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Functional and Transcriptomic Recovery of Infarcted Mouse Myocardium Treated with Bone Marrow Mononuclear Cells

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Abstract

Although bone marrow-derived mononuclear cells (BMNC) have been extensively used in cell therapy for cardiac diseases, little mechanistic information is available to support reports of their efficacy. To address this shortcoming, we compared structural and functional recovery and associated global gene expression profiles in post-ischaemic myocardium treated with BMNC transplantation. BMNC suspensions were injected into cardiac scar tissue 10 days after experimental myocardial infarction. Six weeks later, mice undergoing BMNC therapy were found to have normalized antibody repertoire and improved cardiac performance measured by ECG, treadmill exercise time and echocardiography. After functional testing, gene expression profiles in cardiac tissue were evaluated using high-density oligonucleotide arrays. Expression of more than 18% of the 11981 quantified unigenes was significantly altered in the infarcted hearts. BMNC therapy restored expression of 2099 (96.2%) of the genes that were altered by infarction but led to altered expression of 286 other genes, considered to be a side effect of the treatment. Transcriptional therapeutic efficacy, a metric calculated using a formula that incorporates both recovery and side effect of treatment, was 73%. In conclusion, our results confirm a beneficial role for bone marrow-derived cell therapy and provide new information on molecular mechanisms operating after BMNC transplantation on post ischemic heart failure in mice.

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References

  1. Lloyd-Jones, D., Adams, R., Carnethon, M., De Simone, G., Ferguson, T. B., Flegal, K., et al. (2009). Heart disease and stroke statistics-2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation, 119(3), 480–486.

    Article  PubMed  Google Scholar 

  2. Jackson, K. A., Majka, S. M., Wang, H., Pocius, J., Hartley, C. J., Majesky, M. W., et al. (2001). Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. The Journal of Clinical Investigation, 107(11), 1395–1402.

    Article  PubMed  CAS  Google Scholar 

  3. Orlic, D., Kajstura, J., Chimenti, S., Jakoniuk, I., Anderson, S. M., Li, B., et al. (2001). Bone marrow cells regenerate infarcted myocardium. Nature, 410(6829), 701–705.

    Article  PubMed  CAS  Google Scholar 

  4. Losordo, D. W., & Dimmeler, S. (2004). Therapeutic angiogenesis and vasculogenesis for ischemic disease: part II: cell-based therapies. Circulation, 109(22), 2692–2697.

    Article  PubMed  Google Scholar 

  5. Wollert, K. C., & Drexler, H. (2005). Clinical applications of stem cells for the heart. Circulation Research, 96(2), 151–163.

    Article  PubMed  CAS  Google Scholar 

  6. Singh, S., Arora, R., Handa, K., Khraisat, A., Nagajothi, N., Molnar, J., et al. (2009). Stem cells improve left ventricular function in acute myocardial infarction. Clinical Cardiology, 32(4), 176–180.

    Article  PubMed  Google Scholar 

  7. Abdel-Latif, A., Bolli, R., Tleyjeh, I. M., Montori, V. M., Perin, E. C., Hornung, C. A., et al. (2007). Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Archives of Internal Medicine, 167(10), 989–997.

    Article  PubMed  Google Scholar 

  8. Menasche, P. (2010). Cardiac cell therapy: Lessons from clinical trials. Journal of Molecular and Cellular Cardiology, 50(2), 258–265.

    Article  PubMed  Google Scholar 

  9. Murry, C. E., Soonpaa, M. H., Reinecke, H., Nakajima, H., Nakajima, H. O., Rubart, M., et al. (2004). Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature, 428(6983), 664–668.

    Article  PubMed  CAS  Google Scholar 

  10. Sussman, M. A., & Murry, C. E. (2008). Bones of contention: marrow-derived cells in myocardial regeneration. Journal of Molecular and Cellular Cardiology, 44(6), 950–953.

    Article  PubMed  CAS  Google Scholar 

  11. Balsam, L. B., Wagers, A. J., Christensen, J. L., Kofidis, T., Weissman, I. L., & Robbins, R. C. (2004). Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature, 428(6983), 668–673.

    Article  PubMed  CAS  Google Scholar 

  12. Hatzistergos, K. E., Quevedo, H., Oskouei, B. N., Hu, Q., Feigenbaum, G. S., Margitich, I. S., et al. (2010). Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circulation Research, 107(7), 913–922.

    Article  PubMed  CAS  Google Scholar 

  13. Liao, R., Pfister, O., Jain, M., & Mouquet, F. (2007). The bone marrow-cardiac axis of myocardial regeneration. Progress in Cardiovascular Diseases, 50(1), 18–30.

