Genes & CellsGenes & CellsГены и КлеткиGenes and Cells2313-18292500-2562Human Stem Cells Institute12146410.23868/gc121464ArticlesСтатьиProspects of increasing the effectiveness of cardio-vascular gene and cell therapy: genetically modified cellsПерспективы повышения эффективности генной и клеточной терапии сердечно-сосудистых заболеваний: генетически модифицированные клеткиShevchenkoE KШевченкоЕ К

ФГУ «Российский кардиологический научно-производственный комплекс Федерального агентства по высокотехнологичной медицинской помощи», Москва

TalitskiyA KТалицкийА К

ФГУ «Российский кардиологический научно-производственный комплекс Федерального агентства по высокотехнологичной медицинской помощи», Москва

ParfenovaE VПарфеноваЕ В

ФГУ «Российский кардиологический научно-производственный комплекс Федерального агентства по высокотехнологичной медицинской помощи», Москва

ShevchenkoE K

Russian Cardiology Research and Production Complex, Moscow

TalitskiyA K

Russian Cardiology Research and Production Complex, Moscow

ParfyonovaY V

Russian Cardiology Research and Production Complex, Moscow

ФГУ «Российский кардиологический научно-производственный комплекс Федерального агентства по высокотехнологичной медицинской помощи», МоскваRussian Cardiology Research and Production Complex, Moscow1506201052NO2 (2010)№2 (2010)192811012023Copyright ©; 2010, Eco-VectorCopyright ©; 2010, Эко-Вектор2010Eco-VectorЭко-Векторhttps://genescells.ru/2313-1829/article/view/121464

Many hopes for increasing the effectiveness of therapy for cardio-vascular diseases such as non optimal for cases of ischemic heart diseases, myocardial infarction, heart failure, critical limb ischemia are connected with progress in gene and cell therapy. Experimental studies strongly demonstrated effective angiogenesis and myocardial regeneration, blood flow restoration in ischemic limb by gene and cell therapy approaches. However the results of clinical studies of these methods are very modest. To overcome the insufficient effectiveness of these methods the genetic modification of stem and progenitor cells - an alliance of gene and cell therapy allowing to neutralize disadvantages and to enhance advantages of both methods - could be used. In this review we have provided an overview of pioneering research in the experimental application of genetically engineered cells in cardiovascular pathology. The possibility of using genetically modified progenitor cells of different origin for therapeutic angiogenesis, myocardial regeneration and creation of cardiac pacemakers is discussed.

С развитием генной и клеточной терапии связывают надежды на повышение эффективности лечения сердечно-сосудистых заболеваний, прежде всего неоперабельных случаев ишемической болезни сердца, инфаркта миокарда, сердечной недостаточности, критической ишемии нижних конечностей. Экспериментальные исследования убедительно продемонстрировали возможность стимуляции ангиогенеза, регенераторных процессов в сердце и ишемизированных конечностях животных с помощью генной и клеточной терапии. Однако результаты клинического применения этих методов довольно скромные. Одним их подходов к повышению эффективности генной и клеточной терапии может быть генетическая модификация стволовых и прогениторных клеток - своеобразный альянс клеточной и генной терапии, позволяющий нейтрализовать недостатки и усилить преимущества обеих методик. В данном обзоре анализируются основные экспериментальные работы по использованию генетически модифицированных клеток для стимуляции ангиогенеза и регенеративных процессов в миокарде, создания биологических пейсмейкеров, повышения выживаемости, хоуминга и интеграции клеток при трансплантации в поврежденную ткань, возможные области и перспективы их использования для лечения больных с сердечно-сосудистыми заболеваниями.

