JBiSE  Vol.9 No.4 , March 2016
Stem Cell Therapy of Ischemic Heart Disease
Abstract: Ischemic heart disease (IHD) accelerates death of cardiomyocytes and leads to the onset of cardiac failure. Due to the application of stem cells, there exists a potential for the regeneration of a damaged myocardium. Here we present a brief review of the modern data on the application of various types of stem cells for the IHD therapy. We consider different types of stem cells, which are most preferable for the clinical application, including mesenchymal stem cells, cardiac stem cells, embryonic stem cells, iPS cells and others. In particular, we discuss their advantages and strategies which can be applied in order to boost their regenerative potential, as well as optimization of their delivery. Besides, our review refers to the contemporary achievements in the field of tissue engineering of heart, using both polymer scaffolds and scaffold-free constructs. We also discuss the most prominent known clinical trials on stem cell therapy of ischemic heart disease.
Cite this paper: Konoplyannikov, M. , Kalsin, V. , Averyanov, A. and Troitsky, A. (2016) Stem Cell Therapy of Ischemic Heart Disease. Journal of Biomedical Science and Engineering, 9, 191-215. doi: 10.4236/jbise.2016.94015.

[1]   Lopez, A.D., Mathers, C.D., Ezzati, M., Jamison, D.T. and Murray, C.J. (2006) Global and Regional Burden of Disease and Risk Factors, 2001: Systematic Analysis of Population Health Data. Lancet, 367, 1747-1757.

[2]   Diwan, A. and Dorn II, G.W. (2007) Decompensation of Car-diac Hypertrophy: Cellular Mechanisms and Novel Therapeutic Targets. Physiology, 22, 56-64.

[3]   Diwan, A., Krenz, M., Syed, F.M., Wansapura, J., Ren, X., Koesters, A.G., et al. (2007) Inhibition of Ischemic Cardiomyocyte Apoptosis through Targeted Ablation of Bnip3 Restrains Postinfarction Remodeling in Mice. Journal of Clinical Investigation, 117, 2825-2833.

[4]   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, 989-997.

[5]   Leri, A., Kajstura, J. and Anversa, P. (2005) Cardiac Stem Cells and Mechanisms of Myocardial Regeneration. Physiological Reviews, 85, 1373-1416.

[6]   Borchardt, T. and Braun, T. (2007) Cardiovascular Regeneration in Non-Mammalian Model Systems: What Are the Differences between Newts and Man? Thrombosis and Haemostasis, 98, 311-318.

[7]   Poss, K.D. (2007) Getting to the Heart of Regeneration in Zebrafish. Seminars in Cell & Developmental Biology, 18, 36-45.

[8]   Bergmann, O., Bhardwaj, R.D., Bernard, S., Zdunek, S., Barnabe-Heider, F., Walsh, S., et al. (2009) Evidence for Cardiomyocyte Renewal in Humans. Science, 324, 98-102.

[9]   Beltrami, A.P., Urbanek, K., Kajstura, J., Yan, S.M., Finato, N., Bussani, R., et al. (2001) Evidence That Human Cardiac Myocytes Divide after MI. The New England Journal of Medicine, 344, 1750-1757.

[10]   Ahuja, P., Sdek, P. and MacLellan, W.R. (2007) Cardiac Myocyte Cell Cycle Control in Development, Disease, and Regeneration. Physiological Reviews, 87, 521-544.

[11]   Tongers, J., Losordo, D.W. and Landmesser, U. (2011) Stem and Progenitor Cell-Based Therapy in Ischaemic Heart Disease: Promise, Uncertainties, and Challenges. European Heart Journal, 32, 1197-1206.

[12]   Keller, G. (2005) Embryonic Stem Cell Differentiation: Emergence of a New Era in Biology and Medicine. Genes & Development, 19, 1129-1155.

[13]   Mummery, C., Ward-van Oostwaard, D., Doevendans, P., Spijker, R., van den Brink, S., Hassink, R., et al. (2003) Differentiation of Human Embryonic Stem Cells to Cardiomyocytes: Role of Coculture with Visceral Endoderm-Like Cells. Circulation, 107, 2733-2740.

[14]   Xue, T., Cho, H.C., Akar, F.G., Tsang, S.Y., Jones, S.P., Marban, E., et al. (2005) Functional Integration of Electrically Active Cardiac Derivatives from Genetically Engineered Human Embryonic Stem Cells with Quiescent Recipient Ventricular Cardiomyocytes: Insights into the Development of Cell-Based Pacemakers. Circulation, 111, 11-20.

[15]   Caspi, O., Huber, I., Kehat, I., Habib, M., Arbel, G., Gepstein, A., et al. (2007) Transplantation of Human Embryonic Stem Cell-Derived Cardiomyocytes Improves Myocardial Performance in Infarcted Rat Hearts. Journal of the American College of Cardiology, 50, 1884-1893.

[16]   Mignone, J.L., Kreutziger, K.L., Paige, S.L. and Murry, C.E. (2010) Cardiogenesis from Human Embryonic Stem Cells. Circulation Journal, 74, 2517-2526.

[17]   Condorelli, G. and Catalucci, D. (2007) Human Stem Cells for Heart Failure Treatment Ready for Prime Time? Journal of the American College of Cardiology, 50, 1894-1895.

[18]   Takahashi, K. and Yamanaka, S. (2006) Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell, 126, 663-676.

[19]   Zhang, J., Wilson, G.F., Soerens, A.G., Koonce, C.H., Yu, J., Palecek, S.P., et al. (2009) Functional Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells. Circulation Research, 104, e30-e41.

[20]   Nelson, T.J., Martinez-Fernandez, A., Yamada, S., Perez-Terzic, C., Ikeda, Y. and Terzic, A. (2009) Repair of Acute MI by Human Stemness Factors Induced Pluripotent Stem Cells. Circulation, 120, 408-416.

[21]   Yoshida, Y. and Yamanaka, S. (2011) IPS Cells: A Source of Cardiac Regeneration. Journal of Molecular and Cellular Cardiology, 50, 327-332.

[22]   Ieda, M., Fu, J.D., Delgado-Olguin, P., Vedantham, V., Hayashi, Y., Bruneau, B.G., et al. (2010) Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors. Cell, 142, 375-386.

[23]   Efe, J.A., Hilcove, S., Kim, J., Zhou, H., Ouyang, K., Wang, G., et al. (2011) Conversion of Mouse Fibroblasts into Cardiomyocytes Using a Direct Reprogramming Strategy. Nature Cell Biology, 13, 215-222.

[24]   Qian, L., Huang, Y., Spencer, C.I., Foley, A., Vedantham, V., Liu, L., et al. (2012) In Vivo Reprogramming of Murine Cardiac Fibroblasts into Induced Cardi-omyocytes. Nature, 485, 593-598.

[25]   Orlic, D., Kajstura, J., Chimenti, S., Limana, F., Jakoniuk, I., Quaini, F., et al. (2001) Mobilized Bone Marrow Cells Repair the Infarcted Heart, Improving Func-tion and Survival. Proceedings of the National Academy of Sciences of the United States of America, 98, 10344-10349.

[26]   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 MI. Journal of Clinical Investigation, 115, 326-338.

[27]   Kajstura, J., Rota, M., Whang, B., Cascapera, S., Hosoda, T., Bearzi, C., et al. (2005) Bone Marrow Cells Differentiate in Cardiac Cell Lineages after Infarction Independently of Cell Fusion. Circulation Research, 96, 127-137.

