Abstract
Background
Bone marrow mesenchymal stem cell (MSC) transplantation is a promising strategy in the treatment of myocardial infarction (MI). However, the time for transplanting cells remains controversial. The aim of this study was to find an optimal time point for cell transplantation.
Methods
MSCs were isolated and cultured from Sprague-Dawley (SD) rats. MI model was set up in SD rats by permanent ligation of left anterior descending coronary artery. MSCs were directly injected into the infarct border zone at 1 h, 1 week and 2 weeks after MI, respectively. Sham-operated and MI control groups received equal volume of phosphate buffered saline (PBS). At 4 weeks after MI, cardiac function was assessed by echocardiography; vessel density was analyzed on hematoxylin-eosin stained slides by light microscopy; the apoptosis of cardiomyocytes was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay; the expressions of proteins were analyzed by Western blot.
Results
MSC transplantation improved cardiac function, reduced the apoptosis of cardiomyocytes and increased vessel density. These benefits were more obvious in 1-week group than in 1-h and 2-week groups. There are more obvious increases in the ratio of bcl-2/bax and the expression of vascular endothelial growth factor (VEGF) and more obvious decreases in the expression of cleaved-caspase-3 in 1-week group than those in other two groups.
Conclusion
MSC transplantation was beneficial for the recovery of cardiac function. MSC transplantation at 1 week post-MI exerted the best effects on increases of cardiac function, anti-apoptosis and angiogenesis.
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References
Amado, L.C., Saliaris, A.P., Schuleri, K.H., St John, M., Xie, J.S., Cattaneo, S., Durand, D.J., Fitton, T., Kuang, J.Q., Stewart, G., et al., 2005. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc. Natl. Acad. Sci. USA, 102(32):11474–11479. [doi:10.1073/pnas.0504388102]
Assmus, B., Schachinger, V., Teupe, C., Britten, M., Lehmann, R., Dobert, N., Grunwald, F., Aicher, A., Urbich, C., Martin, H., et al., 2002. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation, 106(24):3009–3017. [doi:10.1161/01.CIR.0000043246.74879.CD]
Baldi, A., Abbate, A., Bussani, R., Patti, G., Melfi, R., Angelini, A., Dobrina, A., Rossiello, R., Silvestri, F., Baldi, F., et al., 2002. Apoptosis and post-infarction left ventricular remodeling. J. Mol. Cell. Cardiol., 34(2):165–174. [doi:10.1006/jmcc.2001.1498]
Braunwald, E., Bristow, M.R., 2000. Congestive heart failure: fifty years of progress. Circulation, 102(20 Suppl. 4): IV14–IV23.
Fukuda, S., Kaga, S., Zhan, L., Bagchi, D., Das, D.K., Bertelli, A., Maulik, N., 2006. Resveratrol ameliorates myocardial damage by inducing vascular endothelial growth factor-angiogenesis and tyrosine kinase receptor Flk-1. Cell Biochem. Biophys., 44(1):43–49. [doi:10.1385/CBB:44: 1:043]
Garbade, J., Schubert, A., Rastan, A.J., Lenz, D., Walther, T., Gummert, J.F., Dhein, S., Mohr, F.W., 2005. Fusion of bone marrow-derived stem cells with cardiomyocytes in a heterologous in vitro model. Eur. J. Cardiothorac. Surg., 28(5):685–691. [doi:10.1016/j.ejcts.2005.06.047]
Janssens, S., Dubois, C., Bogaert, J., Theunissen, K., Deroose, C., Desmet, W., Kalantzi, M., Herbots, L., Sinnaeve, P., Dens, J., et al., 2006. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet, 367(9505):113–121. [doi:10.1016/S0140-6736(05)67861-0]
Kajstura, J., Cheng, W., Reiss, K., Clark, W.A., Sonnenblick, E.H., Krajewski, S., Reed, J.C., Olivetti, G., Anversa, P., 1996. Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Lab. Invest., 74(1):86–107.
Kemp, K.C., Hows, J., Donaldson, C., 2005. Bone marrow-derived mesenchymal stem cells. Leuk. Lymphoma, 46(11):1531–1544. [doi:10.1080/10428190500215076]
Koransky, M.L., Robbins, R.C., Blau, H.M., 2002. VEGF gene delivery for treatment of ischemic cardiovascular disease. Trends Cardiovasc Med., 12(3):108–114. [doi:10.1016/S1050-1738(01)00158-X]
Li, R.K., Mickle, D.A., Weisel, R.D., Rao, V., Jia, Z.Q., 2001. Optimal time for cardiomyocyte transplantation to maximize myocardial function after left ventricular injury. Ann. Thorac. Surg., 72(6):1957–1963. [doi:10.1016/S00 03-4975(01)03216-7]
Litwin, S.E., Katz, S.E., Weinberg, E.O., Lorell, B.H., Aurigemma, G.P., Douglas, P.S., 1995. Serial echocardiographic-Doppler assessment of left ventricular geometry and function in rats with pressure-overload hypertrophy. Chronic angiotensin-converting enzyme inhibition attenuates the transition to heart failure. Circulation, 91(10):2642–2654.
Litwin, S.E., Katz, S.E., Morgan, J.P., Douglas, P.S., 1996. Long-term captopril treatment improves diastolic filling more than systolic performance in rats with large myocardial infarction. J. Am. Coll. Cardiol., 28(3):773–781. [doi:10.1016/0735-1097(96)00215-X]
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. [doi:10.1161/CIRCULATIONAHA.105.575118]
Min, J.Y., Sandmann, S., Meissner, A., Unger, T., Simon, R., 1999. Differential effects of mibefradil, verapamil, and amlodipine on myocardial function and intracellular Ca(2+) handling in rats with chronic myocardial infarction. J. Pharmacol. Exp. Ther., 291(3):1038–1044.
