Abstract
Marrow-derived mesenchymal stem cells (MSCs) have been heralded as a source of great promise for the regeneration of the infarcted heart. There is no clear data indicating whether or not in vitro differentiation of MSCs into major myocardial cells can increase the beneficial effects of MSCs. The aim of this study is to address this issue. To induce MSCs to transdifferentiate into cardiomyocyte-like and endothelial-like cells, 5-azacytidine and vascular endothelial growth factor (VEGF) were used, respectively. Myocardial infarction in rabbits was generated by ligating the left anterior descending coronary artery. Animals were divided into three experimental groups: I, control group; II, undifferentiated mesenchymal stem cell transplantation group; III, differentiated mesenchymal stem cell transplantation group; which respectively received peri-infarct injections of culture media, autologous undifferentiated MSCs and autologous differentiated MSCs. General pathology, immunohistochemistry, electron microscopy and echocardiography were performed in order to search for myocardial regeneration and improvement of cardiac function. In Groups II and III, implanted cells transdifferentiate into myocardial cells within 28 days post injection in a similar manner, and well-developed ultra structures formed within transplanted cells. Improvements in left ventricular function and reductions in infarcted area were observed in both cell-transplanted groups to the same degree. Vascular density was similar in Groups II and III and significantly higher in these groups compared with the control group. There is no need for prior differentiation induction of marrow-derived MSCs before transplantation and peri-infarct implantation of MSCs can efficiently regenerate the infarcted myocardium and improve cardiac function.
Similar content being viewed by others
References
Anversa P., Li P., Zhang X., Olivetti G., Capasso J.M., Ischemic myocardial injury and ventricular remodelling. Cardiovasc. Res. 27: 145–157, 1993
Itescu S., Schuster M.D., Kocher A.A., New directions in strategies using cell therapy for heart disease. J. Mol. Med. 81: 288–296, 2003
Pittenger M.F., Martin B.J., Mesenchymal stem cells and their potential as cardiac therapeutics. Circ. Res. 95: 9–20, 2004
Toma C., Pittenger M.F., Cahill K.S., Byrne B.J., Kessler P.D., Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 105: 93–98, 2002
Makino S., Fukuda K., Miyoshi S., Konishi F., Kodama H., Pan J., Sano M., Takahashi T., Hori S., Abe H., Hata J., Umezawa A., Ogawa S., Cardiomyocytes can be generated from marrow stromal cells in vitro J. Clin. Invest. 103: 697–705, 1999
Oswald J., Boxberger S., Jorgensen B., Feldmann S., Ehninger G., Bornhäuser M., Werner C., Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells 22: 377–384, 2004
Tomita S., Li R.K., Weisel R.D., Mickle D.A.G., Kim E.J., Sakai T. and Jia Z.Q., Autologous transplantation of bone marrow cells improves damaged heart function. Circulation 100(Suppl. II): II-247–56, 1999.
Tomita S., Mickle D.A.G., Weisel R.D., Jia Z.Q., Tumiati L.C., Allidina Y., Liu P., Li R.K., Improved heart function with myogenesis and angiogenesis after autologous porcine bone marrow stromal cell transplantation. J. Thorac. Cardiovasc. Surg. 123: 1132–1140, 2002
Saito T., Kuang J.Q., Lin C.C., Chiu R.C., Transcoronary implantation of bone marrow stromal cells ameliorates cardiac after myocardial function infarction. J. Thorac. Cardiovasc. Surg. 126: 114–123, 2003
Siepe M., Heilmann C., von Samson P., Menasché P., Beyersdorf F., Stem cell research and cell transplantation for myocardial regeneration. Eur. J. Cardiothorac. Surg. 28: 318–324, 2005
Dimarakis I., Habib N.A., Gordon M.Y.A., Adult bone marrow-derived stem cells and the injured heart: just the beginning? Eur. J. Cardiothorac. Surg. 28: 665–676, 2005
Morales C., Gonzalez G.E., Rodriguez M., Bertolasi C.A., Gelpi R.J., Histopathologic time course of myocardial infarct in rabbit hearts. Cardiovasc. Pathol. 11: 339–345, 2002
Kadivar M., Khatami S., Mortazavi Y., Shokrgozar M.A., Taghikhani M., Soleimani M., In vitro cardiomyogenic potential of human umbilical vein-derived mesenchymal stem cells. Biochem. Biophys. Res. Commun. 340: 639–647, 2006
Liu J., Hu Q., Wang Z., Xu C., Wang X., Gong G., Mansoor A., Lee J., Hou M., Zeng L., Zhang J.R., Jerosch-Herold M., Guo T., Bache R.J., Zhang J., Autologous stem cell transplantation for myocardial repair. Am. J. Physiol. Heart Circ. Physiol. 287: H501–H511, 2004
Misao Y., Takemura G., Arai M., Sato S., Suzuki K., Miyata S., Kosai K., Minatoguchi S., Fujiwara T., Fujiwara H., Bone marrow-derived myocyte- like cells and regulation of repair-related cytokines after bone marrow cell transplantation. Cardiovasc. Res. 69: 476–490, 2006