[28]   Clifford, D.M., Fisher, S.A., Brunskill, S.J., Doree, C., Mathur, A., Watt, S., et al. (2012) Stem Cell Treatment for Acute MI. Cochrane Database of Systematic Reviews, 2, CD006536.

[29]   Templin, C., Kotlarz, D., Faulhaber, J., Schnabel, S., Grote, K., Salguero, G., et al. (2008) Ex Vivo Expanded Hematopoietic Progenitor Cells Improve Cardiac Function after MI: Role of Beta-Catenin Transduction and Cell Dose. Journal of Molecular and Cellular Cardiology, 45, 394-403.

[30]   Mansour, S., Roy, D.C., Bouchard, V., Nguyen, B.K., Stevens, L.M., Gobeil, F., et al. (2010) COMPARE-AMI Trial: Comparison of Intracoronary Injection of CD133+ Bone Marrow Stem Cells to Placebo in Patients after Acute MI and Left Ventricular Dysfunction: Study Rationale and Design. Journal of Cardiovascular Translational Research, 3, 153-159.

[31]   Balsam, L.B., Wagers, A.J., Christensen, J.L., Kofidis, T., Weissman, I.L. and Robbins, R.C. (2004) Haematopoietic Stem Cells Adopt Mature Haematopoietic Fates in Ischaemic Myocardium. Nature, 428, 668-673.

[32]   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, 664-668.

[33]   Jujo, K., Ii, M. and Losordo, D.W. (2008) Endothelial Progenitor Cells in Neovascularization of Infarcted Myocardium. Journal of Molecular and Cellular Cardiology, 45, 530-544.

[34]   Leone, A.M., Rutella, S., Giannico, M.B., Perfetti, M., Zaccone, V., Brugaletta, S., et al. (2008) Effect of Intensive vs Standard Statin Therapy on Endothelial Progenitor Cells and Left Ventricular Function in Patients with Acute MI: Statins for Regeneration after Acute MI and PCI (STRAP) Trial. International Journal of Cardiology, 130, 457-462.

[35]   Gruh, I., Beilner, J., Blomer, U., Schmiedl, A., Schmidt-Richter, I., Kruse, M.L., et al. (2006) No Evidence of Transdifferentiation of Human Endothelial Progenitor Cells into Cardiomyocytes after Coculture with Neonatal Rat Cardiomyocytes. Circulation, 113, 1326-1334.

[36]   Barry, F.P. and Murphy, J.M. (2004) Mesenchymal Stem Cells: Clinical Applications and Biological Characterization. The International Journal of Biochemistry & Cell Biology, 36, 568-584.

[37]   Xu, X., Xu, Z., Xu, Y. and Cui, G. (2005) Selective Down-Regulation of Extracellular Matrix Gene Expression by Bone Marrow Derived Stem Cell Transplantation into Infarcted Myocardium. Circulation Journal, 69, 1275-1283.

[38]   Xu, H., Yang, Y.J., Qian, H.Y., Tang, Y.D., Wang, H. and Zhang, Q. (2011) Rosuvastatin Treatment Activates JAK-STAT Pathway and Increases Efficacy of Allogeneic Mesenchymal Stem Cell Transplantation in Infracted Hearts. Circulation Journal, 75, 1476-1485.

[39]   Aggarwal, S. and Pittenger, M.F. (2005) Human Mesenchymal Stem Cells Modulate Allogeneic Immune Cell Responses. Blood, 105, 1815-1822.

[40]   Makino, S., Fukuda, K., Miyoshi, S., Konishi, F., Kodama, H., Pan, J., Sano, M., Takahashi, T., Hori, S., Abe, H., Hata, J., Umezawa, A. and Ogawa, S. (1999) Cardiomyocytes Can Be Generated from Marrow Stromal Cells in Vitro. Journal of Clinical Investigation, 103, 697-705.

[41]   Tomita, S., Li, R.K., Weisel, R.D., Mickle, D.A., Kim, E.J., Sakai, T. and Jia, Z.Q. (1999) Autologous Transplantation of Bone Marrow Cells Improves Damaged Heart Function. Circulation, 100, II247-II256.

[42]   Davani, S., Marandin, A., Mersin, N., Royer, B., Kantelip, B., Hervé, P., Etievent, J.P. and Kantelip, J.P. (2003) Mesenchymal Progenitor Cells Differentiate into an Endothelial Phenotype, Enhance Vascular Density, and Improve Heart Function in a Rat Cellular Cardiomyoplasty Model. Circulation, 108, II253-II258.

[43]   Wang, J.-S., Shum-Tim, D. and Chedrawy, E. (2000) Marrow Stromal Cells for Cellular Cardiomyoplasty: The Importance of Microenvironment for Milieu Dependent Differentiation. Circulation, 102, II-683.

[44]   Richardson, J.D., Nelson, A.J., Zannettino, A.C., Gronthos, S., Worthley, S.G. and Psaltis, P.J. (2013) Optimization of the Cardiovascular Therapeutic Properties of Mesenchymal Stromal/Stem Cells-Taking the Next Step. Stem Cell Reviews and Reports, 9, 281-302.

[45]   Silva, G.V., Litovsky, S., Assad, J.A., Sousa, A.L., Martin, B.J., Vela, D., Coulter, S.C., Lin, J., Ober, J., Vaughn, W.K., Branco, R.V., Oliveira, E.M., He, R., Geng, Y.J., Willerson, J.T. and Perin, E.C. (2005) Mesenchymal Stem Cells Differentiate into an Endothelial Phenotype, Enhance Vascular Density, and Improve Heart Function in a Canine Chronic Ischemia Model. Circulation, 111, 150-156.

[46]   Amado, L.C., Saliaris, A.P., Schuleri, K.H., St John, M., Xie, J.S., Cattaneo, S., et al. (2005) Cardiac Repair with IM Injection of Allogeneic Mesenchymal Stem Cells after MI. Proceedings of the National Academy of Sciences of the United States of America, 102, 11474-11479.

[47]   Gnecchi, M., Zhang, Z., Ni, A. and Dzau, V.J. (2008) Paracrine Mechanisms in Adult Stem Cell Signaling and Therapy. Circulation Research, 103, 1204-1219.

[48]   Maggini, J., Mirkin, G., Bognanni, I., Holmberg, J., Piazzon, I.M., Nepomnaschy, I., et al. (2010) Mouse Bone Marrow-Derived Mesenchymal Stromal Cells Turn Activated Macrophages into a Regulatory-Like Profile. PLoS ONE, 5, e9252.

[49]   Nemeth, K., Leelahavanichkul, A., Yuen, P.S., Mayer, B., Parmelee, A., Doi, K., et al. (2009) Bone Marrow Stromal Cells Attenuate Sepsis via Prostaglandin E2-Dependent Reprogramming of Host Macrophages to Increase Their Interleukin-10 Production. Nature Medicine, 15, 42-49.

[50]   Zhang, Q.Z., Su, W.R., Shi, S.H., Wilder-Smith, P., Xiang, A.P., Wong, A., et al. (2010) Human Gingival Derived Mesenchymal Stem Cells Elicit Polarization of m2 Macrophages and Enhance Cutaneous Wound Healing. Stem Cells, 28, 1856-1868.

[51]   Kronsteiner, B., Peterbauer-Scherb, A., Grillari-Voglauer, R., Redl, H., Gabriel, C., van Griensven, M., et al. (2011) Human Mesenchymal Stem Cells and Renal Tubular Epithelial Cells Differentially Influence Monocyte-Derived Dendritic Cell Differentiation and Maturation. Cellular Immunology, 267, 30-38.