gene therapycell therapyangiogenic growth factorangiogenesishomingгенная терапияклеточная терапияишемияангиогенные факторы ростаангиогенезхоумингHöckel M., Schlenger K., Doctrow S. Therapeutic angiogenesis. Arch. Surg. 1993; 128: 423-9.Springer M.L. A balancing act: therapeutic approaches for the modulation of angiogenesis. Curr. Opin. Investig. Drugs. 2006; 7(3): 243-50.Renault M-A., Osordo D.W. Therapeutic Myocardial Angiogenesis. Microvasc. Res. 2007; 74(2-3): 159-71.Bashir R., Vale P.R., Isner J.M. et al. Angiogenic gene therapy: pre-clinical studies and phase I clinical data. Kidney Int. 2002; 61(1 Suppl): S110-4.Attanasio S., Snell J. Therapeutic angiogenesis in the management of critical limb ischemia: current concepts and review. Cardiol. Rev. 2009; 17(3): 115-20.Gupta R., Tongers J., Losordo D. Human studies of angiogenic gene therapy. Circ. Res. 2009; 105: 724-36.Gyongyosi M., Khorsand A., Zamini S. et al. NOGA-guided analysis of regional myocardial perfusion abnormalities treated with intramyocardial injections of plasmid encoding vascular endothelial growth factor A-165 in patients with chronic myocardial ischemia: subanalysis of the EUROINJECT-ONE multicenter double-blind randomized study. Circulation 2005; 112(suppl I): I157-I65.Grines C.L., Watkins M.W., Helmer G. et al. Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris. Circulation 2002; 105: 1291-7.Grines C.L., Watkins M.W., Mahmarian J.J. et al. A randomized, double-blind, placebocontrolled trial of Ad5FGF-4 gene therapy and its effect on myocardial perfusion in patients with stable angina. J. Am. Coll. Cardiol. 2003; 42: 1339-47.Henry T.D., Grines C.L., Watkins M.W. et al. Effects of Ad5FGF-4 in patients with angina: an analysis of pooled data from the AGENT-3 and AGENT-4 trials. J. Am. Coll. Cardiol. 2007; 50: 1038-46.Makinen K., Manninen H., Hedman M. et al. Increased vascularity detected by digital subtraction angiography after VEGF gene transfer to human lower limb artery: a randomized, placebo-controlled, double-blinded phase II study. Mol. Ther. 2002; 6: 127-33.Kusumanto Y.H., van Weel V., Mulder N.H. et al. Treatment with intramuscular vascular endothelial growth factor gene compared with placebo for patients with diabetes mellitus and critical limb ischemia: a double-blind randomized trial. Hum. Gene. Ther. 2006; 17: 683-91.Yla-Herttuala S., Rissanen T.T., Vajanto I. Vascular endothelial growth factors: biology and current status of clinical application in cardiovascular medicine. JMCC 2007; 49: 1015-26.Rajagopalan S., Mohler E.R., Lederman R.J. et.al. Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: a phase II randomized, double-blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication. Circulation 2003; 108(16): 1933-8.Kalka C., Masuda H., Takahashi T. et al. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. PNAS USA 2000; 97(7): 3422-7.Pesce M., Orlandi A., Iachininoto M.G. et al. Myoendothelial differentiation of human umbilical cord blood-derived stem cells in ischemic limb tissues. Circ Res. 2003; 93(5): e51-62.Iwase T., Nagaya N., Fujii T. et al. Comparison of angiogenic potency between mesenchymal stem cells and mononuclear cells in a rat model of hindlimb ischemia. Cardiovasc Res. 2005; 66(3): 543-51.Miranville A., Heeschen C., Sengenиs C. et al. Improvement of postnatal neovascularization by human adipose tissue-derived stem cells. Circulation 2004; 110(3): 349-55.Lipinski M.J., Biondi-Zoccai G.G., Abbate A. et al. Impact of intracoronary cell therapy on left ventricular function in the setting of acute myocardial infarction: a collaborative systematic review and meta-analysis of controlled clinical trials. J Am Coll Cardiol. 2007; 50(18): 1761-7.Reffelmann T., Kцnemann S., Kloner R.A. Promise of blood- and bone marrow-derived stem cell transplantation for functional cardiac repair: putting it in perspective with existing therapy. J. Am. Coll. Cardiol. 