Immunosuppressive effects of mesenchymal stem cells on tacrolimus therapy in rat heart transplant model
Main Article Content
Abstract
Introduction: Mesenchymal stem cells (MSCs) are used in various clinical settings for effective cell therapy by taking advantage of their immunomodulatory, regenerative, and anti-inflammatory properties. We previously investigated the effects of the regenerative and anti-inflammatory properties of MSCs for consideration of their clinical application in organ transplantation. Since immunosuppressant agents are administered in nearly all clinical cases of organ transplantation, clarification of the immunological interaction between MSCs and the calcineurin inhibitor tacrolimus (TAC) is needed.
Aim: Due to potential use of MSCs in organ transplantation, we assessed immunological interactions between TAC and MSCs in vivo.
Methods: Adipose tissue-derived MSCs (AT-MSCs) were obtained from wild-type Lewis rats. We then used a rat heart transplantation model to observe the immunosuppressive effects of AT-MSCs, TAC, and those in combination. Following allogeneic heterotopic heart transplantation from ACI rats to Lewis rats, graft survival was assessed in groups treated with AT-MSCs, TAC, both, or neither.
Results: Median survival of the allograft was 14.5 days in the TAC-alone group and 11 days in the MSC+TAC group. Although the difference between those groups was not significant, the survival periods of both were significantly longer as compared to that of the control (median survival =5 days, P<0.05) and MSC-alone (median survival =5 days, P<0.05) groups.
Conclusions: Administration of AT-MSCs did not decrease the beneficial immunosuppressive effect of TAC on heart graft survival. TAC appears to be compatible and effective for clinical use as an immunosuppressant with AT-MSCs.
Article Details
How to Cite
DOI, Junshi et al.
Immunosuppressive effects of mesenchymal stem cells on tacrolimus therapy in rat heart transplant model.
Medical Research Archives, [S.l.], v. 5, n. 2, feb. 2017.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/946>. Date accessed: 22 nov. 2024.
Keywords
calcineurin inhibitor, heterotopic heart transplantation model, immunomodulation, immunosuppressant, liver transplantation, mesenchymal stem cells, organ transplantation, tacrolimus
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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Bauer, G., Dao, M. A., Case, S. S., Meyerrose, T., Wirthlin, L., Zhou, P., . . . Nolta, J. A. (2008). In vivo biosafety model to assess the risk of adverse events from retroviral and lentiviral vectors. Mol Ther, 16(7), 1308-1315. doi:10.1038/mt.2008.93
Ben-Haim, M., Emre, S., Fishbein, T. M., Sheiner, P. A., Bodian, C. A., Kim-Schluger, L., . . . Miller, C. M. (2001). Critical graft size in adult-to-adult living donor liver transplantation: impact of the recipient's disease. Liver Transpl, 7(11), 948-953. doi:10.1053/jlts.2001.29033
Blaber, S. P., Webster, R. A., Hill, C. J., Breen, E. J., Kuah, D., Vesey, G., & Herbert, B. R. (2012). Analysis of in vitro secretion profiles from adipose-derived cell populations. J Transl Med, 10, 172. doi:10.1186/1479-5876-10-172
Campos, B. D., & Botha, J. F. (2012). Strategies to optimize donor safety with smaller grafts for adult-to-adult living donor liver transplantation. Curr Opin Organ Transplant, 17(3), 230-234. doi:10.1097/MOT.0b013e32835365b2
Chávez, R., Jamieson, N., Takamori, S., Nivatvongs, S., Pino, G., Metcalfe, A., . . . Metcalfe, S. (1999). Hepatotrophic effect of cyclosporine and FK 506 is not mimicked by rapamycin. Transplant Proc, 31(6), 2429.
Crenesse, D., Laurens, M., Heurteaux, C., Cursio, R., Saint-Paul, M. C., Schmid-Alliana, A., & Gugenheim, J. (2003). Rat liver ischemia-reperfusion-induced apoptosis and necrosis are decreased by FK506 pretreatment. Eur J Pharmacol, 473(2-3), 177-184.