[52]   Li, Q., Turdi, S., Thomas, D.P., Zhou, T. and Ren, J. (2010) Intra-Myocardial Delivery of Mesenchymal Stem Cells Ameliorates Left Ventricular and Cardiomyocyte Contractile Dysfunction Following Myocardial Infarction. Toxicology Letters, 195, 119-126.

[53]   Xu, X., Xu, Z., Xu, Y. and Cui, G. (2005) Effects of Mesenchymal Stem Cell Transplantation on Extracellular Matrix after Myocardial Infarction in Rats. Coronary Artery Disease, 16, 245-255.

[54]   Dixon, J.A., Gorman, R.C., Stroud, R.E., Bouges, S., Hirotsugu, H., Gorman, J.H., Martens, T.P., Itescu, S., Schuster, M.D., Plappert, T., et al. (2009) Mesenchymal Cell Transplantation and Myocardial Remodeling after Myocardial Infarction. Circulation, 120, S220-S229.

[55]   Jiang, Z., Hu, X., Yu, H., Xu, Y., Wang, L., Chen, H., et al. (2013) Human Endometrial Stem Cells Confer Enhanced Myocardial Salvage and Regeneration by Paracrine Mechanisms. Journal of Cellular and Molecular Medicine, 17, 1247-1260.

[56]   Li, B., Zeng, Q., Wang, H., Shao, S., Mao, X., Zhang, F., et al. (2007) Adipose Tissue Stromal Cells Transplantation in Rats of Acute Myocardial Infarction. Coronary Artery Disease, 18, 221-227.

[57]   Sadat, S., Gehmert, S., Song, Y.-H., Yen, Y., Bai, X., Gaiser, S., et al. (2007) The Cardioprotective Effect of Mesenchymal Stem Cells Is Mediated by IGF-I and VEGF. Biochemical and Biophysical Research Communications, 363, 674-679.

[58]   Madonna, R., Geng, Y.-J. and Caterina, R.D. (2009) Adipose Tissue-Derived Stem Cells Characterization and Potential for Cardiovascular Repair. Arteriosclerosis, Thrombosis, and Vascular Biology, 29, 1723-1729.

[59]   Nagaya, N., Fujii, T., Iwase, T., Ohgushi, H., Itoh, T., Uematsu, M., et al. (2004) Intravenous Administration of Mesenchymal Stem Cells Improves Cardiac Function in Rats with Acute Myocardial Infarction through Angiogenesis and Myogenesis. American Journal of Physiology: Heart and Circulatory Physiology, 287, H2670-H2676.

[60]   Rehman, J., Traktuev, D., Li, J., Merfeld-Clauss, S., Temm-Grove, C.J., Bovenkerk, J.E., et al. (2004) Secretion of Angiogenic and Antiapoptotic Factors by Human Adipose Stromal Cells. Circulation, 109, 1292-1298.

[61]   Schenke-Layland, K., Strem, B.M., Jordan, M.C., DeEmedio, M.T., Hedrick, M.H., Roos, K.P., et al. (2009) Adipose Tissue-Derived Cells Improve Cardiac Function Following Myocardial Infarction. Journal of Surgical Research, 153, 217-223.

[62]   Miyahara, Y., Nagaya, N., Kataoka, M., Yanagawa, B., Tanaka, K., Hao, H., et al. (2006) Monolayered Mesenchymal Stem Cells Repair Scarred Myocardium after Myocardial Infarction. Nature Medicine, 12, 459-465.

[63]   Uemura, R., Xu, M., Ahmad, N. and Ashraf, M. (2006) Bone Marrow Stem Cells Prevent Left Ventricular Remodeling of Ischemic Heart through Paracrine Signaling. Circulation Research, 98, 1414-1421.

[64]   Bai, X. and Alt, E. (2010) Myocardial Regeneration Potential of Adipose Tissue-Derived Stem Cells. Biochemical and Biophysical Research Communications, 401, 321-326.

[65]   Bai, X., Yan, Y., Song, Y.-H., Sei-densticker, M., Rabinovich, B., Metzele, R., et al. (2010) Both Cultured and Freshly Isolated Adipose Tissue-Derived Stem Cells Enhance Cardiac Function after Acute Myocardial Infarction. European Heart Journal, 31, 489-501.

[66]   Schuleri, K.H., Amado, L.C., Boyle, A.J., Centola, M., Saliaris, A.P., Gutman, M.R., Hatzistergos, K.E., Oskouei, B.N., Zimmet, J.M., Young, R.G., Heldman, A.W., Lardo, A.C. and Hare, J.M. (2008) Early Improvement in Cardiac Tissue Perfusion Due to Mesenchymal Stem Cells. American Journal of Physiolo-gy—Heart and Circulatory Physiology, 294, H2002-H2011.

[67]   Hatzistergos, K.E., Quevedo, H., Oskouei, B.N., Hu, Q., Feigenbaum, G.S., Margitich, I.S., Mazhari, R., Boyle, A.J., Zambrano, J.P., Rodriguez, J.E., Dulce, R., Pattany, P.M., Valdes, D., Revilla, C., Heldman, A.W., McNiece, I. and Hare, J.M. (2010) Bone Marrow Mesenchymal Stem Cells Stimulate Cardiac Stem Cell Proliferation and Differentiation. Circulation Research, 107, 913-922.

[68]   Katritsis, D.G., Sotiropoulou, P.A., Karvouni, E., Karabinos, I., Korovesis, S., Perez, S.A., et al. (2005) Transcoronary Transplantation of Autologous mesenchymal Stem Cells and Endothelial Progenitors into Infarcted Human Myocardium. Catheterization and Cardiovascular Interventions, 65, 321-329.

[69]   Yang, Z., Zhang, F., Ma, W., Chen, B., Zhou, F., Xu, Z., et al. (2010) A Novel Approach to Transplanting Bone Marrow Stem Cells to Repair Human MI: Delivery via a Noninfarct-Relative Artery. Cardiovascular Therapeutics, 28, 380-385.

[70]   Chen, S., Liu, Z., Tian, N., Zhang, J., Yei, F., Duan, B., Zhu, Z., Lin, S. and Kwan, T.W. (2006) Intracoronary Transplantation of Autologous Bone Marrow Mesenchymal Stem Cells for Ischemic Cardiomyopathy Due to Isolated Chronic Occluded Left Anterior Descending Artery. The Journal of Invasive Car-diology, 18, 552-556.

[71]   Katritsis, D.G., Sotiropoulou, P., Giazitzoglou, E., Karvouni, E. and Papamichail, M. (2007) Electrophysiological Effects of Intracoronary Transplantation of Autologous Mesenchymal and Endothelial Progenitor Cells. Europace, 9, 167-171.

[72]   Williams, A.R., Trachtenberg, B., Velazquez, D.L., McNiece, I., Altman, P., Rouy, D., et al. (2011) IM Stem Cell Injection in Patients with Ischemic Cardiomyopathy: Functional Recovery and Reverse Remodeling. Circulation Research, 108, 792-796.

[73]   Hare, J.M., Traverse, J.H., Henry, T.D., Dib, N., Strumpf, R.K., Schulman, S.P., et al. (2009) A randomized, Double- Blind, Placebo-Controlled, Dose-Escalation Study of Intravenous Adult Human Mesenchymal Stem Cells (Prochymal) after Acute MI. Journal of the American College of Cardiology, 54, 2277-2286.

[74]   Fischer, U.M., Harting, M.T., Jimenez, F., Monzon-Posadas, W.O., Xue, H., Savitz, S.I., Laine, G.A. and Cox Jr., C.S. (2009) Pulmonary Passage Is a Major Obstacle for Intravenous Stem Cell Delivery: The Pulmonary First-Pass Effect. Stem Cells and Development, 18, 683-692.

