CXCR4+ and SDF-1+ Bone Marrow Cells Are Mobilized into the Blood Stream in Acute Myocardial Infarction and Acute Ischemia


Cell therapy has shown beneficial effects on ventricular function and tissue regeneration in patients with acute and chronic myocardial infarction, although with diverse grades of variability in the results, possibly by proportion, subtype and cell cycle status. Objective: Identify and phenotypically characterize, via CXCR4 and SDF-1 expression, the bone marrow cell subpopulations that are mobilized into the bloodstream in patients with Acute Myocardial Infarction (AMI) and Acute Ischemia (AI) such as acute angina and Chronic Ischemia (CI) such as chronic stable angina, and also determine the cell cycle status of these cells. Method: Patients with AMI and AI were recruited in the ICCU, and patients with CI in the departments of cardiology and cardiovascular surgery. The quantification of cellular subpopulations was made by cytofluorometry with a FACS caliburcyto fluorometry (Becton Dickinson) with specific FITC-labeled anti human monoclonal antibodies against CD34, CD133, CD117, CD48, CXCR4, SDF-1 and Ki67 (Becton Dickinson). Serum concentration of IL-6 and IL-8 were determined by a sequential solid phase chemiluminescent assay performed in a SIEMENS IMMULITE 1000 Analyzer. Statistical analysis was made with the SPSS version 20.0 for Windows. A p value < 0.05 was considered as statistical significant. Results: We analyzed 174 patients. 67 had Acute Myocardial Infarction, 55 Acute Ischemia and 52 Chronic Ischemia. Total cellularity of bone marrow and SDF-1+ cells was significantly higher in patients with AMI (14.6 ± 1.5 × 103/ml) than that in AI (9.2 ± 1.3 × 103/ml) and CI (6.6 ± 1.1 × 103/ml) patients (p < 0.001). There were no significant differences in the amount of CD34+, CD117+, CD133+ and CD48+ cells between AMI (49.9 ± 3.9, 45 ± 4.7, 43.2 ± 3.7, 35.4 ± 6.7 respectively) and AI (36.7 ± 2.5, 36 ± 3.2, 33.7 ± 5.1, 32 ± 5 respectively) patients (p = 0.22 to 0.39), but interestingly in AMI and AI patients, cells were CXCR4+ in almost half of these mobilized cells, although the proportion was significantly higher in AMI patients (46.8% ± 7.1% to 55.7% ± 6.3% vs 23% ± 1.6% to 28.4% ± 2.1%, p = 0.03 to 0.05). A similar behavior was observed with the Ki67 antibody (29.9% ± 2.1% to 36.1% ± 6.3% vs 10% ± 1.2% to 24% ± 1.1%, p = 0.001 to 0.05). Bivariate analysis of the results showed a significant correlation of the cell proportion in AMI but not in AI and CI patients (p = 0.001 to 0.05; 0.12 to 0.87 and 0.17 to 0.92 respectively). The amount of myocardial tissue infarcted did not show any correlation with the amount of cellular subpopulations mobilized to peripheral blood (r = 0.10 to 0.20; p = 0.21 to 0.64) from the bone marrow. Conclusion: The proportion of cellular subpopulations with regenerative potential mobilized to circulation during an event of Acute Myocardial Infarction is significantly higher than during an event of acute angina and chronic stable angina, with a significant proportion of mobilized cells that expressed CXCR4, most of which were already in some of the cell cycle phases.

Share and Cite:

Aceves, J. , Vilchis, R. , Medina, M. , Borja, M. , Cortes, S. , Díaz, G. , Castro, A. , Gómez, A. , Parra, J. , Alvarado, M. , Hernández, M. , Poveda, V. , Masso, F. and Montaño, L. (2014) CXCR4+ and SDF-1+ Bone Marrow Cells Are Mobilized into the Blood Stream in Acute Myocardial Infarction and Acute Ischemia. World Journal of Cardiovascular Diseases, 4, 361-367. doi: 10.4236/wjcd.2014.47045.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Kajstura, J., Leri, A., Castaldo, C., Nadal-Ginard, B. and Anversa, P. (2004) Myocyte Growth in the Failing Heart. Surgical Clinics of North America, 84, 161-177.
[2] Timmermans, F., De Sutter, J. and Gillebert, T.C. (2003) Stem Cells for the Heart, Are We There Yet? Cardiology, 100, 176-185.