2009; 53(4): 305-8.Zhang S.N., Sun A.J., Ge J.B. et al. Intracoronary autologous bone marrow stem cells transfer for patients with acute myocardial infarction: a meta-analysis of randomised controlled trials. Int. J. Cardiol. 2009; 136(2): 178-85.Zohlnhцfer D., Dibra A., Koppara T. et al. Stem cell mobilization by granulocyte colony-stimulating factor for myocardial recovery after acute myocardial infarction: a meta-analysis. J. Am. Coll. Cardiol. 2008; 51(15): 1429-37.Formigli L., Zecchi-Orlandini S., Meacci E. et al. Skeletal myoblasts for heart regeneration and repair: state of the art and perspectives on the mechanisms for functional cardiac benefits. Curr. Pharm. Des. 2009. Curr Pharm Des. 2010; 16(8): 915-28.Germani A., Di Campli C., Pompilio G. et al Regenerative therapy in peripheral artery disease. Cardiovasc. Ther. 2009; 27(4): 289-304.Kawamoto A., Katayama M., Handa N., et al. Intramuscular transplantation of G-CSF-mobilized CD34(+) cells in patients with critical limb ischemia: a phase I/IIa, multicenter, single-blinded, dose-escalation clinical trial. Stem Cells 2009; 27(11): 2857-64.Pittenger M.F., Martin B.J. Mesenchymal stem cells and their potential as cardiac therapeutics. Circ. Res. 2004; 95(1): 9-20.Sugihara S., Yamamoto Y., Matsuura T. et al. Age-related BM-MNC dysfunction hampers neovascularization. Mech. Ageing. Dev. 2007; 128(9): 511-6.Ikeda Y., et al. Development of angiogenic cell and gene therapy by transplantation of umbilical cord blood with vascular endothelial growth factor gene. Hypertens. Res. 2004; 27(2): 119-28.Iwaguro H., Yamaguchi J., Kalka C. et al. Endothelial progenitor cell vascular endothelial growth factor gene transfer for vascular regeneration. Circulation 2002; 105(6): 732-8.Choi J.H., Hur J., Yoon C.H. et al. Augmentation of therapeutic angiogenesis using genetically modified human endothelial progenitor cells with altered glycogen synthase kinase-3beta activity. J. Biol. Chem. 2004; 279(47): 49430-8.Jiang M., Wang B., Wang C. et al. Angiogenesis by transplantation of HIF-1 alpha modified EPCs into ischemic limbs. J. Cell. Biochem. 2008; 103(1): 321-34.Jiang M., Wang B., Wang C. et al. In vivo enhancement of angiogenesis by adenoviral transfer of HIF-1alpha-modified endothelial progenitor cells (Ad-HIF-1alpha-modified EPC for angiogenesis). Int. J. Biochem. Cell. Biol. 2008; 40(10): 2284-95.Borselli C., Storrie H., Benesch-Lee F. et al. Functional muscle regeneration with combined delivery of angiogenesis and myogenesis factors. PNAS USA 2009; 107(8): 3287-92.Germani A., Di Carlo A., Mangoni A. et al. Vascular endothelial growth factor modulates skeletal myoblast function. Am. J. Pathol. 2003;163 (4): 1417-28.Niagara M.I., Haider H.Kh., Ye L. et al. Autologous skeletal myoblasts transduced with a new adenoviral bicistronic vector for treatment of hind limb ischemia. J. Vasc. Surg. 2004; 40(4): 774-85.Ye L., Haider H.Kh., Jiang S. et al. Improved angiogenic response in pig heart following ischaemic injury using human skeletal myoblast simultaneously expressing VEGF165 and angiopoietin-1. Eur. J. Heart. Fail. 2007; 9(1): 15-22.Suzuki K., Murtuza B., Smolenski R.T. et al. Cell transplantation for the treatment of acute myocardial infarction using vascular endothelial growth factor-expressing skeletal myoblasts. Circulation 2001; 104(12 Suppl 1): I207-12.Sugimoto T., Inui K., Shimazaki Y. Gene therapy for myocardial angiogenesis: with direct intramuscular gene transfer of naked deoxyribonucleic acid encoding vascular endothelial growth factor and cell transplantation of vascular endothelial growth factor transfected H9c2 myoblast. Jpn. J. Thorac. Cardiovasc. Surg. 2003; 51(5): 192-7.Askari A., Unzek S., Goldman C.K. et al. Cellular, but not direct, adenoviral delivery of vascular endothelial growth factor results in improved left ventricular function and neovascularization in dilated ischemic cardiomyopathy. J Am. Coll. Cardiol. 