 이와 같은 연구결과로부터 갱글리오시드는 미니돼지의 장기중 특히, 간과 심장의 이종장기이식과 관련된 면역거부반응에서 어떤 역할을 수행하고 있다고 여겨진다.

Keywords

References

  1. Bergelson, L. D., E. V. Dyatlovitskaya, T. E. Klyuchareva, E. V. Kryukova, A. F. Lemenovskaya, V. A. Matveeva, and E. V. Sinitsyna. 1989. The role of glycosphingolipids in natural immunity. Gangliosides modulate the cytotoxicity of natural killer cells. Eur. J. Immunol. 19, 1979-1983. https://doi.org/10.1002/eji.1830191102
  2. Bouhours, D., J. Liaigre, J. Naulet, D. Maume, and J. F. Bouhours. 1997. A novel glycosphingolipid expressed in pig kidney: Gal alpha 1-3Lewis(x) hexaglycosylceramide. Glycoconj. J. 14, 29-38. https://doi.org/10.1023/A:1018504813642
  3. Diswall, M., J. Angstrom, H. J. Schuurman, F. J. Dor, L. Rydberg, and M. E. Breimer. 2007. Studies on glycolipid antigens in small intestine and pancreas from alpha1,3-galactosyltransferase knockout miniature swine. Transplantation84, 1348-1356. https://doi.org/10.1097/01.tp.0000287599.46165.15
  4. Fredman, P., G. W. Klinghardt, O. Nilsson, and L. Svennerholm. 1982. Lipid accumulation in liver, spleen, lungs and kidneys of miniature-pigs after chloroquine treatment. Biochem. J. 201, 581-588.
  5. Grayson, G. and S. Ladisch. 1992. Immunosuppression by human gangliosides. II. Carbohydrate structure and inhibition of human NK activity. Cell Immunol. 139, 18-29. https://doi.org/10.1016/0008-8749(92)90096-8
  6. Hakomori, S. I. and Y. Igarashi. 1993. Gangliosides and glycosphingolipids as modulator of cell growth, adhesion, and transmembrane signling. Adv. Lipid. Res. 25, 147-162.
  7. Hallberg, E. C., J. Holgersson, and B. E. Samuelsson. 1998. Glycosphingolipid expression in pig aorta: identification of possible target antigens for human natural antibodies. Glycobiology 8, 637-649. https://doi.org/10.1093/glycob/8.7.637
  8. Hendricks, S. P., P. He, C. L. Stults, and B. A. Macher. 1990. Regulation of the expression of Gal alpha 1-3Gal beta 1-4GlcNAc glycosphingolipids in kidney. J. Biol. Chem. 265, 17621-17626.
  9. Jalali-Araghi, K. and B. A. Macher. 1994. Characterization of porcine kidney neutral glycosphingolipids: identification of a carbohydrate antigen recognized by human natural antibodies. Glycoconj. J. 11, 266-271. https://doi.org/10.1007/BF00731228
  10. Kim, Y. G., D. J. Harvey, Y. H. Yang, C. G. Park, and B. G. Kim. 2009. Mass spectrometric analysis of the glycosphingolipid-derived glycans from miniature pig endothelial cells and islets: identification of NeuGc epitope in pig islets. J. Mass Spectrom. 44, 1489-1499. https://doi.org/10.1002/jms.1638
  11. Kim, Y. G., G. C. Gil, K. S. Jang, S. Lee, H. I. Kim, J. S. Kim, J. Chung, C. G. Park, D. J. Harvey, and B. G. Kim. 2009. Qualitative and quantitative comparison of N-glycans between pig endothelial and islet cells by high-performance liquid chromatography and mass spectrometry-based strategy. J. Mass Spectrom. 44, 1087-1104. https://doi.org/10.1002/jms.1587
  12. Kim, Y. G., D. S. Shin, Y. H. Yang, G. C. Gil, C. G. Park, Y. Mimura, D. K. Cooper, P. M. Rudd, R. A. Dwek, Y. S. Lee, and B. G. Kim. 2008. High-throughput screening of glycan-binding proteins using miniature pig kidney N-glycan-immobilized beads. Chem. Biol. 15, 215-223. https://doi.org/10.1016/j.chembiol.2008.02.009
  13. Kolber-Simonds, D., L. Lai, S. R. Watt, M. Denaro, S. Arn, M. L. Augenstein, J. Betthauser, D. B. Carter, J. L. Greenstein, Y. Hao, G. S. Im, Z. Liu, G. D. Mell, C. N. Murphy, K. W. Park, A. Rieke, D. J. Ryan, D. H. Sachs, E. J. Forsberg, R. S. Prather, and R. J. Hawley. 2004. Production of alpha-1,3-galactosyltransferase null pigs by means of nuclear transfer with fibroblasts bearing loss of heterozygosity mutations. Proc. Natl. Acad. Sci. USA 101, 7335-7340. https://doi.org/10.1073/pnas.0307819101
  14. Ladisch, S., B. Gillard, C. Wong, and L. Ulsh. 1983. Shedding and immunoregulatory activity of YAC-1 lymphoma cell gangliosides. Cancer Res. 43, 3808-3813.