[75]   Tsyb, A.F., Konoplyannikov, A.G., Kaplan, M.A., et al. (2009) Systemic Transplantation of Autologous Mesenchymal Stem Cells for Coplex Therapy of Patients with Chronic Heart Failure. Cell Transplantology and Tissue Engineering, 4, 78-84.

[76]   Guijarro, D., Lebrin, M., Lairez, O., Bourin, P., Piriou, N., Pozzo, J., et al. (2015) 0148: IM Transplantation of Mesenchymal Stromal Cells for Chronic Myocardial Ischemia and Decreased Left Ventricular Function: 1-Year Results of the MESAMI Phase I Clinical Trial. Archives of Cardiovascular Diseases Sup-plements, 7, 20.

[77]   Menasche, P. (2007) Skeletal Myoblasts as a Therapeutic Agent. Progress in Cardiovascular Diseases, 50, 7-17.

[78]   Pagani, F.D., DerSimonian, H., Zawadzka, A., Wetzel, K., Edge, A.S., Jacoby, D.B., et al. (2003) Autologous Skeletal Myoblasts Transplanted to Ischemia Damaged Myocardium in Humans: Histological Analysis of Cell Survival and Differentiation. Journal of the American College of Cardiology, 41, 879-888.

[79]   Ghostine, S., Carrion, C., Souza, L.C., Richard, P., Bruneval, P., Vilquin, J.T., et al. (2002) Long-Term Efficacy of Myoblast Transplantation on Regional Structure and Function after MI. Circulation, 106, I131-I136.

[80]   Reinecke, H., Poppa, V. and Murry, C.E. (2002) Skeletal Muscle Stem Cells Do Not Transdifferentiate into Cardiomyocytes after Cardiac Grafting. Journal of Molecular and Cellular Cardiology, 34, 241-249.

[81]   Eisen, H.J. (2008) Skeletal Myoblast Transplantation: No Magic Bullet for Ischemic Cardiomyopathy. Nature Clinical Practice Cardiovascular Medicine, 5, 520-521.

[82]   Oh, H., Bradfute, S.B., Gallardo, T.D., Nakamura, T., Gaussin, V., Mishina, Y., et al. (2003) Cardiac Progenitor Cells from Adult Myocardium: Homing, Differentiation, and Fusion after In-farction. Proceedings of the National Academy of Sciences of the United States of America, 100, 12313-12318.

[83]   Matsuura, K., Nagai, T., Nishigaki, N., Oyama, T., Nishi, J., Wada, H., et al. (2004) Adult Cardiac Sca-1-Positive Cells Differentiate into Beating Cardiomyocytes. The Journal of Biological Chemistry, 279, 11384-11391.

[84]   Wang, X., Hu, Q., Nakamura, Y., Lee, J., Zhang, G., From, A.H., et al. (2006) The Role of the Sca-1+/CD31? Cardiac Progenitor Cell Population in Postinfarction Left Ventricular Remodeling. Stem Cells, 24, 1779-1788.

[85]   Beltrami, A.P., Barlucchi, L., Torella, D., Baker, M., Limana, F., Chimenti, S., et al. (2003) Adult Cardiac Stem Cells Are Multipotent and Support Myocardial Regeneration. Cell, 114, 763-776.

[86]   Bolli, R., Chugh, A.R., D’Amario, D., Loughran, J.H., Stoddard, M.F., Ikram, S., et al. (2011) Cardiac Stem Cells in Patients with Ischaemic Cardiomyopathy (SCIPIO): Initial Results of a Randomised Phase 1 Trial. Lancet, 378, 1847-1857.

[87]   Zaruba, M.M., Soonpaa, M., Reuter, S. and Field, L.J. (2010) Cardiomyogenic Potential of c-kit+-Expressing Cells Derived from Neonatal and Adult Mouse Hearts. Circulation, 121, 1992-2000.

[88]   Beltrami, A.P., Barlucchi, L., Torella, D., Baker, M., Limana, F., Chimenti, S., Kasahara, H., Rota, M., Musso, E., Urbanek, K., Leri, A., Kajstura, J., Nadal-Ginard, B. and Anversa, P. (2003) Adult Cardiac Stem Cells Are Multipotent and Support Myocardial Regeneration. Cell, 114, 763-776.

[89]   Dawn, B., Stein, A.B., Urbanek, K., Rota, M., Whang, B., Rastaldo, R., Torella, D., Tang, X.-L., Rezazadeh, A., Kajstura, J., Leri, A., Hunt, G., Varma, J., Prabhu, S.D., Anversa, P. and Bolli, R. (2005) Cardiac Stem Cells Delivered Intravascularly Traverse the Vessel Barrier, Regenerate Infarcted Myocardium, and Improve Cardiac Function. Proceedings of the National Academy of Sciences of the United States of America, 102, 3766-3771.

[90]   Fazel, S., Cimini, M., Chen, L., Li, S., Angoulvant, D., Fedak, P., et al. (2006) Cardioprotective c-kit+ Cells Are from the Bone Marrow and Regulate the Myocardial Balance of Angiogenic Cytokines. Journal of Clinical Investigation, 116, 1865-1877.

[91]   Cai, C.L., Liang, X., Shi, Y., Chu, P.H., Pfaff, S.L., Chen, J., et al. (2003) Isl1 Identifies a Cardiac Progenitor Population That Proliferates Prior to Differentiation and Contributes a Majority of Cells to the Heart. Developmental Cell, 5, 877-889.

[92]   Laugwitz, K.L., Moretti, A., Lam, J., Gruber, P., Chen, Y., Woodard, S., et al. (2005) Postnatal Isl1+ Cardioblasts Enter Fully Differentiated Cardiomyocyte Lineages. Nature, 433, 647-653.

[93]   Chien, K.R., Domian, I.J. and Parker, K.K. (2008) Cardiogenesis and the Complex Biology of Regenerative Cardiovascular Medicine. Science, 322, 1494-1497.

[94]   Laugwitz, K.L., Moretti, A., Caron, L., Nakano, A. and Chien, K.R. (2008) Islet1 Cardiovascular Progenitors: A Single Source for Heart Lineages? Development, 135, 193-205.

[95]   Martin-Puig, S., Wang, Z. and Chien, K.R. (2008) Lives of a Heart Cell: Tracing the Origins of Cardiac Progenitors. Cell Stem Cell, 2, 320-331.

[96]   Wu, S.M., Chien, K.R. and Mummery, C. (2008) Origins and Fates of Cardiovascular Progenitor Cells. Cell, 132, 537-543.

[97]   Kattman, S.J., Huber, T.L. and Keller, G.M. (2006) Multipotent Flk-1+ Cardiovascular Progenitor Cells Give Rise to the Cardiomyocyte, Endothelial, and Vascular Smooth Muscle Lineages. Developmental Cell, 11, 723-732.

[98]   Moretti, A., Caron, L., Nakano, A., Lam, J.T., Bernshausen, A., Chen, Y., et al. (2006) Multipotent Embryonic Isl1+ Progenitor Cells Lead to Cardiac, Smooth Muscle, and Endothelial Cell Diversification. Cell, 127, 1151-1165.

[99]   Challen, G.A. and Little, M.H. (2006) A Side Order of Stem Cells: The SP Phenotype. Stem Cells, 24, 3-12.

[100]   Martin, C.M., Meeson, A.P., Robertson, S.M., Hawke, T.J., Rich-ardson, J.A., Bates, S., et al. (2004) Persistent Expression of the ATP-Binding Cassette Transporter, abcg2, Identifies Cardiac SP Cells in the Developing and Adult Heart. Developmental Biology, 265, 262-275.