Dahlke, M. H., Hoogduijn, M., Eggenhofer, E., Popp, F. C., Renner, P., Slowik, P., . . . Group, M. S. (2009). Toward MSC in solid organ transplantation: 2008 position paper of the MISOT study group. Transplantation, 88(5), 614-619. doi:10.1097/TP.0b013e3181b4425a
Engela, A. U., Baan, C. C., Dor, F. J., Weimar, W., & Hoogduijn, M. J. (2012). On the interactions between mesenchymal stem cells and regulatory T cells for immunomodulation in transplantation. Front Immunol, 3, 126. doi:10.3389/fimmu.2012.00126
Francavilla, A., Barone, M., Todo, S., Zeng, Q., Porter, K. A., & Starzl, T. E. (1989). Augmentation of rat liver regeneration by FK 506 compared with cyclosporin. Lancet, 2(8674), 1248-1249.
Fujishiro, J., Takeda, S., Takeno, Y., Takeuchi, K., Ogata, Y., Takahashi, M., . . . Kobayashi, E. (2005). Gene transfer to the rat kidney in vivo and ex vivo using an adenovirus vector: factors influencing transgene expression. Nephrol Dial Transplant, 20(7), 1385-1391. doi:10.1093/ndt/gfh783
Furlani, D., Ugurlucan, M., Ong, L., Bieback, K., Pittermann, E., Westien, I., . . . Ma, N. (2009). Is the intravascular administration of mesenchymal stem cells safe? Mesenchymal stem cells and intravital microscopy. Microvasc Res, 77(3), 370-376. doi:10.1016/j.mvr.2009.02.001
Hakamata, Y., Murakami, T., & Kobayashi, E. (2006). "Firefly rats" as an organ/cellular source for long-term in vivo bioluminescent imaging. Transplantation, 81(8), 1179-1184. doi:10.1097/01.tp.0000203137.06587.4a
Hoogduijn, M. J., Popp, F. C., Grohnert, A., Crop, M. J., van Rhijn, M., Rowshani, A. T., . . . Group, M. S. (2010). Advancement of mesenchymal stem cell therapy in solid organ transplantation (MISOT). Transplantation, 90(2), 124-126. doi:10.1097/TP.0b013e3181ea4240
Inoue, S., Hakamata, Y., Kaneko, M., & Kobayashi, E. (2004). Gene therapy for organ grafts using rapid injection of naked DNA: application to the rat liver. Transplantation, 77(7), 997-1003.
Ishikawa, T., Banas, A., Hagiwara, K., Iwaguro, H., & Ochiya, T. (2010). Stem cells for hepatic regeneration: the role of adipose tissue derived mesenchymal stem cells. Curr Stem Cell Res Ther, 5(2), 182-189.
Jain, A., Reyes, J., Kashyap, R., Rohal, S., Abu-Elmagd, K., Starzl, T., & Fung, J. (1999). What have we learned about primary liver transplantation under tacrolimus immunosuppression? Long-term follow-up of the first 1000 patients. Ann Surg, 230(3), 441-448; discussion 448-449.
Kanazawa, H., Fujimoto, Y., Teratani, T., Iwasaki, J., Kasahara, N., Negishi, K., . . . Kobayashi, E. (2011). Bone marrow-derived mesenchymal stem cells ameliorate hepatic ischemia reperfusion injury in a rat model. PLoS One, 6(4), e19195. doi:10.1371/journal.pone.0019195
Kawano, K., Kim, Y. I., Goto, S., Ono, M., & Kobayashi, M. (1991). A protective effect of FK506 in ischemically injured rat livers. Transplantation, 52(1), 143-145.
