BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Glucocorticoid treatment independently affects expansion and transdifferentiation of porcine neonatal pancreas cell clusters

  • Kim, Ji-Won (Department of Endocrinology and Metabolism, The Catholic University of Korea) ;
  • Sun, Cheng-Lin (Department of Endocrinology and Metabolism, The Catholic University of Korea) ;
  • Jeon, Sung-Yoon (Department of Endocrinology and Metabolism, The Catholic University of Korea) ;
  • You, Young-Hye (Department of Endocrinology and Metabolism, The Catholic University of Korea) ;
  • Shin, Ju-Young (Department of Endocrinology and Metabolism, The Catholic University of Korea) ;
  • Lee, Seung-Hwan (Department of Endocrinology and Metabolism, The Catholic University of Korea) ;
  • Cho, Jae-Hyoung (Department of Endocrinology and Metabolism, The Catholic University of Korea) ;
  • Park, Chung-Gyu (Department of Microbiology, Xenotransplantation Research Center, Cancer Research Institute, Seoul National University) ;
  • Yoon, Kun-Ho (Department of Endocrinology and Metabolism, The Catholic University of Korea)
  • Received : 2011.05.09
  • Accepted : 2011.08.26
  • Published : 2012.01.31
Download PDF
⟨ Previous Next ⟩

Abstract

The purpose of this study was to determine the effects of duration and timing of glucocorticoid treatment on the expansion and differentiation of porcine neonatal pancreas cell clusters (NPCCs) into ${\beta}$-cells. After transplantation of NPCCs, the ductal cyst area and ${\beta}$-cell mass in the grafts both showed positive and negative correlations with duration of dexamethasone (Dx) treatment. Pdx-1 and HNF-3${\beta}$ gene expression was significantly downregulated following Dx treatment, whereas PGC-1${\alpha}$ expression increased. Pancreatic duct cell apoptosis significantly increased following Dx treatment, whereas proliferation did not change. Altogether, transdifferentiation of porcine NPCCs into ${\beta}$-cells was influenced by the duration of Dx treatment, which might have been due to the suppression of key pancreatic transcription factors. PGC-1${\alpha}$ plays an important role in the expansion and transdifferentiation of porcine NPCCs, and the initial 2 weeks following transplantation of porcine NPCCs is a critical period in determining the final ${\beta}$-cell mass in grafts.

