Skip to main content

Advertisement

SpringerLink
Log in

Improved Function and Myocardial Repair of Infarcted Heart by Intracoronary Injection of Mesenchymal Stem Cell-Derived Growth Factors

  • Published:
Journal of Cardiovascular Translational Research Aims and scope Submit manuscript

Abstract

Transplantation of mesenchymal stem cells (MSC) improves repair and function recovery following myocardial infarction (MI), but underlying mechanisms remain to be elucidated. We hypothesize that MSC could achieve protection by paracrine effects through released mediators rather than direct cardiac regeneration. We sought to characterize the effects of MSC-secreted growth factors on extent of early recovery from MI. Swine subjected to acute MI by temporary balloon occlusion of the left anterior descending coronary artery using percutaneous techniques received intracoronary injection of either concentrated MSC-derived growth factors or control medium. Animals were killed at 7 days to evaluate early effects. Treatment with MSC-derived factors significantly reduced cardiac troponin-T elevation and improved echocardiographic parameters, including fractional area shortening, stroke volume, cardiac output, and wall motion score index. Quantitative evaluation of fibrosis by Verhoff staining revealed a reduction of the fibrotic area in the infarcted zone. Similarly, Masson’s trichrome staining revealed reduced myocardial damage as demonstrated by areas of relatively preserved myocardium in the infarcted area. TUNEL assay demonstrated less cardiomyocyte apoptosis. Protein array detected the presence of angiogenic (vascular endothelial growth factor, endothelin, and epiregulin), anti-apoptotic (Galectin-3, Smad-5, sRFP-1, and sRFP-4) and anti-remodeling factors. Reverse transcription polymerase chain reaction confirmed the expression of these factors. In summary, a single intracoronary injection of concentrated biologically active factors secreted by MSC could achieve early protection of ischemic myocardium and improve cardiac repair and contractility. MSC-derived growth factors injection (rather than MSC themselves) should be evaluated as a novel therapy to treat ischemic heart disease, avoiding many practical and technical issues of cell therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Timmermans, F., De Sutter, J., & Gillebert, T. C. (2003). Stem cells for the heart, are we there yet? Cardiology, 100, 176–185.

    Article  CAS  PubMed  Google Scholar 

  2. Dowell, J. D., Rubart, M., Pasumarthi, K. B., Soonpaa, M. H., & Field, L. J. (2003). Myocyte and myogenic stem cell transplantation in the heart. Cardiovascular Research, 58, 336–350.

    Article  CAS  PubMed  Google Scholar 

  3. Raeburn, C. D., Zimmerman, M. A., Arya, J., Banerjee, A., & Harken, A. H. (2002). Stem cells and myocardial repair. Journal of the American College of Surgeons, 195, 686–693.

    Article  PubMed  Google Scholar 

  4. Tomita, S., Mickle, D. A., Weisel, R. D., et al. (2002). Improved heart function with myogenesis and angiogenesis after autologous porcine bone marrow stromal cell transplantation. Journal of Thoracic and Cardiovascular Surgery, 123, 1132–1140.

    Article  PubMed  Google Scholar 

  5. Tomita, S., Li, R. K., Weisel, R. D., et al. (1999). Autologous transplantation of bone marrow cells improves damaged heart function. Circulation, 100, II247–II256.

    CAS  PubMed  Google Scholar 

  6. Shake, J. G., Gruber, P. J., Baumgartner, W. A., et al. (2002). Mesenchymal stem cell implantation in a swine myocardial infarct model: Engraftment and functional effects. Annals of Thoracic Surgery, 73, 1919–1925. discussion 26.

    Article  PubMed  Google Scholar 

  7. Mangi, A. A., Noiseux, N., Kong, D., et al. (2003). Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nature Medicine, 9, 1195–1201. Epub 2003 Aug 10.

    Article  CAS  PubMed  Google Scholar 

  8. Gnecchi, M., He, H., Liang, O. D., et al. (2005). Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nature Medicine, 11, 367–368.

    Article  CAS  PubMed  Google Scholar 

  9. Noiseux, N., Gnecchi, M., Lopez-Ilasaca, M., et al. (2006). Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Molecular Therapy, 14, 840–850.

    Article  CAS  PubMed  Google Scholar 

  10. Kinnaird, T., Stabile, E., Burnett, M. S., et al. (2004). Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circulation Research, 94, 678–685.

    Article  CAS  PubMed  Google Scholar 

  11. Kinnaird, T., Stabile, E., Burnett, M. S., et al. (2004). Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation, 109, 1543–1549.