[3] Urbanek, K., Quaini, F., Tasca, G., Torella, D., Castaldo, C., Nadal-Ginard, B., Leri, A., Kajstura, J., Quaini, E. and Anversa, P. (2003) Intense Myocyte Formation from Cardiac Stem Cells in Human Cardiac Hypertrophy. Proceedings of the National Academy of Sciences of the United States of America, 100, 10440-10445.
[4] Assmus, B., Schachinger, V., Teupe, C., Britten, M., Lehmann, R., Dobert, N., Grunwald, F., Aicher, A., Urbich, C., Martin, H., Hoelzer, D., Dimmeler, S. and Zeiher, A.M. (2002) Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation, 106, 3009-3017.
[5] Vulliet, P.R., Greeley, M., Halloran, S.M., Mac-Donald, K.A. and Kittleson, M.D. (2004) Intra-Coronary Arterial Injection of Mesenchymal Stromal Cells and Microinfarction in Dogs. Lancet, 363, 783-784.
[6] Zhang, G., Nakamura, Y., Wang, X., Hu, Q., Suggs, L.J. and Zhang, J. (2007) Controlled Release of Stromal Cell-Derived Factor-1 Alpha in Situ Increases c-Kit Cell Homing to the Infarcted Heart. Tissue Engineering, 13, 2063-2071.
[7] Tang, Y.L., Zhu, W., Cheng, M., Chen, L., Zhang, J., Sun, T., et al. (2009) Hypoxic Preconditioning Enhances the Benefit of Cardiac Progenitor Cell Therapy for Treatment of Myocardial Infarction by Inducing CXCR4 Expression. Circulation Research, 104, 1209-1216.
[8] Janewit, D., Altuntas, C.Z., Johnson, J.M., Yong, S., Wickley, P.J. and Clark, P. (2007) Beta 1-Adrenergic Receptor Autoantibodies Mediate Dilated Cardiomyopathy by Agonistically Inducing Cardiomyocyte Apoptosis. Circulation, 116, 399-410.
[9] Assmus, B., Fischer-Rasokat, U., Honold, J., Seeger, F.H., Fichtlscherer, S. and Tonn, T. (2007) Transcoronary Transplantation of Functionally Competent BMCs Is Associated with a Decrease in Natriuretic Peptide Serum Levels and Improved Survival of Patients with Chronic Postinfarction Heart Failure: Results of the TOPCARE-CHD Registry. Circulation Research, 100, 1234-1241.
[10] Penn, M.S. (2009) Importance of the SDF-1:CXCR4 Axis in Myocardial Repair. Circulation Research, 104, 1133-1135.
[11] Lévesque, J.P., Hendy, J., Winkler, I.G., Takamatsu, Y. and Simmons, P.J. (2003) Granulocyte Colony-Stimulating Factor Induces the Release in the Bone Marrow of Pro-Teases That Cleave c-KIT Receptor (CD117) from the Surface of Hematopoietic Progenitor Cells. Experimental Hematology, 31, 109-117.
[12] Brunskill, S.J., Hyde, C.J., Doree, C.J., Watt, S.M. and Martin-Rendon, E. (2009) Route of Delivery and Baseline Left Ventricular Ejection Fraction, Key Factors of Bone-Marrow-Derived Cell Therapy for Ischaemic Heart Disease. European Journal of Heart Failure, 11, 887-896.
[13] Yeh, E.T., Zhang, S., Wu, H.D., Korbling, M., Willerson, J.T. and Estrov, Z. (2003) Transdifferentiation of Human Peripheral Blood CD34-Enriched Cell Population into Cardiomyocytes, Endothelial Cells, and Smooth Muscle Cells in Vivo. Circulation, 108, 2070-2073.
[14] Suarez de Lezo, J., Herrera, C., Pan, M., Romero, M., Pavlovic, D., Segura, J., Sanchez, J., Ojeda, S. and Torres, A. (2007) Regenerative Therapy in Patients with a Revascularized Acute Anterior Myocardial Infarction and Depressed Ventricular Function. Revista Española de Cardiología, 60, 357-365.
[15] Archundia, A., Aceves, J.L., Lopez-Hernandez, M., Alvarado, M., Rodriguez, E., Diaz Quiroz, G., Paez, A., Rojas, F.M. and Montaño, L.F. (2005) Direct Cardiac Injection of G-CSF Mobilized Bone-Marrow Stem-Cells Improves Ventricular Function in Old Myocardial Infarction. Life Sciences, 78, 279-283.