2004; 43(10): 1908-14.Law P.K., Haider K., Fang G. et al. Human VEGF165-myoblasts produce concomitant angiogenesis/myogenesis in the regenerative heart. Mol. Cell. Biochem. 2004; 263(1-2): 173-8.Rong S.L., Wang Y.J., Wang X.L. et al. Recombinant human growth hormone secreted from tissue-engineered bioartificial muscle improves left ventricular function in rat with acute myocardial infarction. Chin. Med. J. (Engl). 2009; 122(19): 2352-9.Hagikura K., Fukuda N., Yokoyama S.I. et al. Low invasive angiogenic therapy for myocardial infarction by retrograde transplantation of mononuclear cells expressing the VEGF gene. Int J Cardiol. 2009 Jan 22. [Epub ahead of print].Tokcaer-Keskin Z., Akar A.R., Ayaloglu-Butun F. et al. Timing of induction of cardiomyocyte differentiation for in vitro cultured mesenchymal stem cells: a perspective for emergencies. Can. J. Physiol. Pharmacol. 2009; 87(2) :143-50.Hattan N., Kawaguchi H., Ando K. et al. Purified cardiomyocytes from bone marrow mesenchymal stem cells produce stable intracardiac grafts in mice.Cardiovasc. Res. 2005; 65(2): 334-44.Zou Z., Zhang Y., Hao L. et al. More insight into mesenchymal stem cells and their effects inside the body. Expert. Opin. Biol. Ther. 2010; 10(2): 215-30.Tang J., Xie Q., Pan G. et al. Mesenchymal stem cells participate in angiogenesis and improve heart function in rat model of myocardial ischemia with reperfusion. Eur. J. Cardiothorac. Surg. 2006; 30(2): 353-61.Schдfer R., Northoff H. Cardioprotection and cardiac regeneration by mesenchymal stem cells. Panminerva Med. 2008; 50(1): 31-9.Matsumoto R., Omura T., Yoshiyama M. et al. Vascular endothelial growth factor-expressing mesenchymal stem cell transplantation for the treatment of acute myocardial infarction. Arterioscler. Thromb. Vasc. Biol. 2005; 25(6): 1168-73.Gao F., He T., Wang H. et al. A promising strategy for the treatment of ischemic heart disease: Mesenchymal stem cell-mediated vascular endothelial growth factor gene transfer in rats. Can. J. Cardiol. 2007; 23(11): 891-8.Yang J., Zhou W., Zheng W. et al. Effects of myocardial transplantation of marrow mesenchymal stem cells transfected with vascular endothelial growth factor for the improvement of heart function and angiogenesis after myocardial infarction. Cardiology 2007; 107(1): 17-29.Gao C.Q., Yang M., Li L.B. et al. The experimental studies on cell transplantation into chronic ischemic myocardium using mesenchymal stem cells modified by recombinant adenovirus carrying vascular endothelial growth factors 165 gene. Zhonghua. Wai. Ke. Za. Zhi. 2007; 45(14): 990-3.Sun L., Cui M., Wang Z. et al. Mesenchymal stem cells modified with angiopoietin-1 improve remodeling in a rat model of acute myocardial infarction. Biochem. Biophys. Res. Commun. 2007; 357(3): 779-84.Liu X.H., Bai C.G., Xu Z.Y. et al. Therapeutic potential of angiogenin modified mesenchymal stem cells: angiogenin improves mesenchymal stem cells survival under hypoxia and enhances vasculogenesis in myocardial infarction. Microvasc. Res. 2008; 76(1): 23-30.Yi C.G., Guo S.Z., Zhang L.X. et al. Promotion of the survival of ischemic skin flap by transplanted endothelial progenitor cells transfected with VEGF165 gene: an experimental study with mice. Zhonghua. Yi. Xue. Za. Zhi. 2005; 85(7): 473-8.Rinsch C., Quinodoz P., Pittet B. et al. Delivery of FGF-2 but not VEGF by encapsulated genetically engineered myoblasts improves survival and vascularization in a model of acute skin flap ischemia. Gene. Ther. 2001; 8(7): 523-33.Müller-Ehmsen J., Peterson K.L., Kedes L. et al. Rebuilding a damaged heart: long-term survival of transplanted neonatal rat cardiomyocytes after myocardial infarction and effect on cardiac function. Circulation 2002; 105(14): 1720-6.Pasha Z., Wang Y., Sheikh R. et al. Preconditioning enhances cell survival and differentiation of stem cells during transplantation