Kidd, S., Spaeth, E., Dembinski, J. L., Dietrich, M., Watson, K., Klopp, A., . . . Marini, F. C. (2009). Direct evidence of mesenchymal stem cell tropism for tumor and wounding microenvironments using in vivo bioluminescent imaging. Stem Cells, 27(10), 2614-2623. doi:10.1002/stem.187
Li, H., Rao, A., & Hogan, P. G. (2011). Interaction of calcineurin with substrates and targeting proteins. Trends Cell Biol, 21(2), 91-103. doi:10.1016/j.tcb.2010.09.011
Marigo, I., & Dazzi, F. (2011). The immunomodulatory properties of mesenchymal stem cells. Semin Immunopathol, 33(6), 593-602. doi:10.1007/s00281-011-0267-7
Marote, A., Teixeira, F. G., Mendes-Pinheiro, B., & Salgado, A. J. (2016). MSCs-Derived Exosomes: Cell-Secreted Nanovesicles with Regenerative Potential. Front Pharmacol, 7, 231. doi:10.3389/fphar.2016.00231
Nadalin, S., Malagò, M., Radtke, A., Erim, Y., Saner, F., Valentin-Gamazo, C., . . . Broelsch, C. E. (2007). Current trends in live liver donation. Transpl Int, 20(4), 312-330. doi:10.1111/j.1432-2277.2006.00424.x
Popp, F. C., Renner, P., Eggenhofer, E., Slowik, P., Geissler, E. K., Piso, P., . . . Dahlke, M. H. (2009). Mesenchymal stem cells as immunomodulators after liver transplantation. Liver Transpl, 15(10), 1192-1198. doi:10.1002/lt.21862
Reagan, M. R., & Kaplan, D. L. (2011). Concise review: Mesenchymal stem cell tumor-homing: detection methods in disease model systems. Stem Cells, 29(6), 920-927. doi:10.1002/stem.645
Sakr, M. F., Zetti, G. M., Hassanein, T. I., Farghali, H., Nalesnik, M. A., Gavaler, J. S., . . . Van Thiel, D. H. (1991). FK 506 ameliorates the hepatic injury associated with ischemia and reperfusion in rats. Hepatology, 13(5), 947-951.
Sakuma, S., Kato, Y., Nishigaki, F., Sasakawa, T., Magari, K., Miyata, S., . . . Goto, T. (2000). FK506 potently inhibits T cell activation induced TNF-alpha and IL-1beta production in vitro by human peripheral blood mononuclear cells. Br J Pharmacol, 130(7), 1655-1663. doi:10.1038/sj.bjp.0703472
Sasakawa, T., Sasakawa, Y., Masunaga, T., Fujitsu, T., Hirayama, Y., Ohkubo, Y., & Mutoh, S. (2005). FK506 suppresses E-selectin, ICAM-1 and VCAM-1 expression on vascular endothelial cells by inhibiting tumor necrosis factor alpha secretion from peripheral blood mononuclear cells. Cytokine, 29(2), 67-71. doi:10.1016/j.cyto.2004.04.006
Sasakawa, Y., Sakuma, S., Higashi, Y., Sasakawa, T., Amaya, T., & Goto, T. (2000). FK506 suppresses neutrophil chemoattractant production by peripheral blood mononuclear cells. Eur J Pharmacol, 403(3), 281-288.
Suzuki, S., Nakamura, S., Koizumi, T., Sakaguchi, S., Baba, S., Muro, H., & Fujise, Y. (1991). The beneficial effect of a prostaglandin I2 analog on ischemic rat liver. Transplantation, 52(6), 979-983.
Tamura, F., Masuhara, A., Sakaida, I., Fukumoto, E., Nakamura, T., & Okita, K. (1998). FK506 promotes liver regeneration by suppressing natural killer cell activity. J Gastroenterol Hepatol, 13(7), 703-708.
Tannuri, U., Tannuri, A. C., Coelho, M. C., Mello, E. S., & dos Santos, A. S. (2008). Effect of the immunosuppressants on hepatocyte cells proliferation and apoptosis during liver regeneration after hepatectomy - molecular studies. Pediatr Transplant, 12(1), 73-79.
van der Meer, C., Valkenburg, P. W., & Snijders, P. M. (1986). Studies on hyperkalemia as a cause of death in intestinal ischemia shock in rats. Circ Shock, 19(3), 329-345.
