Similar articles

Abstract: Objective: Mesenchymal stem cell (MSC) transplantation is a promising therapy for ischemic heart diseases. However, poor cell survival after transplantation greatly limits the therapeutic efficacy of MSCs. The purpose of this study was to investigate the protective effect of angiopoietin-1 (Ang1) preconditioning on MSC survival and subsequent heart function improvement after transplantation. Methods: MSCs were cultured with or without 50 ng/ml Ang1 in complete medium for 24 h prior to experiments on cell survival and transplantation. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Hoechst staining were applied to evaluate MSC survival after serum deprivation in vitro, while cell survival in vivo was detected by terminal deoxynucleotidyl transferase biotin-dUPT nick end labeling (TUNEL) assay 24 and 72 h after transplantation. Heart function and infarct size were measured four weeks later by small animal echocardiography and Masson’s trichrome staining, respectively. Results: Ang1 preconditioning induced Akt phosphorylation and increased expression of Bcl-2 and the ratio of Bcl-2/Bax. In comparison with non-preconditioned MSCs, Ang1-preconditioned cell survival was significantly increased while the apoptotic rate decreased in vitro. However, the PI3K/Akt pathway inhibitor, LY294002, abrogated the protective effect of Ang1 preconditioning. After transplantation, the Ang1-preconditioned-MSC group showed a lower death rate, smaller infarct size, and better heart functional recovery compared to the non-preconditioned-MSC group. Conclusions: Ang1 preconditioning enhances MSC survival, contributing to further improvement of heart function.

[1]Augustin, H.G., Koh, G.Y., Thurston, G., Alitalo, K., 2009. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat. Rev. Mol. Cell Biol., 10(3):165-177.

[2]Davis, S., Aldrich, T.H., Jones, P.F., Acheson, A., Compton, D.L., Jain, V., Ryan, T.E., Bruno, J., Radziejewski, C., Maisonpierre, P.C., et al., 1996. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell, 87(7):1161-1169.

[3]Fayard, E., Tintignac, L.A., Baudry, A., Hemmings, B.A., 2005. Protein kinase B/Akt at a glance. J. Cell Sci., 118(Pt 24):5675-5678.

[4]Haider, H., Ashraf, M., 2008. Strategies to promote donor cell survival: combining preconditioning approach with stem cell transplantation. J. Mol. Cell. Cardiol., 45(4):554-566.

[5]Harfouche, R., Hassessian, H.M., Guo, Y., Faivre, V., Srikant, C.B., Yancopoulos, G.D., Hussain, S.N., 2002. Mechanisms which mediate the antiapoptotic effects of angiopoietin-1 on endothelial cells. Microvasc. Res., 64(1):135-147.

[6]Kim, I., Kim, H.G., So, J.N., Kim, J.H., Kwak, H.J., Koh, G.Y., 2000. Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Circ. Res., 86(1):24-29.

[7]Kontos, C.D., Stauffer, T.P., Yang, W.P., York, J.D., Huang, L., Blanar, M.A., Meyer, T., Peters, K.G., 1998. Tyrosine 1101 of Tie2 is the major site of association of p85 and is required for activation of phosphatidylinositol 3-kinase and Akt. Mol. Cell. Biol., 18(7):4131-4140.

[8]Kwak, H.J., So, J.N., Lee, S.J., Kim, I., Koh, G.Y., 1999. Angiopoietin-1 is an apoptosis survival factor for endothelial cells. FEBS Lett., 448(2-3):249-253.

[9]Leenen, F.H., Huang, B.S., Yu, H., Yuan, B., 1995. Brain ‘ouabain’ mediates sympathetic hyperactivity in congestive heart failure. Circ. Res., 77(5):993-1000.

[10]Liu, X.B., Jiang, J., Gui, C., Hu, X.Y., Xiang, M.X., Wang, J.A., 2008. Angiopoietin-1 protects mesenchymal stem cells against serum deprivation and hypoxia-induced apoptosis through the PI3K/Akt pathway. Acta Pharmacol. Sin., 29(7):815-822.

[11]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. Nat. Med., 9(9):1195-1201.

[12]Meyer, G.P., Wollert, K.C., Lotz, J., Steffens, J., Lippolt, P., Fichtner, S., Hecker, H., Schaefer, A., Arseniev, L., Hertenstein, B., et al., 2006. Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months’ follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial. Circulation, 113(10):1287-1294.

[13]Oltvai, Z.N., Milliman, C.L., Korsmeyer, S.J., 1993. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell, 74(4):609-619.

[14]Orlic, D., Kajstura, J., Chimenti, S., Jakoniuk, I., Anderson, S.M., Li, B., Pickel, J., McKay, R., Nadal-Ginard, B., Bodine, D.M., et al., 2001. Bone marrow cells regenerate infarcted myocardium. Nature, 410(6829):701-705.

[15]Saharinen, P., Bry, M., Alitalo, K., 2010. How do angiopoietins Tie in with vascular endothelial growth factors? Curr. Opin. Hematol., 17(3):198-205.

[16]Shi, L.G., Zhang, G.P., Jin, H.M., 2006. Inhibition of microvascular endothelial cell apoptosis by angiopoietin-1 and the involvement of cytochrome C. Chin. Med. J. (Engl.), 119(9):725-730.

[17]Tang, Y.L., Tang, Y., Zhang, Y.C., Qian, K., Shen, L., Phillips, M.I., 2005. Improved graft mesenchymal stem cell survival in ischemic heart with a hypoxia-regulated heme oxygenase-1 vector. J. Am. Coll. Cardiol., 46(7):1339-1350.

[18]Toma, C., Pittenger, M.F., Cahill, K.S., Byrne, B.J., Kessler, P.D., 2002. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation, 105(1):93-98.

[19]Tomita, S., Li, R.K., Weisel, R.D., Mickle, D.A., Kim, E.J., Sakai, T., Jia, Z.Q., 1999. Autologous transplantation of bone marrow cells improves damaged heart function. Circulation, 100(19 Suppl.):II247-II256.

[20]Valable, S., Bellail, A., Lesne, S., Liot, G., Mackenzie, E.T., Vivien, D., Bernaudin, M., Petit, E., 2003. Angiopoietin-1-induced PI3-kinase activation prevents neuronal apoptosis. Faseb. J., 17(3):443-445.

[21]Williams, A.R., Hare, J.M., 2011. Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circ. Res., 109(8):923-940.

[22]Wollert, K.C., Meyer, G.P., Lotz, J., Ringes-Lichtenberg, S., Lippolt, P., Breidenbach, C., Fichtner, S., Korte, T., Hornig, B., Messinger, D., et al., 2004. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet, 364(9429):141-148.

[23]Zeng, H., Li, L., Chen, J.X., 2012. Overexpression of angiopoietin-1 increases CD133⁺/c-kit⁺ cells and reduces myocardial apoptosis in db/db mouse infarcted hearts. PLoS One, 7(4):e35905.

[24]Zhu, W., Chen, J., Cong, X., Hu, S., Chen, X., 2006. Hypoxia and serum deprivation-induced apoptosis in mesenchymal stem cells. Stem Cells, 24(2):416-425.