[16] Aceves, J.L., Archundia, A., Paez, A., Vilchis, R., Varela, E. and Rodriguez, E. (2012) Efficacy and Long-Term Evaluation of Intramyocardial Injection of Autologous CD34-Enriched PBMSC in Old Myocardial Infarction. World Journal of Cardiovascular Diseases, 2, 283-290.
[17] Bartunek, J., Dimmeler, S., Drexler, H., Fernandez-Aviles, F., Galinanes, M. and Janssens, S. (2006) Task Force of the European Society of Cardiology. The Consensus of the Task Force of the European Society of Cardiology Concerning the Clinical Investigation of the Use of Autologous Adult Stem Cells for Repair of the Heart. European Heart Journal, 27, 1338-1340.
[18] Strauer, B.E., Brehm, M., Zeus, T., Kostering, M., Hernandez, A., Sorg, R.V., et al. (2002) Repair of Infarcted Myocardium by Autologous Intra-Coronary Mononuclear Bone Marrow Cell Transplantation in Humans. Circulation, 106, 1913-1918.
[19] Mathur, A. and Martin, J.F. (2004) Stem Cells and Repair of the Heart. Lancet, 364, 183-192.
[20] Tse, H.F., Kwong, Y.L., Chan, J.K., Lo, G., Ho, C.L. and Lau, C.P. (2003) Angiogenesis in Ischaemic Myocardium by Intra-myocardial Autologous Bone Marrow Mononuclear Cell Implantation. Lancet, 361, 47-49.
[21] Askari, A., Unzek, S., Popovic, Z.B., Goldman, C.K., Forudi, F., kiedrowski, M., Rovner, A., Ellis, S.G., Thomas, J.D., DiCorleto, P.E., Topol, E.J. and Penn, M.S. (2003) Effect of Stromal-Cell-Derived Factor-1 on Stem Cell Homing and Tissue Regeneration in Ischemic Cardiomyopathy. Lancet, 362, 697-703.
[22] Schachinger, V., Erbs, S., Elsasser, A., Haberbosch, W., Hambrecht, R., Holschermann, H., Yu, J., Corti, R., Mathey, D.G., Hamm, C.W., Suselbeck, T., Assmus, B., Tonn, T., Dimmeler, S. and Zeiher, A.M. (2006) Intracoronary Bone Marrow Derived Progenitor Cells in Acute Myocardial Infarction. The New England Journal of Medicine, 355, 1210-1221.
[23] Hu, X., Dai, S., Wu, W.J., Tan, W., Zhu, X., Mu, J., Guo, Y., Bolli, R. and Rokosh, G. (2007) Stromal Cell Derived Factor-1 Alpha Confers Protection against Myocardial Ischemia/Reperfusion Injury: Role of the Cardiac Stromal Cell Derived Factor-1 Alpha CXCR4 Axis. Circulation, 116, 654-663.
[24] Zagzag, D., Lukyanov, Y., Lan, L., Ali, M.A., Esencay, M., Mendez, O., Yee, H., Voura, E.B. and Newcomb, E.W. (2006) Hypoxia-Inducible Factor 1 and VEGF Upregulate CXCR4 in Glioblastoma: Implications for Angiogenesis and Glioma Cell Invasion. Laboratory Investigation, 86, 1221-1232.
[25] Phillips, R.J., Mestas, J., Gharaee-Kermani, M., Burdick, M.D., Sica, A., Belperio, J.A., Keane, M.P. and Strieter, R.M. (2005) Epidermal Growth Factor and Hypoxia-Induced Expression of CXC Chemokine Receptor 4 on Non-Small Cell Lung Cancer Cells Is Regulated by the Phosphatidylinositol 3-Kinase/PTEN/AKT/Mammalian Target of Rapamycin Signaling Pathway and Activation of Hypoxia Inducible Factor-1 Alpha. The Journal of Biological Chemistry, 280, 22473-22481.
[26] Burchfield, J.S., Iwasaki, M., Koyanagi, M., Urbich, C., Rosenthal, N., Zeiher, A.M. and Dimmeler, S. (2008) Interleukin-10 from Transplanted Bone Marrow Mononuclear Cells Contributes to Cardiac Protection after Myocardial Infarction. Circulation Research, 103, 203-211.
[27] Bock-Marquette, I., Saxena, A., White, M.D., Dimaio, J.M. and Srivastava, D. (2004) Thymosin Beta4 Activates Integrin-Linked Kinase and Promotes Cardiac Cell Migration, Survival and Cardiac Repair. Nature, 432, 466-472.

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.