Wada, T., Doi, M., Kikuchi, T., & Kobayashi, E. (2013). U.S. Patent No. US20150118196 A1: U. S. P. a. T. Office.
Wang, D., Chen, K., Du, W. T., Han, Z. B., Ren, H., Chi, Y., . . . Han, Z. C. (2010). CD14+ monocytes promote the immunosuppressive effect of human umbilical cord matrix stem cells. Exp Cell Res, 316(15), 2414-2423. doi:10.1016/j.yexcr.2010.04.018
Yagi, H., Soto-Gutierrez, A., Parekkadan, B., Kitagawa, Y., Tompkins, R. G., Kobayashi, N., & Yarmush, M. L. (2010). Mesenchymal stem cells: Mechanisms of immunomodulation and homing. Cell Transplant, 19(6), 667-679. doi:10.3727/096368910X508762
Banas, A., Teratani, T., Yamamoto, Y., Tokuhara, M., Takeshita, F., Osaki, M., . . . Ochiya, T. (2008). IFATS collection: in vivo therapeutic potential of human adipose tissue mesenchymal stem cells after transplantation into mice with liver injury. Stem Cells, 26(10), 2705-2712. doi:10.1634/stemcells.2008-0034
Bauer, G., Dao, M. A., Case, S. S., Meyerrose, T., Wirthlin, L., Zhou, P., . . . Nolta, J. A. (2008). In vivo biosafety model to assess the risk of adverse events from retroviral and lentiviral vectors. Mol Ther, 16(7), 1308-1315. doi:10.1038/mt.2008.93
Ben-Haim, M., Emre, S., Fishbein, T. M., Sheiner, P. A., Bodian, C. A., Kim-Schluger, L., . . . Miller, C. M. (2001). Critical graft size in adult-to-adult living donor liver transplantation: impact of the recipient's disease. Liver Transpl, 7(11), 948-953. doi:10.1053/jlts.2001.29033
Blaber, S. P., Webster, R. A., Hill, C. J., Breen, E. J., Kuah, D., Vesey, G., & Herbert, B. R. (2012). Analysis of in vitro secretion profiles from adipose-derived cell populations. J Transl Med, 10, 172. doi:10.1186/1479-5876-10-172
Campos, B. D., & Botha, J. F. (2012). Strategies to optimize donor safety with smaller grafts for adult-to-adult living donor liver transplantation. Curr Opin Organ Transplant, 17(3), 230-234. doi:10.1097/MOT.0b013e32835365b2
Chávez, R., Jamieson, N., Takamori, S., Nivatvongs, S., Pino, G., Metcalfe, A., . . . Metcalfe, S. (1999). Hepatotrophic effect of cyclosporine and FK 506 is not mimicked by rapamycin. Transplant Proc, 31(6), 2429.
Crenesse, D., Laurens, M., Heurteaux, C., Cursio, R., Saint-Paul, M. C., Schmid-Alliana, A., & Gugenheim, J. (2003). Rat liver ischemia-reperfusion-induced apoptosis and necrosis are decreased by FK506 pretreatment. Eur J Pharmacol, 473(2-3), 177-184.
Dahlke, M. H., Hoogduijn, M., Eggenhofer, E., Popp, F. C., Renner, P., Slowik, P., . . . Group, M. S. (2009). Toward MSC in solid organ transplantation: 2008 position paper of the MISOT study group. Transplantation, 88(5), 614-619. doi:10.1097/TP.0b013e3181b4425a
Engela, A. U., Baan, C. C., Dor, F. J., Weimar, W., & Hoogduijn, M. J. (2012). On the interactions between mesenchymal stem cells and regulatory T cells for immunomodulation in transplantation. Front Immunol, 3, 126. doi:10.3389/fimmu.2012.00126
Francavilla, A., Barone, M., Todo, S., Zeng, Q., Porter, K. A., & Starzl, T. E. (1989). Augmentation of rat liver regeneration by FK 506 compared with cyclosporin. Lancet, 2(8674), 1248-1249.