[101]   Oyama, T., Nagai, T., Wada, H., Naito, A.T., Matsuura, K., Iwanaga, K., et al. (2007) Cardiac Side Population Cells Have a Potential to Migrate and Differentiate into Cardiomyocytes in Vitro and in Vivo. The Journal of Cell Biology, 176, 329-341.

[102]   Messina, E., De Angelis, L., Frati, G., Morrone, S., Chimenti, S., Fiordaliso, F., et al. (2004) Isolation and Expansion of Adult Cardiac Stem Cells from Human and Murine Heart. Circulation Research, 95, 911-921.

[103]   Takehara, N., Tsutsumi, Y., Tateishi, K., Ogata, T., Tanaka, H., Ueyama, T., et al. (2008) Controlled Delivery of Basic Fibroblast Growth Factor Promotes Human Cardiosphere-Derived Cell Engraftment to Enhance Cardiac Repair for Chronic MI. Journal of the American College of Cardiology, 52, 1858-1865.

[104]   Tang, X.L., Rokosh, G., Sanganalmath, S.K., Tokita, Y., Keith, M.C., Shirk, G., Stowers, H., Hunt, G.N., Wu, W., Dawn, B. and Bolli, R. (2015) Effects of Intracoronary Infusion of Escalating Doses of Cardiac Stem Cells in Rats with Acute Myocardial Infarction. Circ Heart Fail, 8, 757-65.

[105]   Smith, R.R., Barile, L., Cho, H.C., Leppo, M.K., Hare, J.M., Messina, E., et al. (2007) Regenerative Potential of Cardiosphere-Derived Cells Expanded from Percutaneous Endomyocardial Biopsy Specimens. Circulation, 115, 896-908.

[106]   Khan, M., Kwiatkowski, P., Rivera, B.K. and Kup-pusamy, P. (2010) Oxygen and Oxygenation in Stem-Cell Therapy for MI. Life Sciences, 87, 269-274.

[107]   Kofoed, H., Sjontoft, E., Siemssen, S.O. and Olesen, H.P. (1985) Bone Marrow Circulation after Osteotomy. Blood Flow, pO2, pCO2, and Pressure Studied in Dogs. Acta Orthopaedica Scandina-vica, 56, 400-403.

[108]   Hu, X., Yu, S.P., Fraser, J.L., Lu, Z., Ogle, M.E., Wang, J.-A. and Wei, L. (2008) Transplantation of Hypoxia-Preconditioned Mesenchymal Stem Cells Improves Infarcted Heart Function via Enhanced Survival of Implanted Cells and Angiogenesis. The Journal of Thoracic and Сardiovascular Surgery, 135, 799-808.

[109]   Li, J.H., Zhang, N. and Wang, J.A. (2008) Improved Antiapoptotic and Anti-Remodeling Potency of Bone Marrow Mesenchymal Stem Cells by Anoxic Pre-Conditioning in Diabetic Cardiomyopathy. Journal of Endocrinological Investigation, 31, 103-110.

[110]   Rebelatto, C.K., Aguiar, A.M., Senegaglia, A.C., Aita, C.M., Hansen, P., Barchiki, F., et al. (2009) Expression of Cardiac Function Genes in Adult Stem Cells Is Increased by Treatment with Nitric Oxide Agents. Biochemical and Biophysical Research Communications, 378, 456-461.

[111]   Afzal, M.R., Haider, H., Idris, N.M., Jiang, S., Ahmed, R.P. and Ashraf, M. (2010) Pre-Conditioning Promotes Survival and Angiomyogenic Potential of Mesenchymal Stem Cells in the In-farcted Heart via NF-kappaB Signaling. Antioxidants & Redox Signaling, 12, 693-702.

[112]   Suzuki, Y., Kim, H.W., Ashraf, M. and Haider, H. (2010) Di-azoxide Potentiates Mesenchymal Stem Cell Survival via NFkappaB-Dependent miR-146a Expression by Targeting Fas. American Journal of Physiology: Heart and Circulatory Physiology, 299, H1077-H1082.

[113]   Suzuki, K., Smolenski, R.T., Jayakumar, J., Murtuza, B., Brand, N.J. and Yacoub, M.H. (2000) Heat Shock Treatment Enhances Graft Cell Survival in Skeletal Myoblast Transplantation to the Heart. Circulation, 102, III216-III221.

[114]   Wang, X., Zhao, T., Huang, W., Wang, T., Qian, J., Xu, M., et al. (2009) Hsp20-Engineered Mesenchymal Stem Cells Are Resistant to Oxidative Stress via Enhanced Activation of Akt and Increased Secretion of Growth Factors. Stem Cells, 27, 3021-3031.

[115]   Chang, W., Song, B.-W., Lim, S., Song, H., Shim, C.Y., Cha, M.-J., et al. (2008) Mesenchymal Stem Cells Pretreated with Delivered Hph-1-Hsp70 Protein Are Protected from Hypoxia-Mediated Cell Death and Rescue Heart Functions from Myocardial Injury. Stem Cells, 27, 2283-2292.

[116]   Yang, Y.J., Qian, H.Y., Huang, J., Li, J.-J., Gao, R.-L., Dou, K.-F., et al. (2009) Combined Therapy with Simvastatin and Bone Marrow-Derived Mesenchymal Stem Cells Increases Benefits in Infarcted Swine Hearts. Arteriosclerosis, Thrombosis, and Vascular Biology, 29, 2076-2082.

[117]   Yang, Y., Mou, Y., Hu, S.J. and Fu, M. (2009) Beneficial Ef-fect of Rosuvastatin on Cardiac Dysfunction Is Associated with Alterations in Calcium-Regulatory Proteins. European Journal of Heart Failure, 11, 6-13.

[118]   Lin, Y.C., Leu, S., Sun, C.K., Yen, C.-H., Kao, Y.-H., Chang, L.-T., et al. (2010) Early Combined Treatment with Sildenafil and Adipose-Derived Mesenchymal Stem Cells Preserves Heart Function in Rat Dilated Cardiomyopathy. Journal of Translational Medicine, 8, 88.

[119]   Haider, H., Lee, Y.J., Jiang, S., Ahmed, R.P., Ryon, M. and Ashraf, M. (2010) Phosphodiesterase Inhibition with Tadalafil Provides Longer and Sustained Protection of Stem Cells. American Journal of Physiology: Heart and Circulatory Physiology, 299, H1395-H1404.

[120]   Numasawa, Y., Kimura, T., Miyoshi, S., Nishiyama, N., Hida, N., Tsuji, H., Tsuruta, H., Segawa, K., Ogawa, S. and Umezawa, A. (2011) Treatment of Human Mesenchymal Stem Cells with Angiotensin Receptor Blocker Improved Efficiency of Cardiomyogenic Transdifferentiation and Improved Cardiac Function via Angiogenesis. Stem Cells, 29, 1405-1414.

[121]   Wang, Y., Zhang, D., Ashraf, M., Zhao, T., Huang, W., Ashraf, A. and Balasubramaniam, A. (2010) Combining Neuropeptide Y and Mesenchymal Stem Cells Reverses Remodeling after MI. American Journal of Physiology: Heart and Circulatory Physiology, 298, H275-H286.

[122]   Kinnaird, T., Stabile, E., Burnett, M.S., Shou, M., Lee, C.W., Barr, S., Fuchs, S. and Epstein, S.E. (2004) Local Delivery of Marrow-Derived Stromal Cells Augments Collateral Perfusion through Paracrine Mechanisms. Circulation, 109, 1543-1549.