    Article  CAS  PubMed  Google Scholar 

  12. Takahashi, M., Li, T. S., Suzuki, R., et al. (2006). Cytokines produced by bone marrow cells can contribute to functional improvement of the infarcted heart by protecting cardiomyocytes from ischemic injury. American Journal of Physiology. Heart and Circulatory Physiology, 291, H886–H893.

    Article  CAS  PubMed  Google Scholar 

  13. Mirotsou, M., Zhang, Z., Deb, A., et al. (2007). Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair. Proceedings of the National Academy of Sciences of the United States of America, 104, 1643–1648.

    Article  CAS  PubMed  Google Scholar 

  14. Rehman, J., Traktuev, D., Li, J., et al. (2004). Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation, 109, 1292–1298.

    Article  PubMed  Google Scholar 

  15. Gnecchi, M., He, H., Noiseux, N., et al. (2006). Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. Faseb Journal, 20, 661–669.

    Article  CAS  PubMed  Google Scholar 

  16. Shabbir, A., Zisa, D., Suzuki, G., & Lee, T. (2009). Heart failure therapy mediated by the trophic activities of bone marrow mesenchymal stem cells: a noninvasive therapeutic regimen. American Journal of Physiology. Heart and Circulatory Physiology, 296, H1888–H1897.

    Article  CAS  PubMed  Google Scholar 

  17. Allan, D. S., Dubé, P., Roy, J., Busque, L., & Roy, D. C. (2007). Endothelial-like vascular progenitor cells from autologous and allogeneic donors: mobilization features distinct from hematopoetic progenitors. Biology of Blood & Marrow Transplantation, 13, 433–439.

    Article  CAS  Google Scholar 

  18. Guimond, M., Balassy, A., Barrette, M., Brochu, S., Perreault, C., & Roy, D. C. (2002). P-glycoprotein targeting: a unique strategy to selectively eliminate immunoreactive T cells. Blood, 100, 375–382.

    Article  CAS  PubMed  Google Scholar 

  19. Perrault, L. P., Malo, O., Desjardins, N., et al. (2002). Surgical experience with retroperitoneal heterotopic heart transplantation in the large white domestic swine. Journal of Investigative Surgery, 15, 45–55.

    Article  PubMed  Google Scholar 

  20. Pye, J., Ardeshirpour, F., McCain, A., et al. (2003). Proteasome inhibition ablates activation of NF-kappa B in myocardial reperfusion and reduces reperfusion injury. American Journal of Physiology. Heart and Circulatory Physiology, 284, H919–H926.

    CAS  PubMed  Google Scholar 

  21. Berry, M. F., Engler, A. J., Woo, Y. J., et al. (2006). Mesenchymal stem cell injection after myocardial infarction improves myocardial compliance. American Journal of Physiology. Heart and Circulatory Physiology, 290, H2196–H2203.

    Article  CAS  PubMed  Google Scholar 

  22. Ananiadou, O. G., Bibou, K., Drossos, G. E., et al. (2007). Effect of profound hypothermia during circulatory arrest on neurologic injury and apoptotic repressor protein Bcl-2 expression in an acute porcine model. Journal of Thoracic and Cardiovascular Surgery, 133, 919–926.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  24. Gnecchi, M., He, H., Melo, L. G., et al. (2009). Early beneficial effects of bone marrow-derived mesenchymal stem cells overexpressing Akt on cardiac metabolism after myocardial infarction. Stem Cells, 27, 971–979.

    Article  CAS  PubMed  Google Scholar 

  25. Benzhi, C., Limei, Z., Ning, W., et al. (2009). Bone marrow mesenchymal stem cells upregulate transient outward potassium currents in postnatal rat ventricular myocytes. Journal of Molecular and Cellular Cardiology, 47, 41–48.

    Article  PubMed  Google Scholar 

  26. Braga, L. M., Rosa, K., Rodrigues, B., et al. (2008). Systemic delivery of adult stem cells improves cardiac function in spontaneously hypertensive rats. Clinical and Experimental Pharmacology and Physiology, 35, 113–119.

    PubMed  Google Scholar 

  27. Xu, R. X., Chen, X., Chen, J. H., Han, Y., & Han, B. M. (2009). Mesenchymal stem cells promote cardiomyocyte hypertrophy in vitro through hypoxia-induced paracrine mechanisms. Clinical and Experimental Pharmacology and Physiology, 36, 176–180.