Fujishiro, J., Takeda, S., Takeno, Y., Takeuchi, K., Ogata, Y., Takahashi, M., . . . Kobayashi, E. (2005). Gene transfer to the rat kidney in vivo and ex vivo using an adenovirus vector: factors influencing transgene expression. Nephrol Dial Transplant, 20(7), 1385-1391. doi:10.1093/ndt/gfh783
Furlani, D., Ugurlucan, M., Ong, L., Bieback, K., Pittermann, E., Westien, I., . . . Ma, N. (2009). Is the intravascular administration of mesenchymal stem cells safe? Mesenchymal stem cells and intravital microscopy. Microvasc Res, 77(3), 370-376. doi:10.1016/j.mvr.2009.02.001
Hakamata, Y., Murakami, T., & Kobayashi, E. (2006). "Firefly rats" as an organ/cellular source for long-term in vivo bioluminescent imaging. Transplantation, 81(8), 1179-1184. doi:10.1097/01.tp.0000203137.06587.4a
Hoogduijn, M. J., Popp, F. C., Grohnert, A., Crop, M. J., van Rhijn, M., Rowshani, A. T., . . . Group, M. S. (2010). Advancement of mesenchymal stem cell therapy in solid organ transplantation (MISOT). Transplantation, 90(2), 124-126. doi:10.1097/TP.0b013e3181ea4240
Inoue, S., Hakamata, Y., Kaneko, M., & Kobayashi, E. (2004). Gene therapy for organ grafts using rapid injection of naked DNA: application to the rat liver. Transplantation, 77(7), 997-1003.
Ishikawa, T., Banas, A., Hagiwara, K., Iwaguro, H., & Ochiya, T. (2010). Stem cells for hepatic regeneration: the role of adipose tissue derived mesenchymal stem cells. Curr Stem Cell Res Ther, 5(2), 182-189.
Jain, A., Reyes, J., Kashyap, R., Rohal, S., Abu-Elmagd, K., Starzl, T., & Fung, J. (1999). What have we learned about primary liver transplantation under tacrolimus immunosuppression? Long-term follow-up of the first 1000 patients. Ann Surg, 230(3), 441-448; discussion 448-449.
Kanazawa, H., Fujimoto, Y., Teratani, T., Iwasaki, J., Kasahara, N., Negishi, K., . . . Kobayashi, E. (2011). Bone marrow-derived mesenchymal stem cells ameliorate hepatic ischemia reperfusion injury in a rat model. PLoS One, 6(4), e19195. doi:10.1371/journal.pone.0019195
Kawano, K., Kim, Y. I., Goto, S., Ono, M., & Kobayashi, M. (1991). A protective effect of FK506 in ischemically injured rat livers. Transplantation, 52(1), 143-145.
Kidd, S., Spaeth, E., Dembinski, J. L., Dietrich, M., Watson, K., Klopp, A., . . . Marini, F. C. (2009). Direct evidence of mesenchymal stem cell tropism for tumor and wounding microenvironments using in vivo bioluminescent imaging. Stem Cells, 27(10), 2614-2623. doi:10.1002/stem.187
Li, H., Rao, A., & Hogan, P. G. (2011). Interaction of calcineurin with substrates and targeting proteins. Trends Cell Biol, 21(2), 91-103. doi:10.1016/j.tcb.2010.09.011
Marigo, I., & Dazzi, F. (2011). The immunomodulatory properties of mesenchymal stem cells. Semin Immunopathol, 33(6), 593-602. doi:10.1007/s00281-011-0267-7
Marote, A., Teixeira, F. G., Mendes-Pinheiro, B., & Salgado, A. J. (2016). MSCs-Derived Exosomes: Cell-Secreted Nanovesicles with Regenerative Potential. Front Pharmacol, 7, 231. doi:10.3389/fphar.2016.00231
Nadalin, S., Malagò, M., Radtke, A., Erim, Y., Saner, F., Valentin-Gamazo, C., . . . Broelsch, C. E. (2007). Current trends in live liver donation. Transpl Int, 20(4), 312-330. doi:10.1111/j.1432-2277.2006.00424.x
Popp, F. C., Renner, P., Eggenhofer, E., Slowik, P., Geissler, E. K., Piso, P., . . . Dahlke, M. H. (2009). Mesenchymal stem cells as immunomodulators after liver transplantation. Liver Transpl, 15(10), 1192-1198. doi:10.1002/lt.21862
Reagan, M. R., & Kaplan, D. L. (2011). Concise review: Mesenchymal stem cell tumor-homing: detection methods in disease model systems. Stem Cells, 29(6), 920-927. doi:10.1002/stem.645
Sakr, M. F., Zetti, G. M., Hassanein, T. I., Farghali, H., Nalesnik, M. A., Gavaler, J. S., . . . Van Thiel, D. H. (1991). FK 506 ameliorates the hepatic injury associated with ischemia and reperfusion in rats. Hepatology, 13(5), 947-951.