[123]   Herrmann, J.L., Wang, Y., Abarbanell, A.M., Weil, B.R., Tan, J. and Meldrum, D.R. (2010) Pre-Conditioning Mesenchymal Stem Cells with Transforming Growth Factor-Alpha Improves Mesenchymal Stem Cell-Mediated Cardioprotection. Shock, 33, 24-30.

[124]   Pasha, Z., Wang, Y., Sheikh, R., Zhang, D., Zhao, T. and Ashraf, M. (2008) Pre-Conditioning Enhances Cell Survival and Differentiation of Stem Cells during Transplantation in Infarcted Myocardium. Cardiovascular Research, 77, 134-142.

[125]   Yao, Y., Zhang, F., Wang, L., Zhang, G., Wang, Z., Chen, J. and Gao, X. (2009) Lipopolysaccharide Pre-Conditioning Enhances the Efficacy of Mesenchymal Stem Cells Transplantation in a Rat Model of Acute MI. Journal of Biomedical Science, 16, 74.

[126]   Matsumoto, R., Omura, T., Yoshiyama, M., Hayashi, T., Inamoto, S., Koh, K.-R., et al. (2005) Vascular Endothelial Growth Factor-Expressing Mesenchymal Stem Cell Transplantation for the Treatment of Acute MI. Arteriosclerosis, Thrombosis, and Vascular Biology, 25, 1168-1173.

[127]   Guo, J., Lin, G., Bao, C., Hu, Z., Chu, H. and Hu, M. (2008) Insulin-Like Growth Factor 1 Improves the Efficacy of Mesenchymal Stem Cells Transplantation in a Rat Model of MI. Journal of Biomedical Science, 15, 89-97.

[128]   Abbott, J.D., Huang, Y., Liu, D., Hickey, R., Krause, D.S. and Giordano, F.J. (2004) Stromal Cell-Derived Factor-1α Plays a Critical Role in Stem Cell Recruitment to the Heart after MI but Is Not Sufficient to Induce Homing in the Absence of Injury. Circulation, 110, 3300-3305.

[129]   Kijowski, J., Baj-Krzyworzeka, M., Majka, M., Reca, R., Marquez, L.A., Christofidou-Solomidou, M., et al. (2001) The SDF-1-CXCR4 Axis Stimulates VEGF Secretion and Activates Integrins but Does Not Affect Proliferation and Survival in Lymphohematopoietic Cells. Stem Cells, 19, 453-466.

[130]   Zhuang, Y., Chen, X., Xu, M., Zhang, L.Y. and Xiang, F. (2009) Chemokine Stromal Cell-Derived Factor 1/CXCL12 Increases Homing of Mesenchymal Stem Cells to Injured Myocardium and Neovascularization Following MI. Chinese Medical Journal, 122, 183-187.

[131]   Tang, J., Wang, J., Guo, L., Kong, X., Yang, J., Zheng, F., Zhang, L. and Huang, Y. (2010) Mesenchymal Stem Cells Modified with Stromal Cell-Derived Factor 1 Alpha Improve Cardiac Remodeling via Paracrine Activation of Hepatocyte Growth Factor in a Rat Model of MI. Molecules and Cells, 29, 9-19.

[132]   Guo, Y.H., He, J.G., Wu, J.L., Yang, L., Zhang, D.-S., Tan, X.-Y. and Qi, R.-D. (2008) Hepatocyte Growth Factor and Granulocyte Colony-Stimulating Factor Form a Combined Neovasculogenic Therapy for Ischemic Cardiomyopathy. Cytotherapy, 10, 857-867.

[133]   Huang, J., Zhang, Z., Guo, J., Ni, A., Deb, A., Zhang, L., Mirotsou, M., Pratt, R.E. and Dzau, V.J. (2010) Genetic Modification of Mesenchymal Stem Cells Overexpressing CCR1 Increases Cell Viability, Migration, Engraftment, and Capillary Density in the Injured Myocardium. Circulation Research, 106, 1753-1762.

[134]   Tang, J., Wang, J., Zheng, F., Kong, X., Guo, L., Yang, J., Zhang, L. and Huang, Y. (2010) Combination of Chemokine and Angiogenic Factor Genes and Mesenchymal Stem Cells Could Enhance Angiogenesis and Improve Cardiac Function after Acute MI in Rats. Molecular and Cellular Biochemistry, 339, 107-118.

[135]   Chen, J., Crawford, R., Chen, C. and Xiao, Y. (2013) The Key Regulatory Roles of the PI3K/Akt Signaling Pathway in the Functionalities of Mesenchymal Stem Cells and Applications in Tissue Regeneration. Tissue Engineering Part B— Reviews, 19, 516-528.

[136]   Datta, S.R., Brunet, A. and Greenberg, M.E. (1999) Cellular Survival: A Play in Three Akts. Genes & Development, 13, 2905-2927.

[137]   Somanath, P.R., Razorenova, O.V., Chen, J. and Byzova, T.V. (2006) Akt1 in Endothelial Cell and Angiogenesis. Cell Cycle, 5, 512-518.

[138]   Gnecchi, M., He, H., Liang, O.D., Melo, L.G., Morello, F., Mu, H., et al. (2005) Paracrine Action Accounts for Marked Protection of Ischemic Heart by Akt Modified Mesenchymal Stem Cells. Nature Medicine, 11, 367-368.

[139]   Gnecchi, M., He, H., Noiseux, N., Liang, O.D., Zhang, L., Morello, F., et al. (2006) Evidence Supporting Paracrine Hypothesis for Akt-Modified Mesenchymal Stem Cell-Mediated Cardiac Protection and Functional Improvement. The FASEB Journal, 20, 661-669.

[140]   Gnecchi, M., He, H., Melo, L.G., Noiseaux, N., Morello, F., de Boer, R.A., et al. (2009) Early Beneficial Effects of Bone Marrow-Derived Mesenchymal Stem Cells Overexpressing Akt on Cardiac Metabolism after MI. Stem Cells, 27, 971-979.

[141]   Mirotsou, M., Zhang, Z., Deb, A., Zhang, L., Gnecchi, M., Noiseux, N., Mu, H., Pachori, A. and Dzau, V. (2007) Secreted Frizzled Related Protein 2 (Sfrp2) Is the Key Akt-Mesenchymal Stem Cellreleased Paracrine Factor Mediating Myocardial Survival and Repair. Proceedings of the National Academy of Sciences of the United States of America, 104, 1643-1648.

[142]   Song, S.W., Chang, W., Song, B.W., Song, H., Lim, S., Kim, H.-J., et al. (2009) Integrin-Linked Kinase Is Required in Hypoxic Mesenchymal Stem Cells for Strengthening Cell Adhesion to Ischemic Myocardium. Stem Cells, 27, 1358-1365.

[143]   Jiang, Y., Chen, L., Tang, Y., Ma, G., Shen, C., Qi, C., et al. (2010) HO-1 Gene Overexpression Enhances the Beneficial Effects of Superparamagnetic Iron Oxide Labeled Bone Marrow Stromal Cells Transplantation in Swine Hearts Underwent Ischemia/Reperfusion: An MRI Study. Basic Research in Cardiology, 105, 431-442.

[144]   Taljaard, M., Ward, M.R., Kutryk, M.J., Courtman, D.W., Camack, N.J., Goodman, S.G., et al. (2010) Rationale and Design of Enhanced Angiogenic Cell Therapy in Acute MI (ENACT-AMI): The First Randomized Placebo-Controlled Trial of Enhanced Progenitor Cell Therapy for Acute MI. American Heart Journal, 159, 354-360.

