Improving stem cell engraftment to enhance functional efficacy in cardiovascular disease: where are we now?

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Anh Thi-Van Bui Truc Le-Buu Pham Jitka Virag


Stem cell therapy is a promising therapy for repairing damaged tissue. A growing body of research shows that stem cells work effectively in several diseases such as cardiovascular disease, hepatic disease, and diabetes. It has been shown that stem cells not only differentiate into functional cells and replace dead cells, but also release growth factors and cytokines which can recruit autologous cells. The most significant barrier to achieve clinical relevance of this treatment mode is the poor survival rate of injected cells. To improve transplantation and enhance functional outcome, investigations of gene transfection (overexpression of anti-apoptotic and antioxidant proteins), growth factor supplementation, and scaffolding matrices are being conducted. In this review, we will focus on methods to increase cell survival in stem cell transplantation as a novel treatment for cardiovascular disease.


Abbott, A. (2014). Doubts over heart stem-cell therapy. Nature 509, 15-16.
Abdalla, S., Makhoul, G., Duong, M., Chiu, R.C., and Cecere, R. (2013). Hyaluronic acid-based hydrogel induces neovascularization and improves cardiac function in a rat model of myocardial infarction. Interactive cardiovascular and thoracic surgery 17, 767-772.
Aho, T.L., Sandholm, J., Peltola, K.J., Mankonen, H.P., Lilly, M., and Koskinen, P.J. (2004). Pim-1 kinase promotes inactivation of the pro-apoptotic Bad protein by phosphorylating it on the Ser112 gatekeeper site. FEBS letters 571, 43-49.
Behfar, A., Yamada, S., Crespo-Diaz, R., Nesbitt, J.J., Rowe, L.A., Perez-Terzic, C., Gaussin, V., Homsy, C., Bartunek, J., and Terzic, A. (2010). Guided cardiopoiesis enhances therapeutic benefit of bone marrow human mesenchymal stem cells in chronic myocardial infarction. Journal of the American College of Cardiology 56, 721-734.
Behfar, A., Zingman, L.V., Hodgson, D.M., Rauzier, J.M., Kane, G.C., Terzic, A., and Puceat, M. (2002). Stem cell differentiation requires a paracrine pathway in the heart. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16, 1558-1566.
Benoit, D.S., Schwartz, M.P., Durney, A.R., and Anseth, K.S. (2008). Small functional groups for controlled differentiation of hydrogel-encapsulated human mesenchymal stem cells. Nature materials 7, 816-823.
Boheler, K.R., Czyz, J., Tweedie, D., Yang, H.T., Anisimov, S.V., and Wobus, A.M. (2002). Differentiation of pluripotent embryonic stem cells into cardiomyocytes. Circulation research 91, 189-201.
Bonafe, F., Govoni, M., Giordano, E., Caldarera, C.M., Guarnieri, C., and Muscari, C. (2014). Hyaluronan and cardiac regeneration. Journal of biomedical science 21, 100.
Boyd, A.W., Bartlett, P.F., and Lackmann, M. (2014). Therapeutic targeting of EPH receptors and their ligands. Nat Rev Drug Discov 13, 39-62.
Burridge, P.W., and Zambidis, E.T. (2013). Highly efficient directed differentiation of human induced pluripotent stem cells into cardiomyocytes. Methods in molecular biology (Clifton, NJ) 997, 149-161.
Carvalho, P.H., Daibert, A.P., Monteiro, B.S., Okano, B.S., Carvalho, J.L., Cunha, D.N., Favarato, L.S., Pereira, V.G., Augusto, L.E., and Del Carlo, R.J. (2013). Differentiation of adipose tissue-derived mesenchymal stem cells into cardiomyocytes. Arquivos brasileiros de cardiologia 100, 82-89.
Chen, D., Zhao, M., and Mundy, G.R. (2004). Bone morphogenetic proteins. Growth factors (Chur, Switzerland) 22, 233-241.
Chen, K., Wu, L., and Wang, Z.Z. (2008). Extrinsic regulation of cardiomyocyte differentiation of embryonic stem cells. Journal of cellular biochemistry 104, 119-128.
Dai, Y., Xu, M., Wang, Y., Pasha, Z., Li, T., and Ashraf, M. (2007). HIF-1alpha induced-VEGF overexpression in bone marrow stem cells protects cardiomyocytes against ischemia. Journal of molecular and cellular cardiology 42, 1036-1044.