Keywords

References

  1. Ohkubo, Y., Kishikawa, H., Araki, E., Miyata, T., Isami, S., Motoyoshi, S., Kojima, Y., Furuyoshi, N. and Shichiri, M. (1995) Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res. Clin. Pract. 28, 103-117. https://doi.org/10.1016/0168-8227(95)01064-K
  2. Weir, S. B. (2001) Beta-cell turnover: its assessment and implications. Diabetes 50, S20-24. https://doi.org/10.2337/diabetes.50.2007.S20
  3. Shapiro, A. M., Ryan, E. A. and Lakey, J. R. (2001) Pancreatic islet transplantation in the treatment of diabetes mellitus. Best Pract. Res. Clin. Endocrinol. Metab. 15, 241-246. https://doi.org/10.1053/beem.2001.0138
  4. Bellin, M. D., Kandaswamy, R., Parkey, J., Zhang, H. J., Liu, B., Ihm, S. H., Ansite, J. D., Witson, J., Bansal-Pakala, P., Balamurugan, A. N., Papas, K. K., Sutherland, D. E., Moran, A. and Hering, B. J. (2008) Prolonged insulin independence after islet allotransplants in recipients with type 1 diabetes. Am. J. Transplantation 8, 2463-2470. https://doi.org/10.1111/j.1600-6143.2008.02404.x
  5. Faradji, R. N., Tharavanij, T., Messinger, S., Froud, T., Pileggi, A., Monroy, K., Mineo, D., Baidal, D. A., Cure, P., Ponte, G., Mendez, A. J., Selvaggi, G., Ricordi, C. and Alejandro, R. (2008) Long-term insulin independence and improvement in insulin secretion after supplemental islet infusion under exenatide and etanercept. Transplantation 86, 1658-1665. https://doi.org/10.1097/TP.0b013e31818fe448
  6. Koh, A., Imes, S., Kin, T., Dinyari, P., Malcolm, A., Toso, C., Shapiro, A. M. and Senior, P. (2010) Supplemental islet infusions restore insulin independence after graft dysfunction in islet transplant recipients. Transplantation 89, 361-365. https://doi.org/10.1097/TP.0b013e3181bcdbe8
  7. Jeon, S. Y., Baek, K. H., Kim, Y. S., Park, C. G., Kwon, H. S., Ko, S. H., Song, K. H., Yoo, S. J., Son, H. S., Cha, B. Y., Lee, K. W., Son, H. Y., Kang, S. K. and Yoon, K. H. (2004) Differentially up-regulated genes in proliferating porcine neonatal pancreas cells caused by epidermal growth factor. J. Cell Biochem. 91, 354-364. https://doi.org/10.1002/jcb.10752
  8. Tatarkiewicz, K., Lopez-Avalos, M. D., Yoon, K. H., Trivedi, N., Quickel, R. R., Bonner-Weir, S. and Weir, G. C. (2003) Development and retroviral transduction of porcine neonatal pancreatic islet cells in monolayer culture. Dev. Growth Differ. 45, 39-50. https://doi.org/10.1046/j.1440-169X.2003.00673.x
  9. Valdes-Gonzalez, R. A., Dorantes, L. M., Garibay, G. N., Bracho-Blanchet, E., Mendez, A. J., Davila-Perez, R., Elliott, R. B., Teran, L. and White, D. J. (2005) Xenotransplantation of porcine neonatal islets of Langerhans and Sertoli cells: a 4-year study. Eur. J. Endocrinol. 153, 419-427. https://doi.org/10.1530/eje.1.01982
  10. Weir, G. C., Quickel, R. R., Yoon, K. H. Tatarkiewicz, K. Ulrich, T. R. Lock, J. H. and Weir, S. B. (1997) Porcine neonatal pancreatic cell clusters (NPCCs): a potential source of tissue for islet transplantation. Ann. Transplantation 2, 63-68.
  11. Delaunay, F., Khan, A., Cintra, A., Davani, B., Ling, Z. C., Andersson, A., Ostenson, C. G., Gustafsson, J., Efendic, S. and Okret, S. (1997) Pancreatic beta cells are important targets for the diabetogenic effects of glucocorticoids. J. Clin. Invest. 100, 2094-2098. https://doi.org/10.1172/JCI119743
  12. Shapiro, A. M., Lakey, J. R., Ryan, E. A., Korbutt, G. S., Toth, E., Warnock, G. L., Kneteman, N. M. and Rajotte, R. V. (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N. Engl. J. Med. 343, 230-238. https://doi.org/10.1056/NEJM200007273430401