[145]   Behfar, A., Zingman, L.V., Hodgson, D.M., Rauzier, J.-M., Kane, G.C., Terzic, A. and Pucéat, M. (2002) Stem Cell Differentiation Requires a Paracrine Pathway in the Heart. The FASEB Journal, 16, 1558-1566.

[146]   Behfar, A., Perez-Terzic, C., Faustino, R.S., Arrell, D.K., Hodgson, D.M., Yamada, S., et al. (2007) Cardiopoietic Programming of Embryonic Stem Cells for Tumor Free Heart Repair. The Journal of Experimental Medicine, 204, 405-420.

[147]   Behfar, A., Yamada, S., Crespo-Diaz, R., Nesbitt, J.J., Rowe, L.A., Perez-Terzic, C., et al. (2010) Guided Cardiopoiesis Enhances Therapeutic Benefit of Bone Marrow Human Mesenchymal Stem Cells in Chronic MI. Journal of the American College of Cardiology, 56, 721-734.

[148]   Bartunek, J., Wijns, W., Dolatabadi, D., Vanderheyden, M., Dens, J., Ostojic, M., et al. (2011) C-Cure Multicenter Trial: Lineage Specific Bone Marrow Derived Cardiopoietic Mesenchymal Stem Cells for the Treatment of Ischaemic Cardiomyopathy. Journal of the American College of Cardiology, 57, E200.

[149]   Lakshmipathy, U. and Hart, R.P. (2008) Concise Review: Mi-croRNA Expression in Multipotent Mesenchymal Stromal Cells. Stem Cells, 26, 356-363.

[150]   Valtieri, M. and Sorrentino, A. (2008) The Mesenchymal Stromal Cell Contribution to Homeostasis. Journal of Cellular Physiology, 217, 296-300.

[151]   Karp, X. and Ambros, V. (2005) Developmental Biology: Encountering mi-croRNAs in Cell Fate Signaling. Science, 310, 1288-1289.

[152]   Kloosterman, W.P. and Plasterk, R.H. (2006) The Diverse Functions of microRNAs in Animal Development and Disease. Developmental Cell, 11, 441-450.

[153]   van Rooij, E., Sutherland, L.B., Liu, N., Williams, A.H., McAnally, J., Gerard, R.D., et al. (2006) A Signature Pattern of Stress-Responsive microRNAs That Can Evoke Cardiac Hypertrophy and Heart Failure. Proceedings of the National Academy of Sciences of the United States of America, 103, 18255-18260.

[154]   Kim, J., Inoue, K., Ishii, J., Vanti, W.B., Voronov, S.V., Murchison, E., et al. (2007) A microRNA Feedback Circuit in Midbrain Dopamine Neurons. Science, 317, 1220-1224.

[155]   Calin, G.A. and Croce, C.M. (2006) MicroRNA Signatures in Human Cancers. Nature Reviews Cancer, 6, 857-866.

[156]   Guo, L., Zhao, R.C. and Wu, Y. (2011) The Role of miRNAs in Self-Renewal and Differentiation of Mesenchymal Stem Cells. Experimental Hematology, 39, 608-616.

[157]   Eskildsen, T., Taipaleenm?ki, H., Stenvang, J., Abdallah, B.M., Ditzel, N., Nossent, A.Y., Bak, M., Kauppinen, S. and Kassem, M. (2011) MicroRNA-138 Regulates Osteogenic Differentiation of Human Stromal (Mesenchymal) Stem Cells in Vivo. Proceedings of the National Academy of Sciences of the United States of America, 108, 6139-6144.

[158]   Yang, Z., Bian, C., Zhou, H., Huang, S., Wang, S., Liao, L. and Zhao, R.C. (2011) MicroRNA Hsa-miR-138 Inhibits Adipogenic Differentiation of Human Adipose Tissue-Derived Mesenchymal Stem Cells through Adenovirus EID-1. Stem Cells and Development, 20, 259-267.

[159]   Huang, J., Zhao, L., Xing, L. and Chen, D. (2010) MicroRNA-204 Regulates Runx2 Protein Expression and Mesenchymal Progenitor Cell Differentiation. Stem Cells, 28, 357-364.

[160]   Zhang, J.F., Fu, W.M., He, M.L., Wang, H., Wang, W.M., Yu, S.C., et al. (2011) MiR-637 Maintains the Balance between Adipocytes and Osteoblasts by Directly Targeting Osterix. Molecular Biology of the Cell, 22, 3955-3961.

[161]   Shan, Z.X., Lin, Q.X., Yu, X.Y., Deng, C.Y., Li, X.H., Zhang, X.C., Liu, X.Y. and Fu, Y.H. (2007) MicroRNAs Can Be Expressed in Cardiomyocyte-Like Cells Differentiated from Human Mesenchymal Stem Cells. Journal of Southern Medical University, 27, 1813-1816.

[162]   Liu, J.L., Jiang, L., Lin, Q.X., Deng, C.Y., Mai, L.P., Zhu, J.N., Li, X.H., Yu, X.Y., Lin, S.G. and Shan, Z.X. (2012) MicroRNA 16 Enhances Differentiation of Human Bone Marrow Mesenchymal Stem Cells in a Cardiac Niche toward Myogenic Phenotypes in Vitro. Life Sciences, 90, 1020-1026.

[163]   Psaltis, P.J., Simari, R.D. and Rodriguez-Porcel, M. (2012) Emerging Roles for Integrated Imaging Modalities in Cardiovascular Cell-Based Therapeutics: A Clinical Perspective. European Journal of Nuclear Medicine and Molecular Imaging, 39, 165-181.

[164]   Lunde, K., Solheim, S., Aakhus, S., Arnesen, H., Abdelnoor, M., Egeland, T., et al. (2006) Intracoronary Injection of Mononuclear Bone Marrow Cells in Acute MI. The New England Journal of Medicine, 355, 1199-1209.

[165]   Schachinger, V., Erbs, S., Elsasser, A., Haberbosch, W., Hambrecht, R., H?lschermann, H., et al. (2006) Intracoronary Bone Marrow-Derived Progenitor Cells in Acute MI. The New England Journal of Medicine, 355, 1210-1221.

[166]   Traverse, J.H., Henry, T.D., Ellis, S.G., Pepine, C.J., Willerson, J.T., Zhao, D.X.M., et al. (2011) Effect of Intracoronary Delivery of Autologous Bone Marrow Mononuclear Cells 2 to 3 Weeks Following Acute MI on Left Ventricular Function: The LateTIME Randomized Trial. Journal of the American Medical Associ-ation, 306, 2110-2119.

[167]   Vulliet, P.R., Greeley, M., Halloran, S.M., MacDonald, K.A. and Kittleson, M.D. (2004) Intra-Coronary Arterial Injection of Mesenchymal Stromal Cells and Microinfarction in Dogs. Lancet, 363, 783-784.

[168]   Freyman, T., Polin, G., Osman, H., Crary, J., Lu, M.M., Cheng, L., et al. (2006) A Quantitative, Randomized Study Evaluating Three Methods of Mesenchymal Stem Cell Delivery Following MI. European Heart Journal, 27, 1114-1122.

[169]   Ly, H.Q., Hoshino, K., Pomerantseva, I., Kawase, Y., Yoneyama, R., Takewa, Y., et al. (2009) In Vivo Myocardial Distribution of Multipotent Progenitor Cells Following Intracoronary Delivery in a Swine Model of MI. European Heart Journal, 30, 2861-2868.