    Article  PubMed  CAS  Google Scholar 

  14. Mouquet, F., Pfister, O., Jain, M., Oikonomopoulos, A., Ngoy, S., Summer, R., et al. (2005). Restoration of cardiac progenitor cells after myocardial infarction by self-proliferation and selective homing of bone marrow-derived stem cells. Circulation Research, 97(11), 1090–1092.

    Article  PubMed  CAS  Google Scholar 

  15. Nasef, A., Ashammakhi, N., & Fouillard, L. (2008). Immunomodulatory effect of mesenchymal stromal cells: possible mechanisms. Regenerative Medicine, 3(4), 531–546.

    Article  PubMed  CAS  Google Scholar 

  16. Rota, M., Kajstura, J., Hosoda, T., Bearzi, C., Vitale, S., Esposito, G., et al. (2007). Bone marrow cells adopt the cardiomyogenic fate in vivo. Proceedings of the National Academy of Sciences of the United States of America, 104(45), 17783–17788.

    Article  PubMed  CAS  Google Scholar 

  17. Yoon, Y. S., Wecker, A., Heyd, L., Park, J. S., Tkebuchava, T., Kusano, K., et al. (2005). Clonally expanded novel multipotent stem cells from human bone marrow regenerate myocardium after myocardial infarction. The Journal of Clinical Investigation, 115(2), 326–338.

    PubMed  CAS  Google Scholar 

  18. Lachtermacher, S., Esporcatte, B. L., Montalvao, F., Costa, P. C., Rodrigues, D. C., Belem, L., et al. (2010). Cardiac gene expression and systemic cytokine profile are complementary in a murine model of post-ischemic heart failure. Brazilian Journal of Medical and Biological Research, 43(4), 377–389.

    Article  PubMed  CAS  Google Scholar 

  19. Martin-Rendon, E., Brunskill, S. J., Hyde, C. J., Stanworth, S. J., Mathur, A., & Watt, S. M. (2008). Autologous bone marrow stem cells to treat acute myocardial infarction: a systematic review. European Heart Journal, 29(15), 1807–1818.

    Article  PubMed  CAS  Google Scholar 

  20. Ahn, D., Cheng, L., Moon, C., Spurgeon, H., Lakatta, E. G., & Talan, M. I. (2004). Induction of myocardial infarcts of a predictable size and location by branch pattern probability-assisted coronary ligation in C57BL/6 mice. American Journal of Physiology. Heart and Circulatory Physiology, 286(3), H1201–H1207.

    Article  PubMed  CAS  Google Scholar 

  21. Patten, R. D., Aronovitz, M. J., Deras-Mejia, L., Pandian, N. G., Hanak, G. G., Smith, J. J., et al. (1998). Ventricular remodeling in a mouse model of myocardial infarction. The American Journal of Physiology, 274(5 Pt 2), H1812–H1820.

    PubMed  CAS  Google Scholar 

  22. Salto-Tellez, M., Yung, L. S., El Oakley, R. M., Tang, T. P., ALmsherqi, Z. A., & Lim, S. K. (2004). Myocardial infarction in the C57BL/6J mouse: a quantifiable and highly reproducible experimental model. Cardiovascular Pathology, 13(2), 91–97.

    Article  PubMed  Google Scholar 

  23. Bayat, H., Swaney, J. S., Ander, A. N., Dalton, N., Kennedy, B. P., Hammond, H. K., et al. (2002). Progressive heart failure after myocardial infarction in mice. Basic Research in Cardiology, 97(3), 206–213.

    Article  PubMed  Google Scholar 

  24. Gao, X. M., Dart, A. M., Dewar, E., Jennings, G., & Du, X. J. (2000). Serial echocardiographic assessment of left ventricular dimensions and function after myocardial infarction in mice. Cardiovascular Research, 45(2), 330–338.

    Article  PubMed  CAS  Google Scholar 

  25. Barbash, I. M., Chouraqui, P., Baron, J., Feinberg, M. S., Etzion, S., Tessone, A., et al. (2003). Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: feasibility, cell migration, and body distribution. Circulation, 108(7), 863–868.

    Article  PubMed  Google Scholar 

  26. Iacobas, D. A., Iacobas, S., Urban-Maldonado, M., & Spray, D. C. (2005). Sensitivity of the brain transcriptome to connexin ablation. Biochimica et Biophysica Acta, 1711(2), 183–196.

    Article  PubMed  CAS  Google Scholar 

  27. Iacobas, D. A., Iacobas, S., Li, W. E., Zoidl, G., Dermietzel, R., & Spray, D. C. (2005). Genes controlling multiple functional pathways are transcriptionally regulated in connexin43 null mouse heart. Physiological Genomics, 20(3), 211–223.

    Article  PubMed  CAS  Google Scholar 

  28. Dahlquist, K. D., Salomonis, N., Vranizan, K., Lawlor, S. C., & Conklin, B. R. (2002). GenMAPP, a new tool for viewing and analyzing microarray data on biological pathways. Nature Genetics, 31(1), 19–20.