in infarcted myocardium. Cardiovasc. Res. 2008; 77(1): 134-42.Niagara M.I., Haider H.K., Jiang S. et al. Pharmacologically preconditioned skeletal myoblasts are resistant to oxidative stress and promote angiomyogenesis via release of paracrine factors in the infracted heart. Circ. Res. 2007; 100: 545-55.Hu X., Yu S.P., Fraser J.L. et al. Transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis. J. Thorac. Cardiovasc. Surg. 2008; 135(4): 7ЭЭ-808.BO. Suzuki K., Smolenski R.T., Jayakumar J. et al. Heat shock treatment enhances graft cell survival in skeletal myoblast transplantation to the heart. Circulation 2000; 102: 111216-21.Datta S.R., Brunet A., Greenberg M.E. Cellular survival: a play in three Akts, Genes. Dev. 1999; 13: 2905-27.Mangi A.A., Noiseux N., Kong D. et al. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat. Med. 2003; 9: 1195-201.Gnecchi M., He H., Liang O.D. et al. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat. Med. 2005; 11(4): 367-8.Shujia J., Haider H.K., Idris N.M. et al. Stable therapeutic effects of mesenchymal stem cell-based multiple gene delivery for cardiac repair. Cardiovasc Res. 2008; 77(3): 525-33.Meuillet E.J., Mahadevan D., Vankayalapati H. et al. Specific inhibition of the Akt1 pleckstrin homology domain by D-3-deoxy-phosphatidyl-myo-inositol analogues. Mol. Cancer Ther. 2003; 2:389-99.Li W., Ma N., Ong L.L. et al. Bcl-2 engineered MSCs inhibited apoptosis and improved heart function. Stem Cells 2007; 25(8): 2118-27.Otterbein L.E., Choi A.M. Heme oxygenase: colors of defense against cellular stress. Am. J. Physiol. Lung Cell. Mol. Physiol. 2000; 279: L1029-37.Tang Y.L., Zhao Q., Qin X. et al. Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction. Ann. Thorac. Surg. 2005; 80: 229-36.Lapidot T. Mechanism of human stem cell migration and repopulation of NOD/SCID and B2mnull NOD/SCID mice. The role of SDF-1/CXCR4 interactions. Ann. N. Y. Acad. Sci. 2001; 938: 83-95.Bhakta S., Hong P., Кос О. The surface adhesion molecule CXCR4 stimulates mesenchymal stem cell migration to stromal cell-derived factor-1 in vitro but does not decrease apoptosis under serum deprivation. Cardiovasc. Revasc. Med. 2006; 7(1): 19-24.Zhang D., Fan G.C., Zhou X. et al. Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium. J. Mol. Cell. Cardiol. 2008; 44(2): 281-92.Abraham M.R., Henrikson C.A., Tung L. et al. Antiarrhythmic Engineering of Skeletal Myoblasts for Cardiac Transplantation. Circ Res. 2005; 97(2): 159-67.Menaschn P. Skeletal myoblasts as a therapeutic agent. Prog Cardiovasc Dis. 2007; 50(1): 7-17.Abraham M.R., Henrikson C.A., Tung .L et al. Antiarrhythmic engineering of skeletal myoblasts for cardiac transplantation. Circ Res. 2005; 97(2): 159-67.Cao В., Bruder J., Kovesdi I. et al. Muscle stem cells can act as antigen-presenting cells: implication for gene therapy. Gene. Ther. 2004; 11(17): 1321-30.Cordier L, Gao G.P., Hack A.A. et al. Muscle-specific promoters may be necessary for adeno-associated virus-mediated gene transfer in the treatment of muscular dystrophies. Hum Gene Ther. 2001; 12(2): 205-15.Wiendl H., Mitsdoerffer M., Hofmeister V. et al. The non-classical MHC molecule HLA-G protects human muscle cells from immune-mediated lysis: implications for myoblast transplantation and gene therapy. Brain 2003; 126(Pt 1): 176-85.Mocini D., Colivicchi F., Santini M. Stem cell therapy for cardiac arrhythmias. Ital Heart J. 2005; 6(3): 267-71.Rosen M.R., Brink P.R., Cohen I.S. et al. Genes, stem cells and biological pacemakers. Cardiovasc. Res. 2004; 64(1): 12-23.Potapova I., Plotnikov A., Lu Z. et al. Human mesenchymal stem cells as a gene delivery system to create cardiac pacemakers. Circ. Res. 2004; 94(7): 952-9.Tomita Y., Makino S., Hakuno D. et al. Application of mesenchymal stem cell-derived cardiomyocytes as bio-pacemakers: current status and problems to be solved. Med. Biol. Eng. Comput. 2007; 45(2): 209-20.