  15. Lai, L., D. Kolber-Simonds, K. W. Park, H. T. Cheong, J. L. Greenstein, G. S. Im, M. Samuel, A. Bonk, A. Rieke, B. N. Day, C. N. Murphy, and D. B. Carter. 2002. Production of alpha-1,3-galactosyltransferase knockout pigs by nucleartransfer cloning. Science 295, 1089-1092. https://doi.org/10.1126/science.1068228
  16. Lee, D. H., D. B. Koo, K. Ko, K. Ko, K., S. M. Kim, J. U. Jung, J. S. Ryu, J. W. Jin, H. J. Yang, S. I. Do, K. Y. Jung, and Y. K. Choo. 2007. Effects of daunorubicin on ganglioside expression and neuronal differentiation of mouse embryonic stem cells. Biochem. Biophys. Res. Commun. 362, 313-318. https://doi.org/10.1016/j.bbrc.2007.07.142
  17. Lu, P. and F. J. Sharom. 1996. Immunosuppression by YAC-1 lymphoma: role of shed gangliosides. Cell Immunol. 173, 22-32. https://doi.org/10.1006/cimm.1996.0248
  18. Magnusson, S., V. Strokan, L. Svensson, J. E., Mansson, L. Rydberg, and M. E. Breimer. 2005. Expression of carbohydrate xenoantigens on porcine peripheral nerve. Xenotransplantation 12, 49-58. https://doi.org/10.1111/j.1399-3089.2004.00192.x
  19. Paller, A. S., S. L. Arnsmeier, G. J. Fisher, and Q. C. Yu. 1995. Ganglioside GT1b induces keratinocyte differentiation without activating protein kinase C. Exp. Cell Res. 217, 118-124. https://doi.org/10.1006/excr.1995.1070
  20. Park, K. W., H. T. Cheong, L. X. Lai, G. S. Im, B. Kuhholzer, A. Bonk, M. Samuel, A. Rieke, B. N. Day, C. N. Murphy, B. D. Carter, and R. S. Prather. 2001. Production of nuclear transfer-derived swine that express the enhanced green fluorescent protein. Anim. Biotechnol. 12, 173-181. https://doi.org/10.1081/ABIO-100108344
  21. Phelps, C. J., C. Koike, T. D. Vaught, J. Boone, K. D. Wells, S. H. Chen, S. Ball, S. M. Specht, I. A. Polejaeva, J. A. Monahan, P. M. Jobst, S. B. Sharma, A. E. Lamborn, A. S. Garst, M. Moore, A. J. Demetris, W. A. Rudert, R. Bottino,S. Bertera, M. Trucco, T. E. Starzl, Y. Dai, and D. L. Ayares. 2003. Production of alpha 1,3-galactosyltransferase-deficient pigs. Science 299, 411-414.