Datta, S.R., Brunet, A., and Greenberg, M.E. (1999). Cellular survival: a play in three Akts. Genes & development 13, 2905-2927.
Davis, M.E., Hsieh, P.C., Takahashi, T., Song, Q., Zhang, S., Kamm, R.D., Grodzinsky, A.J., Anversa, P., and Lee, R.T. (2006). Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction. Proceedings of the National Academy of Sciences of the United States of America 103, 8155-8160.
Detillieux, K.A., Sheikh, F., Kardami, E., and Cattini, P.A. (2003). Biological activities of fibroblast growth factor-2 in the adult myocardium. Cardiovascular research 57, 8-19.
Doppler, S.A., Deutsch, M.A., Lange, R., and Krane, M. (2013). Cardiac regeneration: current therapies-future concepts. Journal of thoracic disease 5, 683-697.
Dries, J.L., Kent, S.D., and Virag, J.A. (2011). Intramyocardial administration of chimeric ephrinA1-Fc promotes tissue salvage following myocardial infarction in mice. The Journal of physiology 589, 1725-1740.
DuSablon, A., Kent, S., Coburn, A., and Virag, J. (2014). EphA2-receptor deficiency exacerbates myocardial infarction and reduces survival in hyperglycemic mice. Cardiovascular diabetology 13, 114.
Fischer, K.M., Cottage, C.T., Wu, W., Din, S., Gude, N.A., Avitabile, D., Quijada, P., Collins, B.L., Fransioli, J., and Sussman, M.A. (2009). Enhancement of myocardial regeneration through genetic engineering of cardiac progenitor cells expressing Pim-1 kinase. Circulation 120, 2077-2087.
Fisher, S.A., Brunskill, S.J., Doree, C., Mathur, A., Taggart, D.P., and Martin-Rendon, E. (2014). Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. The Cochrane database of systematic reviews 4, Cd007888.
Fisher, S.A., Zhang, H., Doree, C., Mathur, A., and Martin-Rendon, E. (2015). Stem cell treatment for acute myocardial infarction. The Cochrane database of systematic reviews 9, Cd006536.
Fitzpatrick, L.E., and McDevitt, T.C. (2015). Cell-derived matrices for tissue engineering and regenerative medicine applications. Biomaterials science 3, 12-24.
Frieden, L.A., Townsend, T.A., Vaught, D.B., Delaughter, D.M., Hwang, Y., Barnett, J.V., and Chen, J. (2010). Regulation of heart valve morphogenesis by Eph receptor ligand, ephrin-A1. Developmental dynamics : an official publication of the American Association of Anatomists 239, 3226-3234.
Fuster, V. (2014). Top 10 cardiovascular therapies and interventions for the next decade. Nature reviews Cardiology 11, 671-683.
Gherghiceanu, M., Barad, L., Novak, A., Reiter, I., Itskovitz-Eldor, J., Binah, O., and Popescu, L.M. (2011). Cardiomyocytes derived from human embryonic and induced pluripotent stem cells: comparative ultrastructure. Journal of cellular and molecular medicine 15, 2539-2551.
Gnecchi, M., He, H., Noiseux, N., Liang, O.D., Zhang, L., Morello, F., Mu, H., Melo, L.G., Pratt, R.E., Ingwall, J.S., et al. (2006). Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20, 661-669.
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.
Goichberg, P., Bai, Y., D'Amario, D., Ferreira-Martins, J., Fiorini, C., Zheng, H., Signore, S., del Monte, F., Ottolenghi, S., D'Alessandro, D.A., et al. (2011). The ephrin A1-EphA2 system promotes cardiac stem cell migration after infarction. Circulation research 108, 1071-1083.
Hahn, J.Y., Cho, H.J., Kang, H.J., Kim, T.S., Kim, M.H., Chung, J.H., Bae, J.W., Oh, B.H., Park, Y.B., and Kim, H.S. (2008). Pre-treatment of mesenchymal stem cells with a combination of growth factors enhances gap junction formation, cytoprotective effect on cardiomyocytes, and therapeutic efficacy for myocardial infarction. Journal of the American College of Cardiology 51, 933-943.
Haider, H., and Ashraf, M. (2008). Strategies to promote donor cell survival: combining preconditioning approach with stem cell transplantation. Journal of molecular and cellular cardiology 45, 554-566.
Highley, C.B., Prestwich, G.D., and Burdick, J.A. (2016). Recent advances in hyaluronic acid hydrogels for biomedical applications. Current opinion in biotechnology 40, 35-40.