[170]   Hou, D., Youssef, E.A., Brinton, T.J., Zhang, P., Rogers, P., Price, E.T., et al. (2005) Radiolabeled Cell Distribution after Intramyocardial, Intracoronary, and Interstitial Retrograde Coronary Venous Delivery: Implications for Current Clinical Trials. Circulation, 112, I150-I156.

[171]   Perin, E.C., Silva, G.V., Assad, J.A., Vela, D., Buja, L.M., Sousa, A.L.S., et al. (2008) Comparison of Intracoronary and Transendocardial Delivery of Allogeneic Mesenchymal Cells in a Canine Model of Acute MI. Journal of Molecular and Cellular Cardiology, 44, 486-495.

[172]   Menasche, P., Hagege, A.A., Vilquin, J.T., Desnos, M., Abergel, E., Pouzet, B., et al. (2003) Autologous Skeletal Myoblast Transplantation for Severe Postinfarction Left Ventricular Dysfunction. Journal of the American College of Cardiology, 41, 1078-1083.

[173]   Mitchell, A.J., Sabondjian, E., Sykes, J., Deans, L., Zhu, W., Lu, X., et al. (2010) Comparison of Initial Cell Retention and Clearance Kinetics after Subendocardial or Subepicardial Injections of Endothelial Progenitor Cells in a Canine MI Model. Journal of Nuclear Medicine, 51, 413-417.

[174]   Psaltis, P., Zannettino, A., Gronthos, S. and Worthley, S. (2010) IM Navigation and Mapping for Stem Cell Delivery. Journal of Cardiovascular Translational Research, 3, 135-146.

[175]   Okano, T., Yamada, N., Okuhara, M., Sakai, H. and Sakurai, Y. (1995) Mechanism of Cell Detachment from Temperature-Modulated, Hydrophilic-Hydrophobic Polymer Surfaces. Biomaterials, 16, 297-303.

[176]   Shimizu, T., Yamato, M., Isoi, Y., Akutsu, T., Setomaru, T., Abe, K., et al. (2002) Fabrication of Pulsatile Cardiac Tissue Grafts Using a Novel 3-Dimensional Cell Sheet Manipulation Technique and Temperature-Responsive Cell Culture Surfaces. Circulation Research, 90, e40-e48.

[177]   Kofidis, T., Lebl, D.R., Martinez, E.C., Hoyt, G., Tanaka, M. and Robbins, R.C. (2005) Novel Injectable Bioartificial Tissue Facilitates Targeted, Less Invasive, Large-Scale Tissue Restoration on the Beating Heart after Myocardial Injury. Circulation, 112, I173-I177.

[178]   Zhang, Y., Thorn, S., DaSilva, J.N., Lamoureux, M., DeKemp, R.A., Beanlands, R.S., et al. (2008) Collagen-Based Matrices Improve the Delivery of Transplanted Circulating Progenitor Cells: Development and Demonstration by ex Vivo Radionuclide Cell Labeling and in Vivo Tracking with Positron-Emission Tomography. Circulation: Cardiovascular Imaging, 1, 197-204.

[179]   Roura, S., Bago?, J.R., Soler-Botija, C., Pujal, J.M., Ga?lvez-Monto?n, C., Prat-Vidal, C., et al. (2012) Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Promote Vascular Growth in Vivo. PLoS ONE, 7, e49447.

[180]   Dawson, E., Mapili, G., Erickson, K., Taqvi, S. and Roy, K. (2008) Biomaterials for Stem Cell Differentiation. Advanced Drug Delivery Reviews, 60, 215-228.

[181]   Li, Z. and Guan, J. (2011) Hydrogels for Cardiac Tissue Engineering. Polymers, 3, 740-761.

[182]   Eschenhagen, T., Fink, C., Remmers, U., Scholz, H., Wattchow, J., Weil, J., et al. (1997) Threedimensional Reconstitution of Embryonic Cardiomyocites in a Collagen Matrix: A New Heart Muscle Model System. The FASEB Journal, 11, 683-694.

[183]   Morritt, A.N., Bortolotto, S.K., Dilley, R.J., Han, X., Kompa, A.R., McCombe, D., et al. (2007) Cardiac Tissue Engineering in an in Vivo Vascularized Chamber. Circulation, 115, 353-360.

[184]   Munoz, J., Zhou, Y. and Jarrett, H.W. (2010) LG4-5 Domains of Laminin-211 Binds α-Dystroglycan to Allow Myotube Attachment and Prevent Anoikis. Journal of Cellular Physiology, 222, 111-119.

[185]   Eschenhagen, T., Eder, A., Vollert, I. and Hansen, A. (2012) Physiological Aspects of Cardiac Tissue Engineering. American Journal of Physiology: Heart and Circulatory Physiology, 303, H133-H143.

[186]   Chachques, J.C., Trainini, J.C., Lago, N., Cortes-Morichetti, M., Schussler, O. and Carpentier, A. (2008) Myocardial Assistance by Grafting a New Bioartificial Upgraded Myocardium (MAGNUM trial): Clinical Feasibility Study. The Annals of Thoracic Surgery, 85, 901-908.

[187]   RECATABI. Regeneration of Cardiac Tissue Assisted by Bioactive Implants.

[188]   Laurie, G.W., Horikoshi, S., Killen, P.D., Segui-Real, B. and Yamada, Y. (1989) In Situ Hybridization Reveals Temporal and Spatial Changes in Cellular Expression of mRNA for a Laminin Receptor, Laminin, and Basement Membrane (Type IV) Collagen in the Developing Kidney. The Journal of Cell Biology, 109, 1351-1362.

[189]   Baldwin, H.S. (1996) Early Embryonic Vascular Development. Cardiovascular Research, 31, E34-E45.

[190]   Midwood, K.S., Williams, L.V. and Schwarzbauer, J.E. (2004) Tissue Repair and the Dynamics of the Extracellular Matrix. The International Journal of Biochemistry & Cell Biology, 36, 1031-1037.

[191]   Bader, A., Schilling, T., Teebken, O.E., Brandes, G., Herden, T., Steinhoff, G., et al. (1998) Tissue Engineering of Heart Valves—Human Endothelial Cell Seeding of Detergent Acellularized Porcine Valves. European Journal Cardio-Thoracic Surgery, 14, 279-284.

[192]   Booth, C., Korossis, S.A., Wilcox, H.E., Watterson, K.G., Kearney, J.N., Fisher, J., et al. (2002) Tissue Engineering of Cardiac Valve Prostheses I: Development and Histological Characterization of an Acellular Porcine Scaffold. The Journal of Heart Valve Disease, 11, 457-462.

[193]   Korossis, S.A., Booth, C., Wilcox, H.E., Watterson, K.G., Kearney, J.N., Fisher, J., et al. (2002) Tissue Engineering of Cardiac Valve Prostheses II: Biomechanical Characterization of Decellularized Porcine Aortic Heart Valves. The Journal of Heart Valve Disease, 11, 463-471.

[194]   Dahl, S.L., Koh, J., Prabhakar, V. and Niklason, L.E. (2003) Decellularized Native and Engineered Arterial Scaffolds for Transplantation. Cell Transplant, 12, 659-666.

[195]   Schmidt, C.E. and Baier, J.M. (2000) Acellular Vascular Tissues: Natural Biomaterials for Tissue Repair and Tissue Engineering. Biomaterials, 21, 2215-2231.

[196]   Ekser, B. and Cooper, D.K. (2010) Overcoming the Barriers to Xenotransplantation: Prospects for the Future. Expert Review of Clinical Immunology, 6, 219-230.