Improved Function and Myocardial Repair of Infarcted Heart by Intracoronary Injection of Mesenchymal Stem Cell-Derived Growth Factors
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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.
KeywordsCardiac Function Cellular Therapy Growth Factors Myocardial Ischemia Stem Cells
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).
No conflict of interest to disclose.
- 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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
- 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.Google Scholar