    Article  CAS  PubMed  Google Scholar 

  28. Guo, J., Lin, G. S., Bao, C. Y., Hu, Z. M., & Hu, M. Y. (2007). Anti-inflammation role for mesenchymal stem cells transplantation in myocardial infarction. Inflammation, 30, 97–104.

    Article  CAS  PubMed  Google Scholar 

  29. Nakanishi, C., Yamagishi, M., Yamahara, K., et al. (2008). Activation of cardiac progenitor cells through paracrine effects of mesenchymal stem cells. Biochemical and Biophysical Research Communications, 374, 11–16.

    Article  CAS  PubMed  Google Scholar 

  30. De Sousa, E., Veksler, V., Minajeva, A., et al. (1999). Subcellular creatine kinase alterations. Implications in heart failure. Circulation Research, 85, 68–76.

    PubMed  Google Scholar 

  31. O'Brien, P. J., Dameron, G. W., Beck, M. L., et al. (1997). Cardiac troponin T is a sensitive, specific biomarker of cardiac injury in laboratory animals. Laboratory Animal Science, 47, 486–495.

    PubMed  Google Scholar 

  32. Vikenes, K., Westby, J., Matre, K., Kuiper, K. K., Farstad, M., & Nordrehaug, J. E. (2002). Release of cardiac troponin I after temporally graded acute coronary ischaemia with electrocardiographic ST depression. International Journal of Cardiology, 85, 243–251. discussion 52-3.

    Article  PubMed  Google Scholar 

  33. Abbate, A., Bussani, R., Amin, M. S., Vetrovec, G. W., & Baldi, A. (2006). Acute myocardial infarction and heart failure: role of apoptosis. International Journal of Biochemistry and Cell Biology, 38, 1834–1840.

    Article  CAS  PubMed  Google Scholar 

  34. Galasko, G. I., Basu, S., Lahiri, A., & Senior, R. (2001). A prospective comparison of echocardiographic wall motion score index and radionuclide ejection fraction in predicting outcome following acute myocardial infarction. Heart, 86, 271–276.

    Article  CAS  PubMed  Google Scholar 

  35. Noiseux, N., Lopez Ilasaca, M., Gnecchi, M., et al. (2006). Mesenchymal stem cells over-expressing akt dramatically repairs infarcted myocardium and improves cardiac function despite infrequent cellular fusion or differentiation. Molecular Therapy Journal, 14, 840–850.

    Google Scholar 

  36. Janssens, S., Dubois, C., Bogaert, 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, 113–121.

    Article  PubMed  Google Scholar 

  37. Lunde, K., Solheim, S., Aakhus, S., et al. (2006). Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. New England Journal of Medicine, 355, 1199–1209.

    Article  CAS  PubMed  Google Scholar 

  38. Strauer, B. E., Brehm, M., Zeus, T., et al. (2002). Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation, 106, 1913–1918.

    Article  PubMed  Google Scholar 

  39. Vulliet, P. R., Greeley, M., Halloran, S. M., MacDonald, K. A., & Kittleson, M. D. (2004). Intra-coronary arterial injection of mesenchymal stromal cells and microinfarction in dogs. Lancet, 363, 783–784.

    Article  PubMed  Google Scholar 

  40. Freyman, T., Polin, G., Osman, H., et al. (2006). A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction. European Heart Journal, 27, 1114–1122.

    Article  PubMed  Google Scholar 

  41. Buschmann, I., Heil, M., Jost, M., & Schaper, W. (2003). Influence of inflammatory cytokines on arteriogenesis. Microcirculation, 10, 371–379.

    CAS  PubMed  Google Scholar 

  42. Heil, M., Ziegelhoeffer, T., Mees, B., & Schaper, W. (2004). A different outlook on the role of bone marrow stem cells in vascular growth: bone marrow delivers software not hardware. Circulation Research, 94, 573–574.

    Article  CAS  PubMed  Google Scholar 

  43. Kinnaird, T., Stabile, E., Burnett, M. S., & Epstein, S. E. (2004). Bone marrow-derived cells for enhancing collateral development: mechanisms, animal data, and initial clinical experiences. Circulation Research, 95, 354–363.

    Article  CAS  PubMed  Google Scholar 

  44. 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, 93–98.

    Article  PubMed  Google Scholar 

  45. Singla, D. K., & McDonald, D. E. (2007). Factors released from embryonic stem cells inhibit apoptosis of H9c2 cells. American Journal of Physiology. Heart and Circulatory Physiology, 293, H1590–H1595.

