Stem Cell Reviews and Reports

, Volume 8, Issue 1, pp 251–261 | Cite as

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

  • Stephan Lachtermacher
  • Bruno L. B. Esporcatte
  • Fábio da Silva de Azevedo Fortes
  • Nazareth Novaes Rocha
  • Fabrício Montalvão
  • Patricia C. Costa
  • Luciano Belem
  • Arnaldo Rabischoffisky
  • Hugo C. C. Faria Neto
  • Rita Vasconcellos
  • Dumitru A. Iacobas
  • Sanda Iacobas
  • David C. Spray
  • Neil M. Thomas
  • Regina C. S. Goldenberg
  • Antonio C. Campos de Carvalho
Article

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.

Keywords

Heart failure Microarray analysis Immune-inflammatory response Cardiac function 

Notes

Disclosure of potential conflicts of interest

The authors indicate no potential conflicts of interest.

Supplementary material

12015_2011_9282_MOESM1_ESM.doc (227 kb)
Supplementary Table Gene ontology (GO) categories of regulated genes with highest Z scores infarcted treated with MNC (DOC 227 kb)

References

  1. 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.PubMedCrossRefGoogle Scholar
  2. 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.PubMedCrossRefGoogle Scholar
  3. 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.PubMedCrossRefGoogle Scholar
  4. 4.
    Losordo, D. W., & Dimmeler, S. (2004). Therapeutic angiogenesis and vasculogenesis for ischemic disease: part II: cell-based therapies. Circulation, 109(22), 2692–2697.PubMedCrossRefGoogle Scholar
  5. 5.
    Wollert, K. C., & Drexler, H. (2005). Clinical applications of stem cells for the heart. Circulation Research, 96(2), 151–163.PubMedCrossRefGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. 8.
    Menasche, P. (2010). Cardiac cell therapy: Lessons from clinical trials. Journal of Molecular and Cellular Cardiology, 50(2), 258–265.PubMedCrossRefGoogle Scholar
  9. 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.PubMedCrossRefGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 15.
    Nasef, A., Ashammakhi, N., & Fouillard, L. (2008). Immunomodulatory effect of mesenchymal stromal cells: possible mechanisms. Regenerative Medicine, 3(4), 531–546.PubMedCrossRefGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. 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.PubMedGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 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.PubMedCrossRefGoogle Scholar
  20. 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.PubMedCrossRefGoogle Scholar
  21. 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.PubMedGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 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.PubMedCrossRefGoogle Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. 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.PubMedCrossRefGoogle Scholar
  26. 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.PubMedCrossRefGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 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.PubMedCrossRefGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 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.PubMedCrossRefGoogle Scholar
  33. 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), 1448-1455Google Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Stephan Lachtermacher
    • 1
  • Bruno L. B. Esporcatte
    • 1
  • Fábio da Silva de Azevedo Fortes
    • 1
  • Nazareth Novaes Rocha
    • 1
    • 5
  • Fabrício Montalvão
    • 1
  • Patricia C. Costa
    • 1
  • Luciano Belem
    • 2
  • Arnaldo Rabischoffisky
    • 2
  • Hugo C. C. Faria Neto
    • 3
  • Rita Vasconcellos
    • 4
  • Dumitru A. Iacobas
    • 6
  • Sanda Iacobas
    • 6
  • David C. Spray
    • 6
  • Neil M. Thomas
    • 6
  • Regina C. S. Goldenberg
    • 1
  • Antonio C. Campos de Carvalho
    • 1
    • 6
  1. 1.Instituto de Biofísica Carlos Chagas FilhoUniversidade Federal do Rio de JaneiroRio de JaneiroBrazil
  2. 2.PROCEP-Centro de Ensino e Pesquisa do Hospital Pró-CardíacoRio de JaneiroBrazil
  3. 3.Laboratório de ImunofarmacologiaInstituto Oswaldo Cruz, FiocruzRio de JaneiroBrazil
  4. 4.Departamento de ImunobiologiaUniversidade Federal FluminenseNiteróiBrazil
  5. 5.Departamento de Fisiologia e FarmacologiaUniversidade Federal FluminenseNiteróiBrazil
  6. 6.Albert Einstein College of MedicineBronxUSA

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