Huang, Y.-l., Qiu, R.-f., Mai, W.-y., Kuang, J., Cai, X.-y., Dong, Y.-g., Hu, Y.-z., Song, Y.-b., Cai, A.-p., and Jiang, Z.-g. (2012). Effects of insulin-like growth factor-1 on the properties of mesenchymal stem cells in vitro. Journal of Zhejiang University Science B 13, 20-28.
Jha, A.K., Tharp, K.M., Ye, J., Santiago-Ortiz, J.L., Jackson, W.M., Stahl, A., Schaffer, D.V., Yeghiazarians, Y., and Healy, K.E. (2015). Enhanced survival and engraftment of transplanted stem cells using growth factor sequestering hydrogels. Biomaterials 47, 1-12.
Kang, H., Wen, C., Hwang, Y., Shih, Y.R., Kar, M., Seo, S.W., and Varghese, S. (2014). Biomineralized matrix-assisted osteogenic differentiation of human embryonic stem cells. Journal of materials chemistry B, Materials for biology and medicine 2, 5676-5688.
Kardami, E., Padua, R.R., Pasumarthi, K.B.S., Liu, L., Doble, B.W., Davey, S.E., and Cattini, P.A. (1993). Basic fibroblast growth factor in cardiac myocytes: expression and effects. In Growth Factors and the Cardiovascular System, P. Cummins, ed. (Boston, MA: Springer US), pp. 55-75.
Kastrup, J., Mygind, N.D., Qayyum, A.A., Mathiasen, A.B., Haack-Sorensen, M., and Ekblond, A. (2016). Mesenchymal stromal cell therapy in ischemic heart disease. Scandinavian cardiovascular journal : SCJ, 1-20.
Kinnaird, T., Stabile, E., Burnett, M.S., Lee, C.W., Barr, S., Fuchs, S., and Epstein, S.E. (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.
Krishna, K.A., Krishna, K.S., Berrocal, R., Rao, K.S., and Sambasiva Rao, K.R.S. (2011). Myocardial infarction and stem cells. Journal of Pharmacy and Bioallied Sciences 3, 182-188.
Laflamme, M.A., Chen, K.Y., Naumova, A.V., Muskheli, V., Fugate, J.A., Dupras, S.K., Reinecke, H., Xu, C., Hassanipour, M., Police, S., et al. (2007). Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nature biotechnology 25, 1015-1024.
Leri, A., Kajstura, J., and Anversa, P. (2005). Cardiac stem cells and mechanisms of myocardial regeneration. Physiological reviews 85, 1373-1416.
Li, Q., Guo, Z.K., Chang, Y.Q., Yu, X., Li, C.X., and Li, H. (2015). Gata4, Tbx5 and Baf60c induce differentiation of adipose tissue-derived mesenchymal stem cells into beating cardiomyocytes. The international journal of biochemistry & cell biology 66, 30-36.
Li, X., Tamama, K., Xie, X., and Guan, J. (2016). Improving Cell Engraftment in Cardiac Stem Cell Therapy. Stem cells international 2016, 7168797.
Lu, T.Y., Lin, B., Kim, J., Sullivan, M., Tobita, K., Salama, G., and Yang, L. (2013). Repopulation of decellularized mouse heart with human induced pluripotent stem cell-derived cardiovascular progenitor cells. Nature communications 4, 2307.
Maher, B. (2013). Tissue engineering: How to build a heart. Nature 499, 20-22.
Maltsev, V.A., Rohwedel, J., Hescheler, J., and Wobus, A.M. (1993). Embryonic stem cells differentiate in vitro into cardiomyocytes representing sinusnodal, atrial and ventricular cell types. Mechanisms of development 44, 41-50.
Maltsev, V.A., Wobus, A.M., Rohwedel, J., Bader, M., and Hescheler, J. (1994). Cardiomyocytes differentiated in vitro from embryonic stem cells developmentally express cardiac-specific genes and ionic currents. Circulation research 75, 233-244.
Manalo, D.J., Rowan, A., Lavoie, T., Natarajan, L., Kelly, B.D., Ye, S.Q., Garcia, J.G., and Semenza, G.L. (2005). Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 105, 659-669.
Mangi, A.A., Noiseux, N., Kong, D., He, H., Rezvani, M., Ingwall, J.S., and Dzau, V.J. (2003). Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nature medicine 9, 1195-1201.