    Article  CAS  PubMed  Google Scholar 

  46. Zisa, D., Shabbir, A., Suzuki, G., & Lee, T. (2009). Vascular endothelial growth factor (VEGF) as a key therapeutic trophic factor in bone marrow mesenchymal stem cell-mediated cardiac repair. Biochemical and Biophysical Research Communications, 390, 834–838.

    Article  CAS  PubMed  Google Scholar 

  47. Topol, E. J. (2003). Current status and future prospects for acute myocardial infarction therapy. Circulation, 108, III6–III13.

    PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  49. Ince, H., Valgimigli, M., Petzsch, M., et al. (2008). Cardiovascular events and re-stenosis following administration of G-CSF in acute myocardial infarction: systematic review and meta-analysis. Heart, 94, 610–616.

    Article  CAS  PubMed  Google Scholar 

  50. Mansour, S., Roy, D. C., Bouchard, V., et al. (2009). COMPARE-AMI Trial: Comparison of Intracoronary Injection of CD133+ Bone Marrow Stem Cells to Placebo in Patients After Acute Myocardial Infarction and Left Ventricular Dysfunction: Study Rationale and Design. Journal of Cardiovascular Translational Research, in press.

Download references

Acknowledgements

We acknowledge Dr. D.C. Roy (Hôpital Maisonneuve-Rosemont) for his contribution in flow cytometric analyses. We thank M.P. Mathieu, E. Reny-Nolin, S. Gilligan, P. Geoffroy, and D. Lauzier for their precious help in this study and Dr Yan Fen Shi for the echocardiographic analysis. Drs. Noiseux and Perrault are scholars of Fonds de la Recherche en Santé du Québec (FRSQ). Dr. Noiseux and Perrault are supported by the Heart and Stroke Foundation of Québec, and Department of Surgery, Université de Montréal. Dr Stevens is supported by the Canadian Institutes of Health Research (CIHR).

Disclosures

No conflict of interest to disclose.

Author information

Authors and Affiliations

  1. Cardiac Surgery, Montreal University Hospital Centre (CHUM), Montreal, QC, Canada

    Ba-Khoi Nguyen, Louis-Mathieu Stevens & Nicolas Noiseux

  2. Cardiac Surgery, Montreal Heart Institute, Montreal, QC, Canada

    Simon Maltais & Louis P. Perrault

  3. Cardiology, Montreal Heart Institute, Montreal, QC, Canada

    Jean-François Tanguay & Jean-Claude Tardif

  4. CHUM Research Center (CRCHUM), Montréal, QC, Canada

    Louis-Mathieu Stevens, Mélanie Borie, Samer Mansour & Nicolas Noiseux

  5. Nuclear Medicine, Montreal Heart Institute, Montreal, QC, Canada

    François Harel

  6. Cardiology, CHUM, Montreal, QC, Canada

    Samer Mansour

  7. CHUM Hôtel-Dieu de Montréal, 3840 Saint-Urbain, Montréal, QC, H2W 1T8, Canada

    Nicolas Noiseux

Authors
  1. Ba-Khoi Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Simon Maltais
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Louis P. Perrault
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jean-François Tanguay
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jean-Claude Tardif
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Louis-Mathieu Stevens
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mélanie Borie
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. François Harel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Samer Mansour
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nicolas Noiseux
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nicolas Noiseux.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary data

(DOC 42 kb)

Supplementary figure

Echocardiographic analysis up to 28 days. A Intracoronary injection of MSC-derived growth factors after acute MI had persistent favorable effects on cardiac function as revealed by a significantly improved WMSI, used as an indicator of LV function and contractility (P < 0.001). B Similarly, LVEF tended to be worst in the control group (P = 0.072). Number of animals: n = 11 and 12 at baseline, n = 5 at 3 days, n = 6 and 7 at 7 days, and n = 3 at 30 days for controls and MSC-CM, respectively. Statistical analyses were made using longitudinal mixed effect models (JPEG 408 kb) (JPEG 408 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nguyen, BK., Maltais, S., Perrault, L.P. et al. Improved Function and Myocardial Repair of Infarcted Heart by Intracoronary Injection of Mesenchymal Stem Cell-Derived Growth Factors. J. of Cardiovasc. Trans. Res. 3, 547–558 (2010). https://doi.org/10.1007/s12265-010-9171-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-010-9171-0

Keywords

Search

Navigation