    Article  PubMed  CAS  Google Scholar 

  29. Brazma, A., Hingamp, P., Quackenbush, J., Sherlock, G., Spellman, P., Stoeckert, C., et al. (2001). Minimum information about a microarray experiment (MIAME)-toward standards for microarray data. Nature Genetics, 29(4), 365–371.

    Article  PubMed  CAS  Google Scholar 

  30. Malanchere, E., Marcos, M. A., Nobrega, A., & Coutinho, A. (1995). Studies on the T cell dependence of natural IgM and IgG antibody repertoires in adult mice. European Journal of Immunology, 25(5), 1358–1365.

    Article  PubMed  CAS  Google Scholar 

  31. Szodoray, P., Alex, P., Brun, J. G., Centola, M., & Jonsson, R. (2004). Circulating cytokines in primary Sjogren’s syndrome determined by a multiplex cytokine array system. Scandinavian Journal of Immunology, 59(6), 592–599.

    Article  PubMed  CAS  Google Scholar 

  32. Loffredo, F. S., Steinhauser, M. L., Gannon, J., & Lee, R. T. (2011). Bone marrow-derived cell therapy stimulates endogenous cardiomyocyte progenitors and promotes cardiac repair. Cell Stem Cell, 8(4), 389–398.

    Article  PubMed  CAS  Google Scholar 

  33. Soares, M.B.P., Lima, R.S., Souza, B.S.F., Vasconcelos, J.F., Rocha, L.L., Ribeiro dos Santos, R., et al (2011). Reversion of gene expression alterations in hearts of mice with chronic chagasic cardiomyopathy after transplantation of bone marrow cells. Cell Cycle 10(9), 1448-1455

    Google Scholar 

  34. Yoon, Y. S., Lee, N., & Scadova, H. (2005). Myocardial regeneration with bone-marrow-derived stem cells. Biology of the Cell, 97(4), 253–263.

    Article  PubMed  CAS  Google Scholar 

  35. Soares, M. B. P., Lima, R. S., Rocha, L. L., Takyia, C. M., Pontes-de-Carvalho, L., de Carvalho, A. C. C., et al. (2004). Transplanted bone marrow cells repair heart tissue and reduce myocarditis in chronic chagasic mice. The American Journal of Pathology, 164(2), 441–447.

    Article  PubMed  Google Scholar 

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The authors indicate no potential conflicts of interest.

Author information

Authors and Affiliations

  1. Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Bloco G, Ilha do Fundão 21949–900, Rio de Janeiro, RJ, Brazil

    Stephan Lachtermacher, Bruno L. B. Esporcatte, Fábio da Silva de Azevedo Fortes, Nazareth Novaes Rocha, Fabrício Montalvão, Patricia C. Costa, Regina C. S. Goldenberg & Antonio C. Campos de Carvalho

  2. PROCEP-Centro de Ensino e Pesquisa do Hospital Pró-Cardíaco, Rio de Janeiro, RJ, Brazil

    Luciano Belem & Arnaldo Rabischoffisky

  3. Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil

    Hugo C. C. Faria Neto

  4. Departamento de Imunobiologia, Universidade Federal Fluminense, Niterói, Brazil

    Rita Vasconcellos

  5. Departamento de Fisiologia e Farmacologia, Universidade Federal Fluminense, Niterói, Brazil

    Nazareth Novaes Rocha

  6. Albert Einstein College of Medicine, Bronx, USA

    Dumitru A. Iacobas, Sanda Iacobas, David C. Spray, Neil M. Thomas & Antonio C. Campos de Carvalho

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  1. Stephan Lachtermacher
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  2. Bruno L. B. Esporcatte
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  9. Hugo C. C. Faria Neto
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  11. Dumitru A. Iacobas
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  15. Regina C. S. Goldenberg
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  16. Antonio C. Campos de Carvalho
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Corresponding author

Correspondence to Antonio C. Campos de Carvalho.

Additional information

Stephan Lachtermacher and Bruno L. B. Esporcatte contributed equally to this work

Support

CAPES-MEC, FAPERJ, CNPq, Decit/MS and NIH (RO1 HL73732-01).

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Supplementary Table

Gene ontology (GO) categories of regulated genes with highest Z scores infarcted treated with MNC (DOC 227 kb)

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Lachtermacher, S., Esporcatte, B.L.B., da Silva de Azevedo Fortes, F. et al. Functional and Transcriptomic Recovery of Infarcted Mouse Myocardium Treated with Bone Marrow Mononuclear Cells. Stem Cell Rev and Rep 8, 251–261 (2012). https://doi.org/10.1007/s12015-011-9282-2

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