Nagaya, N., Kangawa, K., Itoh, T., Iwase, T., Murakami, S., Miyahara, Y., Fujii, T., Uematsu, M., Ohgushi, H., Yamagishi, M., et al., 2005. Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy. Circulation, 112(8): 1128–1135. [doi:10.1161/CIRCULATIONAHA.104.500447]
Nygren, J.M., Jovinge, S., Breitbach, M., Sawen, P., Roll, W., Hescheler, J., Taneera, J., Fleischmann, B.K., Jacobsen, S.E., 2004. Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat. Med., 10(5): 494–501. [doi:10.1038/nm1040]
Olivetti, G., Quaini, F., Sala, R., Lagrasta, C., Corradi, D., Bonacina, E., Gambert, S.R., Cigola, E., Anversa, P., 1996. Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving portion of the heart. J. Mol. Cell. Cardiol., 28(9):2005–2016. [doi:10.1006/jmcc.1996.0193]
Piro, F.R., di Gioia, C.R., Gallo, P., Giordano, C., d’Amati, G., 2000. Is apoptosis a diagnostic marker of acute myocardial infarction? Arch. Pathol. Lab Med., 124(6):827–831.
Saraste, A., Pulkki, K., Kallajoki, M., Henriksen, K., Parvinen, M., Voipio-Pulkki, L.M., 1997. Apoptosis in human acute myocardial infarction. Circulation, 95(2):320–323.
Schachinger, V., Assmus, B., Britten, M.B., Honold, J., Lehmann, R., Teupe, C., Abolmaali, N.D., Vogl, T.J., Hofmann, W.K., Martin, H., et al., 2004. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI trial. J. Am. Coll. Cardiol., 44(8):1690–1699. [doi:10.1016/j.jacc.2004.08.014]
Shim, W.S., Jiang, S., Wong, P., Tan, J., Chua, Y.L., Tan, Y.S., Sin, Y.K., Lim, C.H., Chua, T., Teh, M., et al., 2004. Ex vivo differentiation of human adult bone marrow stem cells into cardiomyocyte-like cells. Biochem. Biophys. Res. Commun., 324(2):481–488. [doi:10.1016/j.bbrc.2004. 09.087]
Silva, W.A.Jr., Covas, D.T., Panepucci, R.A., Proto-Siqueira, R., Siufi, J.L., Zanette, D.L., Santos, A.R., Zago, M.A., 2003. The profile of gene expression of human marrow mesenchymal stem cells. Stem Cells, 21(6):661–669. [doi:10.1634/stemcells.21-6-661]
Stamm, C., Westphal, B., Kleine, H.D., Petzsch, M., Kittner, C., Klinge, H., Schumichen, C., Nienaber, C.A., Freund, M., Steinhoff, G., 2003. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet, 361(9351):45–46. [doi:10.1016/S0140-6736(03) 12110-1]
Strauer, B.E., Brehm, M., Zeus, T., Kostering, M., Hernandez, A., Sorg, R.V., Kogler, G., Wernet, P., 2002. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation, 106(15):1913–1918. [doi:10.1161/01.CIR.0000034046.87607.1C]
Tang, J., Xie, Q., Pan, G., Wang, J., Wang, M., 2006. Mesenchymal stem cells participate in angiogenesis and improve heart function in rat model of myocardial ischemia with reperfusion. Eur. J. Cardiothorac. Surg., 30(2): 353–361. [doi:10.1016/j.ejcts.2006.02.070]
Uemura, R., Xu, M., Ahmad, N., Ashraf, M., 2006. Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circ. Res., 98(11):1414–1421. [doi:10.1161/01.RES.0000225952. 61196.39]
US National Institutes of Health, 1996. Guide for the Care and Use of Laboratory Animals. US National Institutes of Health, No. 85-23.
Virag, J.I., Murry, C.E., 2003. Myofibroblast and endothelial cell proliferation during murine myocardial infarct repair. Am. J. Pathol., 163(6):2433–2440.
Wang, P.P., Wang, J.H., Yan, Z.P., Hu, M.Y., Lau, G.K., Fan, S.T., Luk, J.M., 2004. Expression of hepatocyte-like phenotypes in bone marrow stromal cells after HGF induction. Biochem. Biophys. Res. Commun., 320(3):712–716. [doi:10.1016/j.bbrc.2004.05.213]
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. [doi:10.1016/S0140-6736(04)16626-9]
Xie, X.J., Wang, J.A., Cao, J., Zhang, X., 2006. Differentiation of bone marrow mesenchymal stem cells induced by myocardial medium under hypoxic conditions. Acta Pharmacol. Sin., 27(9):1153–1158. [doi:10.1111/j.1745-7254.2006.00436.x]
Yoon, Y.S., Lee, N., Scadova, H., 2005. Myocardial regeneration with bone-marrow-derived stem cells. Biol. Cell, 97(4):253–263. [doi:10.1042/BC20040099]
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Project (No. 2004QN018) supported by the Health Bureau of Zhejiang Province, China
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Jiang, Cy., Gui, C., He, An. et al. Optimal time for mesenchymal stem cell transplantation in rats with myocardial infarction. J. Zhejiang Univ. Sci. B 9, 630–637 (2008). https://doi.org/10.1631/jzus.B0820004
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DOI: https://doi.org/10.1631/jzus.B0820004