  13. Blondeau, B., Lesage, J., Czernichow, P., Dupouy, J. P. and Breant, B. (2001) Glucocorticoids impair fetal beta-cell development in rats. Am. J. Physiol. Endocrinol. Metab. 281, E592-599. https://doi.org/10.1152/ajpendo.2001.281.3.E592
  14. Lambillotte, C., Gilon, P. and Henquin, J. C. (1997) Direct glucocorticoid inhibition of insulin secretion. An in vitro study of dexamethasone effects in mouse islets. J. Clin. Invest. 99, 414-423. https://doi.org/10.1172/JCI119175
  15. Ko, S. H., Kwon, H. S, Suh, S. H., Yang, J. H., Kim, S. R., Ahn, Y. B., Song, K. H., Yoo, S. J., Son, H. S., Cha, B. Y. Lee, K. W., Son, H. Y., Kang, S. K., Park, C. G. and Yoon, K. H. (2004) Dexamethasone suppresses the expansion and transdifferentiation of transplanted porcine neonatal pancreas cell clusters (NPCCs) into beta-cells in normal nude mice. Diabetes Res. Clin. Pract. 66, S97-191. https://doi.org/10.1016/j.diabres.2003.12.010
  16. Finck, B. N. and Kelly, D. P. (2006) PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J. Clin. Invest. 116, 615-622. https://doi.org/10.1172/JCI27794
  17. Herzig, S., Long, F., Jhala, U. S., Hedrick, S., Quinn, R., Bauer, A., Rudolph, D., Schutz, G., Yoonk, C., Puigserverk, P., Spiegelmank, B. and Montminy, M. (2001) CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 413, 179-181. https://doi.org/10.1038/35093131
  18. Puigserver, P. and Spiegelman, B. M. (2003) Peroxisome Proliferator-Activated Receptor-{gamma} Coactivator 1{alpha} (PGC-1{alpha}): Transcriptional Coactivator and Metabolic Regulator. Endocr. Rev. 24, 78-90. https://doi.org/10.1210/er.2002-0012
  19. Yoon, J. C., Xu, G., Deeney, J. T., Yang, S. N., Rhee, J., Puigserver, P., Levens, A. R., Yang, R., Zhang, C. Y., Lowell, B. B., Berggren, P. O., Newgard, C. B., Weir, S. B., Weir, G. C. and Spiegelman, B. M. (2003) Suppression of beta cell energy metabolism and insulin release by PGC-1alpha. Dev. Cell 5, 73-83. https://doi.org/10.1016/S1534-5807(03)00170-9
  20. Shinozuka, Y., Okada, M., Oki, T., Sagane, K., Mizui, Y., Tanaka, I., Katayama, K. and Murakami-Murofushi, K. (2001) Altered expression of HES-1, BETA2/NeuroD, and PDX-1 is involved in impaired insulin synthesis induced by glucocorticoids in HIT-T15 cells. Biochem. Biophys. Res. Commun. 287, 229-235. https://doi.org/10.1006/bbrc.2001.5573
  21. Yoon, K. H., Quickel, R. R., Tatarkiewicz, K., Ulrich, T. R., Lock, J. H., Trivedi, N., Weir, S. B. and Weir, G. C. (1999) Differentiation and expansion of beta cell mass in porcine neonatal pancreatic cell clusters transplanted into nude mice. Cell Transplantation 8, 673-689.
  22. Gesina, E., Tronche, F., Herrera, P., Duchene, B., Tales, W., Czernichow, P. and Breant, B. (2004) Dissecting the role of glucocorticoids on pancreas development. Diabetes 53, 2322-2329. https://doi.org/10.2337/diabetes.53.9.2322
  23. Shen, C. N., Seckl, J. R., Slack, J. M. and Tosh, D. (2003) Glucocorticoids suppress beta-cell development and induce hepatic metaplasia in embryonic pancreas. Biochem. J. 375, 41-50. https://doi.org/10.1042/BJ20030140
  24. Korbutt, G. S., Elliott, J. F., Ao, Z., Smith, D. K., Warnock, G. L. and Rajotte. R. V. (1996) Large scale isolation, growth, and function of porcine neonatal islet cells. J. Clin. Invest. 97, 2119-2129. https://doi.org/10.1172/JCI118649

Cited by

  1. PGC-1α, glucose metabolism and type 2 diabetes mellitus vol.229, pp.3, 2016, https://doi.org/10.1530/JOE-16-0021
  2. Fetal PGC-1  Overexpression Programs Adult Pancreatic  -Cell Dysfunction vol.62, pp.4, 2013, https://doi.org/10.2337/db12-0314
  3. Functional Maturation and In Vitro Differentiation of Neonatal Porcine Islet Grafts vol.102, pp.10, 2018, https://doi.org/10.1097/TP.0000000000002354