Boodhwani M., Nakai Y., Mieno S., Voisine P., Bianchi C., Araujo E.G., Feng J., Michael K., Li J., Sellke F.W., Hypercholesterolemia impairs the myocardial angiogenic response in a swine model of chronic ischemia: role of endostatin and oxidative stress. Ann. Thorac. Surg. 81: 634–641, 2006
Kinnaird T., Stabile E., Burnett M.S., Shou M., Lee C.W., Barr S., Fuchs S., Epstein S.E., Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation 109: 1543–1549, 2004
Shyu K.G., Wang B.W., Hung H.F., Chang C.C., Shih D.T.B., Mesenchymal stem cells are superior to angiogenic growth factor genes for improving myocardial performance in the mouse model of acute myocardial infarction. J. Biomed. Sci. 13: 47–58, 2006
Tang Y.L., Zhao Q., Zhang Y.C., Cheng L., Liu M., Shi J., Yang Y.Z., Pan C., Ge J., Philips M.I., Autologous mesenchymal stem cell transplantation induce VEGF and neovascularization in ischemic myocardium. Regul. Pept. 117: 3–10, 2004
Kajstura J., Rota M., Whang B., Cascapera S., Hosoda T., Bearzi C., Nurzynska D., Kasahara H., Zias E., Bonafé M., Nadal-Ginard B., Torella D., Nascimbene A., Quaini F., Urbanek K., Leri A., Anversa P., Bone marrow cells differentiate in cardiac cell lineages after infarction independently of cell fusion. Circ. Res. 96: 127–137, 2005
Deb A., Wang S., Skelding K.A., Miller D., Simper D., Caplice N.M., Bone marrow–derived cardiomyocytes are present in adult human heart: a study of gender-mismatched bone marrow transplantation patients. Circulation 107: 1247–1249, 2003
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., Bolli R., Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function. Proc. Natl. Acad. Sci. USA 102: 3766–3771, 2005
Gartner L.P., Hiatt J.L. (Ed), Color textbook of histology. WB Saunders, Philadelphia, USA, 2001
Brette F., Orchard C., T-tubule function in mammalian cardiac myocytes. Circ. Res. 92: 1182–92, 2003
Haddock P.S., Coetzee W.A., Cho E., Porter L., Katoh H., Bers D.M., Jafri M.S., Artman M., Subcellular [Ca2+]i gradients during excitation- contraction coupling in newborn rabbit ventricular myocytes. Circ. Res. 85: 415–427, 1999
Kinnaird T., Stabile E., Burnett M.S., Lee C.W., Barr S., Fuchs S., Epstein S.E., Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ. Res. 94: 678–685, 2004
Davani S., Marandin A., Mersin N., Royer B., Kantelip B., Hervé P., Etievent J.P., Kantelip J.P. and Mesenchymal progenitor cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a rat cellular cardiomyoplasty model. Circulation 108(Suppl I): II-253–8, 2003.
Silva G.V., Litovsky S., Assad J.A.R., Sousa A.L.S., Martin B.J., Vela D., Coulter S.C., Lin J., Ober J., Vaughn W.K., Branco R.V.C., Oliveira E.M., He R., Geng Y.J., Willerson J.T., Perin E.C., 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, 2005
Zhang S., Jia Z., Ge J., Gong L., Ma Y., Li T., Guo J., Chen P., Hu Q., Zhang P., Liu Y., Li Z., Ma K., Li L., Zhou C., Purified human bone marrow multipotent mesenchymal stem cells regenerate infarcted myocardium in experimental rats. Cell Transplant. 14: 787–798, 2005
Kocher A.A., Schuster M.D., Szabolcs M.J., Takuma S., Burkhoff D., Wang J., Homma S., Edwards N.M., Itescu S., Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat. Med. 7: 430–436, 2001
Xu H.X., Li G.S., Jiang H., Wang J., Lu J.J., Jiang W., Qian H.Y., Jiang X.J., Li X.Y., Li J.J., Liu W.H., Implantation of BM cells transfected with phVEGF165 enhances functional improvement of the infarcted heart. Cytotherapy 6: 204–211, 2004.
Bittira B., Kuang J.Q., Al-Khaldi A., Shum-Tim D., Chiu R.C.J., In vitro preprogramming of marrow stromal cells for myocardial regeneration. Ann. Thorac. Surg. 74: 1154–1160, 2002.
Wang J.S., Shum-Tim D., Galipeau J., Chedrawy E., Eliopoulos N., Chiu R.C.J., Marrow stromal cells for cellular cardiomyoplasty: feasibility and potential clinical advantages. J. Thorac. Cardiovasc. Surg. 120: 999–1006, 2000.
Acknowledgements
We are grateful to Dr. Farzad Asadi for his help with statistical analysis. We thank the staff of Rastegar Central Research Laboratory of the Faculty of Veterinary Medicine as well as the staff of the Immunohistochemistry Department of Imam Khomeini Hospital Complex for their help in this study.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Nassiri, S.M., Khaki, Z., Soleimani, M. et al. The similar effect of transplantation of marrow-derived mesenchymal stem cells with or without prior differentiation induction in experimental myocardial infarction. J Biomed Sci 14, 745–755 (2007). https://doi.org/10.1007/s11373-007-9188-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11373-007-9188-9