  22. Prather, R. S., R. J. Hawley, D. B. Carter, L. Lai, and J. L. Greenstein. 2003. Transgenic swine for biomedicine and agriculture. Theriogenology 59, 115-123 https://doi.org/10.1016/S0093-691X(02)01263-3
  23. Rogers, C. S., D. A. Stoltz, D. K. Meyerholz, L. S. Ostedgaard, T. Rokhlina, P. J. Taft, M. P. Rogan, A. A. Pezzulo, P. H. Karp, O. A. Itani, A. C. Kabel, and C. L. Wohlford-Lenane. 2008. Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science 321, 1837-1841. https://doi.org/10.1126/science.1163600
  24. Rogers, C. S., Y. Hao, T. Rokhlina, M. Samuel, D. A. Stoltz, Y. Li, E. Petroff, D. W. Vermeer, A. C. Kabel, Z. Yan, L. Spate, and D. Wax. 2008. Production of CFTR-null and CFTR-DeltaF508 heterozygous pigs by adeno-associated virus-mediated gene targeting and somatic cell nuclear transfer. J. Clin. Invest. 118, 1571-1577. https://doi.org/10.1172/JCI34773
  25. Rydberg, L., J. Holgersson, B. E. Samuelsson, and M. E. Breimer. 1999. alpha-Gal epitopes in animal tissue glycoproteins and glycolipids. Subcell Biochem. 32, 107-125. https://doi.org/10.1007/978-1-4615-4771-6_5
  26. Sachs, D. H., G. Leight, J. Cone, S. Schwarz, L. Stuart, and S. Rosenberg. 1976. Transplantation in miniature swine, I: fixation of the major histocompatibility complex. Transplantation 22, 559-567. https://doi.org/10.1097/00007890-197612000-00004
  27. Sun, P., X. Q. Wang, K. Lopatka, S. Bangash, and A. S. Paller. 2002. Ganglioside loss promotes survival primarily by activating integrin-linked kinase/Akt without phosphoinositide 3-OH kinase signaling. J. Invest. Dermatol. 119, 107-117. https://doi.org/10.1046/j.1523-1747.2002.01802.x
  28. Sung, C. C., E. A. O'Toole, B. J. Lannutti, J. Hunt, M. O'Gorman, D. T. Woodley, and A. S. Paller. 1998. Integrin alpha 5 beta 1 expression is required for inhibition of keratinocyte migration by ganglioside GT1b. Exp. Cell Res. 239,311-319. https://doi.org/10.1006/excr.1997.3897
  29. Varki, A., R. Cummings, J. Esko, H. Freeze, G. Hart, and J. Marth. 1999. Essentials of Glycobiology. Cold Spring Harber Laboratory Press, New York.
  30. Wang, X., Z. Rahman, P. Sun, E. Meuillet, D. George, E. G. Bremer, A. Al-Qamari, and A. S. Paller, 2001. Ganglioside modulates ligand binding to the epidermal growth factor receptor. J. Invest. Dermatol. 116, 69-76. https://doi.org/10.1046/j.1523-1747.2001.00222.x
  31. Wang, X., P. Sun, A. Al-Qamari, T. Tai, I. Kawashima, and A. S. Paller. 2001. Carbohydrate-carbohydrate binding of ganglioside to integrin alpha(5) modulates alpha(5)beta(1) function. J. Biol. Chem. 276, 8436-8444. https://doi.org/10.1074/jbc.M006097200
  32. Wang, X. Q., P. Sun, M. O'Gorman, T. Tai, and A. S. Paller. 2001. Epidermal growth factor receptor glycosylation is required for ganglioside GM3 binding and GM3-mediated suppression [correction of suppresion] of activation. Glycobiology 11, 515-522. https://doi.org/10.1093/glycob/11.7.515
  33. Wang, X. Q., P. Sun, and A. S. Paller. 2001, Inhibition of integrin-linked kinase/protein kinase B/Akt signaling: mechanism for ganglioside-induced apoptosis. J. Biol. Chem. 276, 44504-44511. https://doi.org/10.1074/jbc.M106563200
  34. Wang, X. Q., P. Sun, and A. S. Paller. 2002. Ganglioside modulation regulates epithelial cell adhesion and spreading via ganglioside-specific effects on signaling. J. Biol. Chem. 277, 40410-40419. https://doi.org/10.1074/jbc.M207117200
  35. Wang, X. Q., P. Sun, and A. S. Paller. 2002. Ganglioside induces caveolin-1 redistribution and interaction with the epidermal growth factor receptor. J. Biol. Chem. 277, 47028-47034. https://doi.org/10.1074/jbc.M208257200

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