Mansson-Broberg, A., Siddiqui, A.J., Genander, M., Grinnemo, K.H., Hao, X., Andersson, A.B., Wardell, E., Sylven, C., and Corbascio, M. (2008). Modulation of ephrinB2 leads to increased angiogenesis in ischemic myocardium and endothelial cell proliferation. Biochemical and biophysical research communications 373, 355-359.
Marelli, D., Desrosiers, C., el-Alfy, M., Kao, R.L., and Chiu, R.C. (1992). Cell transplantation for myocardial repair: an experimental approach. Cell transplantation 1, 383-390.
McAllister, T.N., Maruszewski, M., Garrido, S.A., Wystrychowski, W., Dusserre, N., Marini, A., Zagalski, K., Fiorillo, A., Avila, H., Manglano, X., et al. (2009). Effectiveness of haemodialysis access with an autologous tissue-engineered vascular graft: a multicentre cohort study. Lancet (London, England) 373, 1440-1446.
Metzele, R., Alt, C., Bai, X., Yan, Y., Zhang, Z., Pan, Z., Coleman, M., Vykoukal, J., Song, Y.H., and Alt, E. (2011). Human adipose tissue-derived stem cells exhibit proliferation potential and spontaneous rhythmic contraction after fusion with neonatal rat cardiomyocytes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 25, 830-839.
Muller-Ehmsen, J., Whittaker, P., Kloner, R.A., Dow, J.S., Sakoda, T., Long, T.I., Laird, P.W., and Kedes, L. (2002). Survival and development of neonatal rat cardiomyocytes transplanted into adult myocardium. Journal of molecular and cellular cardiology 34, 107-116.
Muraski, J.A., Rota, M., Misao, Y., Fransioli, J., Cottage, C., Gude, N., Esposito, G., Delucchi, F., Arcarese, M., Alvarez, R., et al. (2007). Pim-1 regulates cardiomyocyte survival downstream of Akt. Nature medicine 13, 1467-1475.
Nygren, J.M., Jovinge, S., Breitbach, M., Sawen, P., Roll, W., Hescheler, J., Taneera, J., Fleischmann, B.K., and Jacobsen, S.E. (2004). Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nature medicine 10, 494-501.
O'Neal, W.T., Griffin, W.F., Dries-Devlin, J.L., Kent, S.D., Chen, J., Willis, M.S., and Virag, J.A. (2013). Ephrin-Eph signaling as a potential therapeutic target for the treatment of myocardial infarction. Medical hypotheses 80, 738-744.
O'Neal, W.T., Griffin, W.F., Kent, S.D., Faiz, F., Hodges, J., Vuncannon, J., and Virag, J.A. (2014). Deletion of the EphA2 receptor exacerbates myocardial injury and the progression of ischemic cardiomyopathy. Frontiers in physiology 5, 132.
Oh, H., Bradfute, S.B., Gallardo, T.D., Nakamura, T., Gaussin, V., Mishina, Y., Pocius, J., Michael, L.H., Behringer, R.R., Garry, D.J., et al. (2003). Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proceedings of the National Academy of Sciences of the United States of America 100, 12313-12318.
Ott, H.C., Matthiesen, T.S., Goh, S.K., Black, L.D., Kren, S.M., Netoff, T.I., and Taylor, D.A. (2008). Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart. Nature medicine 14, 213-221.
Pal, R., and Khanna, A. (2007). Similar pattern in cardiac differentiation of human embryonic stem cell lines, BG01V and ReliCellhES1, under low serum concentration supplemented with bone morphogenetic protein-2. Differentiation; research in biological diversity 75, 112-122.
Parisi-Amon, A., Mulyasasmita, W., Chung, C., and Heilshorn, S.C. (2013). Protein-engineered injectable hydrogel to improve retention of transplanted adipose-derived stem cells. Advanced healthcare materials 2, 428-432.
Pham, T., Nguyen, T.T., Bui, A., Pham, T.H., Phan, K.N., Nguyen, M., and Pham, P. (2015). Preliminary evaluation of treatment efficacy of umbilical cord blood-derived mesenchymal stem cell-differentiated cardiac progenitor cells in a myocardial injury mouse model. Biomedical Research and Therapy 2, 1-11.
Poulin, M.F., Deka, A., Mohamedali, B., and Schaer, G.L. (2016). Clinical Benefits of Stem Cells for Chronic Symptomatic Systolic Heart Failure A Systematic Review of the Existing Data and Ongoing Trials. Cell transplantation.
Prestwich, G.D. (2008). Engineering a clinically-useful matrix for cell therapy. Organogenesis 4, 42-47.