Sakuma, S., Kato, Y., Nishigaki, F., Sasakawa, T., Magari, K., Miyata, S., . . . Goto, T. (2000). FK506 potently inhibits T cell activation induced TNF-alpha and IL-1beta production in vitro by human peripheral blood mononuclear cells. Br J Pharmacol, 130(7), 1655-1663. doi:10.1038/sj.bjp.0703472
Sasakawa, T., Sasakawa, Y., Masunaga, T., Fujitsu, T., Hirayama, Y., Ohkubo, Y., & Mutoh, S. (2005). FK506 suppresses E-selectin, ICAM-1 and VCAM-1 expression on vascular endothelial cells by inhibiting tumor necrosis factor alpha secretion from peripheral blood mononuclear cells. Cytokine, 29(2), 67-71. doi:10.1016/j.cyto.2004.04.006
Sasakawa, Y., Sakuma, S., Higashi, Y., Sasakawa, T., Amaya, T., & Goto, T. (2000). FK506 suppresses neutrophil chemoattractant production by peripheral blood mononuclear cells. Eur J Pharmacol, 403(3), 281-288.
Suzuki, S., Nakamura, S., Koizumi, T., Sakaguchi, S., Baba, S., Muro, H., & Fujise, Y. (1991). The beneficial effect of a prostaglandin I2 analog on ischemic rat liver. Transplantation, 52(6), 979-983.
Tamura, F., Masuhara, A., Sakaida, I., Fukumoto, E., Nakamura, T., & Okita, K. (1998). FK506 promotes liver regeneration by suppressing natural killer cell activity. J Gastroenterol Hepatol, 13(7), 703-708.
Tannuri, U., Tannuri, A. C., Coelho, M. C., Mello, E. S., & dos Santos, A. S. (2008). Effect of the immunosuppressants on hepatocyte cells proliferation and apoptosis during liver regeneration after hepatectomy - molecular studies. Pediatr Transplant, 12(1), 73-79.
van der Meer, C., Valkenburg, P. W., & Snijders, P. M. (1986). Studies on hyperkalemia as a cause of death in intestinal ischemia shock in rats. Circ Shock, 19(3), 329-345.
Wada, T., Doi, M., Kikuchi, T., & Kobayashi, E. (2013). U.S. Patent No. US20150118196 A1: U. S. P. a. T. Office.
Wang, D., Chen, K., Du, W. T., Han, Z. B., Ren, H., Chi, Y., . . . Han, Z. C. (2010). CD14+ monocytes promote the immunosuppressive effect of human umbilical cord matrix stem cells. Exp Cell Res, 316(15), 2414-2423. doi:10.1016/j.yexcr.2010.04.018
Yagi, H., Soto-Gutierrez, A., Parekkadan, B., Kitagawa, Y., Tompkins, R. G., Kobayashi, N., & Yarmush, M. L. (2010). Mesenchymal stem cells: Mechanisms of immunomodulation and homing. Cell Transplant, 19(6), 667-679. doi:10.3727/096368910X508762