Pugh, C.W., and Ratcliffe, P.J. (2003). Regulation of angiogenesis by hypoxia: role of the HIF system. Nature medicine 9, 677-684.
Quevedo, H.C., Hatzistergos, K.E., Oskouei, B.N., Feigenbaum, G.S., Rodriguez, J.E., Valdes, D., Pattany, P.M., Zambrano, J.P., Hu, Q., McNiece, I., et al. (2009). Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity. Proceedings of the National Academy of Sciences of the United States of America 106, 14022-14027.
Quint, C., Arief, M., Muto, A., Dardik, A., and Niklason, L.E. (2012). Allogeneic human tissue-engineered blood vessel. Journal of vascular surgery 55, 790-798.
Ren, J., Samson, W.K., and Sowers, J.R. (1999). Insulin-like growth factor I as a cardiac hormone: physiological and pathophysiological implications in heart disease. Journal of molecular and cellular cardiology 31, 2049-2061.
Rosenblatt-Velin, N., Lepore, M.G., Cartoni, C., Beermann, F., and Pedrazzini, T. (2005). FGF-2 controls the differentiation of resident cardiac precursors into functional cardiomyocytes. Journal of Clinical Investigation 115, 1724-1733.
Tapias, L.F., and Ott, H.C. (2014). Decellularized Scaffolds as a Platform for Bioengineered Organs. Current opinion in organ transplantation 19, 145-152.
Thisse, B., and Thisse, C. (2005). Functions and regulations of fibroblast growth factor signaling during embryonic development. Developmental Biology 287, 390-402.
Toma, C., Pittenger, M.F., Cahill, K.S., Byrne, B.J., and Kessler, P.D. (2002). Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 105, 93-98.
Travan, A., Scognamiglio, F., Borgogna, M., Marsich, E., Donati, I., Tarusha, L., Grassi, M., and Paoletti, S. (2016). Hyaluronan delivery by polymer demixing in polysaccharide-based hydrogels and membranes for biomedical applications. Carbohydrate polymers 150, 408-418.
van der Spoel, T.I., Jansen of Lorkeers, S.J., Agostoni, P., van Belle, E., Gyongyosi, M., Sluijter, J.P., Cramer, M.J., Doevendans, P.A., and Chamuleau, S.A. (2011). Human relevance of pre-clinical studies in stem cell therapy: systematic review and meta-analysis of large animal models of ischaemic heart disease. Cardiovascular research 91, 649-658.
Wang, Z., Bhattacharya, N., Weaver, M., Petersen, K., Meyer, M., Gapter, L., and Magnuson, N.S. (2001). Pim-1: a serine/threonine kinase with a role in cell survival, proliferation, differentiation and tumorigenesis. Journal of veterinary science 2, 167-179.
Westerdahl, D.E., Chang, D.H., Hamilton, M.A., Nakamura, M., and Henry, T.D. (2016). Allogeneic mesenchymal precursor cells (MPCs): an innovative approach to treating advanced heart failure. Expert opinion on biological therapy, 1-7.
Wystrychowski, W., Cierpka, L., Zagalski, K., Garrido, S., Dusserre, N., Radochonski, S., McAllister, T.N., and L'Heureux, N. (2011). Case study: first implantation of a frozen, devitalized tissue-engineered vascular graft for urgent hemodialysis access. The journal of vascular access 12, 67-70.
Xu, W., Zhang, X., Qian, H., Zhu, W., Sun, X., Hu, J., Zhou, H., and Chen, Y. (2004). Mesenchymal stem cells from adult human bone marrow differentiate into a cardiomyocyte phenotype in vitro. Experimental biology and medicine (Maywood, NJ) 229, 623-631.
Zhang, M., Mal, N., Kiedrowski, M., Chacko, M., Askari, A.T., Popovic, Z.B., Koc, O.N., and Penn, M.S. (2007). SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 21, 3197-3207.
Zhang, M., Methot, D., Poppa, V., Fujio, Y., Walsh, K., and Murry, C.E. (2001). Cardiomyocyte grafting for cardiac repair: graft cell death and anti-death strategies. Journal of molecular and cellular cardiology 33, 907-921.


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BUI, Anh Thi-Van; PHAM, Truc Le-Buu; VIRAG, Jitka. Improving stem cell engraftment to enhance functional efficacy in cardiovascular disease: where are we now?. Biomedical Research and Therapy, [S.l.], v. 4, n. 1, p. 1082-1097, jan. 2017. ISSN 2198-4093. Available at: <>. Date accessed: 23 oct. 2017. doi: