Cover Page
  • Authors: Maslov L.N.1, Podoksenov Y.K.1, Portnichenko A.G.2, Naumova A.V.3
  • Affiliations:
    1. Research Institute for Cardiology of Siberian Branch under the Russian Academy of Medical Sciences, Tomsk, Russian Federation
    2. Bogomoletz Institute of Physiology National Academy of Sciences of Ukraine, Kiev
    3. Department of Radiology, University of Washington, Seattle, USA
  • Issue: Vol 68, No 12 (2013)
  • Pages: 16-25
  • URL: https://vestnikramn.spr-journal.ru/jour/article/view/103
  • DOI: https://doi.org/10.15690/vramn.v68i12.855
  • Cite item


During the last decade, stem cell research has developed at an accelerated pace. Various types of stem cells have been tested for myocardial infarction therapy. Despite the preclinical benefits of cell therapy success in clinical trials remains modest. The main obstacles to regeneration of the infarcted heart using stem cells are: 1) not every stem cell type can differentiate into cardiomyocytes; and 2) low survival rates of transplanted cells, due to the harsh environment of the infarcted myocardium. Hypoxic preconditioning (HP) has been shown to improve transplantation efficacy of mesenchymal stem cells and cardiac progenitor cells in animal models of myocardial infarction. It has also been shown that transplantation of preconditioned cells decreases infarct size, prevents postinfarction remodeling of the heart, and positively modulates development of ischemic cardiomyopathy. Hypoxic preconditioning also prevents extensive death of transplanted cells due to necrosis and apoptosis during long-term hypoxia or oxidative stress. The protective effect of HP is based on three main processes: (1) modification of cell phenotypes to help survival during hypoxia (enhancement of HIF-1α expression, ERK1/2 and Akt activation, enhancement of erythropoietin receptor expression and erythropoietin production, and an elevation in levels of antiapoptotic proteins Bcl-2 and Bcl-xL); (2) upregulation of various secretable factors including the vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), and expression of VEGF-2 and HGF-receptors; (3) enhancement in the formation of CXCR4 and CXCR7 receptors, which play an important role in mobilization and homing of stem cells in the ischemic region.


About the authors

L. N. Maslov

Research Institute for Cardiology of Siberian Branch under the Russian Academy of Medical Sciences, Tomsk, Russian Federation

Author for correspondence.
Email: maslov@cardio.tsu.ru

Russian Federation PhD, professor, Head of Laboratory of Experimental Surgery, Federal State Budget Institution “Research Center of Cardiology”, Siberian Department of Russian Academy of Medical Sciences. Address: 111, Kievskaya Street, Tomsk, RF, 634012; tel.: +7 (3822) 26-21-74

Yu. K. Podoksenov

Research Institute for Cardiology of Siberian Branch under the Russian Academy of Medical Sciences, Tomsk, Russian Federation

Email: uk@cardio-tomsk.ru

Russian Federation PhD, Head of the Department of Anesthesiology and Resuscitation, Federal State Budget Institution “Scientific Research Center of Cardiology”, Siberian Department of Russian Academy of Medical Sciences Address: 111, Kievskaya Street, Tomsk, RF, 634012; tel.: +7 (3822) 26-21-74

A. G. Portnichenko

Bogomoletz Institute of Physiology National Academy of Sciences of Ukraine, Kiev

Email: port@serv.biph.kiev.ua

Ukraine MD, senior research scientist of the Department of Common and Molecular Pathophysiology of A.A. Bogomolets Institute of Physiology, National Academy of Sciences, Ukraine Address: 4, Bogomoltsa str., Kiev, Ukraine

A. V. Naumova

Department of Radiology, University of Washington, Seattle, USA

Email: anabella1710@gmail.com

United States MD, research scientist of the Department of Radiology, Washington University. Address: Seattle, USA


  1. Markov V.A., Ryabov V.V., Maksimov I.V. et al. Yesterday, today and tomorrow in the diagnosis and treatment of acute myocardial infarction. Sib. med. zhur. = Siberian oncological journal. 2011; 26(2), issue1: 8–14.
  2. Suleiman M., Aronson D., Reisner S.A. et al. Admission C-reactive protein levels and 30-day mortality in patients with acute myocardial infarction. Am. J. Med. 2003; 115 (9): 695-701.
  3. Solomon S.D., St John Sutton M., Lamas G. et al. Survival And Ventricular Enlargement (SAVE) Investigators. Ventricular remodeling does not accompany the development of heart failure in diabetic patients after myocardial infarction. Circulation. 2002; 106 (10): 1251-1255.
  4. Richards A.M., Nicholls M.G., Troughton R.W. et al. Antecedent hypertension and heart failure after myocardial infarction. J. Am. Coll. Cardiol. 2002; 39 (7): 1182-1188.
  5. Parodi G., Carrabba N., Santoro G.M. et al. Heart failure and left ventricular remodeling after reperfused acute myocardial infarction in patients with hypertension. Hypertension. 2006; 47 (4): 706-710.
  6. Araszkiewicz A., Lesiak M., Grajek S. et al. Relationship between tissue reperfusion and postinfarction left ventricular remodelling in patients with anterior wall myocardial infarction treated with primary coronary angioplasty. Kardiol. Pol. 2006; 64 (4): 383-388.
  7. Soonpaa M.H., Field L.J. Assessment of cardiomyocyte DNA synthesis in normal and injured adult mouse hearts. Am. J. Physiol. 1997; 272 (1 Pt 2): H220-H226.
  8. Quaini F., Cigola E., Lagrasta C. et al. End-stage cardiac failure in humans is coupled with the induction if proliferating cell nuclear antigen and nuclear mitotic division in ventricular myocytes. Circ. Res. 1994; 75 (6): 1050-1063.
  9. Reiss K., Kajstura J., Zhang X., Li P. et al. Acute myocardial infarction leads to upregulation of the IGF-1 autocrine system, DNA replication, and nuclear mitotic division in the remaining viable cardiac myocytes. Exp. Cell. Res. 1994; 213 (2): 463-472.
  10. Beltrami A.P., Urbanek K., Kajstura J. et al. Evidence that human cardiac myocytes divide after myocardial infarction. N. Engl. J. Med. 2001; 344 (23): 1750-1757.
  11. Hsieh P.C., Segers V.F., Davis M.E. et al. Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nature Med. 2007; 13 (8): 970-974.
  12. Neckár J., Ostádal B., Kolar F. Acute but not chronic tempol treatment increases ischemic and reperfusion ventricular arrhythmias in open chest rats. Physiol. Res. 2008; 57 (4): 653-656.
  13. Marelli D., Desrosiers C., el-Alfy M. et al. Cell transplantation for myocardial repair: an experimental approach. Cell Transplant 1992; 1 (6): 383-390.
  14. Chiu R.C., Zibaitis A., Kao R.L. Cellular cardiomyoplasty: myocardial regeneration with satellite cell implantation. Ann. Thorac. Surg 1995; 60 (1): 12-18.
  15. Koh G.Y., Klug M.G., Soonpaa M.H., Field L.J. Differentiation and long-term survival of C2C12 myoblast grafts in heart. J. Clin. Invest. 1993; 92 (3): 1548-1554.
  16. Grounds M.D., White J.D., Rosenthal N., Bogoyevitch M.A. The role of stem cells in skeletal and cardiac muscle repair. J. Histochem. Cytochem. 2002; 50 (5): 589-610.
  17. Hughes S. Cardiac stem cells. J. Physiology. 2002; 197 (4): 468-478.
  18. Orlic D., Hill J.M., Arai A.E. Stem cells for myocardial regeneration. Circ. Res. 2002, 91 (12): 1092-1102.
  19. Toma C., Pittenger M.F., Cahill K.S. et al. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation. 2002; 105 (1): 93-98.
  20. Murry C.E., Soonpaa M.H., Reinecke H. et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature. 2004; 428 (6983): 664-668.
  21. Balsam L.B., Wagers A.J., Christensen J.L. et al. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature. 2004; 428 (6983): 668-673.
  22. Limbourg F.P., Ringes-Lichtenberg S., Schaefer A. et al. Haematopoietic stem cells improve cardiac function after infarction without permanent cardiac engraftment. Eur. J. Heart Fail. 2005; 7 (5): 722-729.
  23. Bianco P., Cao X., Frenette P.S. et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat. Med. 2013; 19 (1): 35-42.
  24. Yoshioka T., Ageyama N., Shibata H. et al. Repair of infarcted myocardium mediated by transplanted bone marrow-derived CD34+ stem cells in a nonhuman primate model. Stem. Cells. 2005; 23 (3): 355-364.
  25. Mirotsou M., Zhang Z., Deb A. et al. Secreted frizzled related protein 2 (Sfrp2) is the key Aktmesenchymal stem cell-released paracrine factor mediating myocardial survival and repair. Proc. Natl Acad. Sci. USA 2007; 104 (5): 1643-1648.
  26. Fazel S., Cimini M., Chen L., Li S. et al. Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines. J. Clin. Invest. 2006; 116 (7): 1865-1877.
  27. Uemura R., Xu M., Ahmad N., Ashraf M. Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circ. Res. 2006; 98 (11): 1414-1421.
  28. Abkowitz J.L., Catlin S.N., McCallie M.T., Guttorp P. Evidence that the number of hematopoietic stem cells per animal is conserved in mammals. Blood. 2002; 100 (7): 2665-2667.
  29. Hatzistergos K.E., Quevedo H., Oskouei B.N. et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ. Res. 2010; 107(7): 913-922.
  30. Bittner R.E., Schofer C., Weipoltshammer K. et al. Recruitment of bone-marrow-derived cells by skeletal and cardiac muscle in adult dystrophic mdx mice. Anat. Embryol. 1999; 199 (5): 391-396.
  31. Quaini F., Urbanek K., Beltrami A.P. et al. Chimerism of the transplanted heart. N. Engl. J. Med. 2002; 346 (1): 5-15.
  32. Hruban R.H., Long P.P., Perlman E.J. et al. Fluorescence in situ hybridization for the Y-chromosome can be used to detect cells of recipient origin in allografted hearts following cardiac transplantation. Am. J. Pathol. 1993; 142 (4): 975-980.
  33. Strauer B.E., Brehm M., Zeus T. et al. Repair of infracted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation. 2002; 106 (15): 1913-1918.
  34. Strauer B.E., Kornowski R. Stem cell therapy in perspective. Circulation. 2003, 107 (7): 929-934.
  35. Assmus B., Schachinger V., Teupe C. et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation. 2002; 106 (24): 3009-3017.
  36. Ryabov V.V., Suslova T.E., Krylov A.L. etc. Ter. arkhiv = Therapeutic Archive. 2006; 78(8): 47–52.
  37. Vesnina Zh.V., Sazonova S.I., Krylov A.L. etc. Vestnik NGU = Bulletin of NSU. 2011; 9(1): 71–76.
  38. Ryabov V.V., Krylov A.L., Poponina Yu.S., Maslov L.N. Kletoch. tekhnol. v biol. i med. = Molecular technologies in biology and medicine. 2006; 1: 15–20.
  39. Krylov A.L., Ryabov V.V., Poponina Yu.S., Maslov L.N. Klin. med = Clinical medicine. 2006; 84(9): 31–35.
  40. Britten M.B., Abolmaali N.D., Assmus B. et al. Infarct remodeling after intracoronary progenitor cell treatment in patients with acute myocardial infarction (TOPCARE-AMI): mechanistic insights from serial contrast-enhanced magnetic resonance imaging. Circulation. 2003; 108 (18): 2212-2218.
  41. Dobert N., Britten M., Assmus B. et al. Transplantation of progenitor cells after reperfused acute myocardial infarction: evaluation of perfusion and myocardial viability with FDG-PET and thallium SPECT. Eur. J. Nucl. Med. Mol. Imaging. 2004; 31 (8): 1146-1151.
  42. Das R., Jahr H., van Osch G.J., Farrell E. The role of hypoxia in bone marrow-derived mesenchymal stem cells: considerations for regenerative medicine approaches. Tissue Eng. Part B Rev. 2010; 16 (2): 159-168.
  43. Herrmann J.L., Abarbanell A.M., Weil B.R. et al. Optimizing stem cell function for the treatment of ischemic heart disease. J. Surg. Res. 2011; 166 (1): 138-145.
  44. Rosova I., Dao M., Capoccia B. et al. Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells. Stem Cells. 2008; 26 (8): 2173-2182.
  45. Hu X., Wei L., Taylor T.M. et al. Hypoxic preconditioning enhances bone marrow mesenchymal stem cell migration via Kv2.1 channel and FAK activation. Am. J. Physiol. Cell. Physiol. 2011; 301 (2): C362-C372.
  46. Kofoed H., Sjontoft E., Siemssen S.O., Olesen H.P. Bone marrow circulation after osteotomy. Blood flow, pO2, pCO2, and pressure studied in dogs. Acta Orthop. Scand. 1985; 56 (5): 400-403.
  47. Tsai C.C., Yew T.L., Yang D.C. et al. Benefits of hypoxic culture on bone marrow multipotent stromal cells. Am. J. Blood Res. 2012; 2 (3): 148-159.
  48. Tang Y.L., Zhu W., Cheng M. et al. Hypoxic preconditioning enhances the benefit of cardiac progenitor cell therapy for treatment of myocardial infarction by inducing CXCR4 expression. Circ. Res. 2009; 104 (10): 1209-1216.
  49. Maslov L.N., Lishmanov Yu.B., Kolar F. etc. Ross. fiziol. zhur = Russian physiological journal. 2010; 96(12): 1170–1189.
  50. Maslov L.N., Lishmanov Yu.B., Emel'yanova T.V. etc. Angiol. sosud. khirurgiya = Angiology and vascular surgery. 2011; 17(3): 27–36.
  51. Akita T., Murohara T., Ikeda H. et al. Hypoxic preconditioning augments efficacy of human endothelial progenitor cells for therapeutic neovascularization. Lab. Invest. 2003; 83 (1): 65-73.
  52. Maslov L.N., Mrochek A.G., Shchepetkin I.A. etc. Ross. fiziol. zhur. = Russian physiological journal. 2013; 99(4): 433–452.
  53. Wang J.A., Chen T.L., Jiang J. et al. Hypoxic preconditioning attenuates hypoxia/reoxygenation-induced apoptosis in mesenchymal stem cells. Acta Pharmacol. Sin. 2008; 29 (1): 74-82.
  54. Kroemer G., Galluzzi L., Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol. Rev. 2007; 87 (1): 99-163.
  55. Naryzhnaya N.V., Lishmanov Yu.B., Kolar F. etc. Ross. fiziol. zhur. = Russian physiological journal. 2011; 97(9): 35–50.
  56. Chang C.P., Chio C.C., Cheong C.U. et al. Hypoxic preconditioning enhances the therapeutic potential of the secretome from cultured human mesenchymal stem cells in experimental traumatic brain injury. Clin. Sci. (Lond). 2013; 124 (3): 165-176.
  57. 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): 799-808.
  58. Lishmanov Yu.B., Maslov L.N., Ugdyzhekova D.S., Smagin G.N. Participation of central kappa-opioid receptors in arrhythmogenesis. Life Sci. 1997; 61 (3): 33-38.
  59. Maslov L.N. The role of erythropoetin in ischemic preconditioning, postconditioning, and regeneration of the brain after ischemia. Neurosci. Behav. Physiol. 2011; 41 (4): 353-363.
  60. Wang J.A., He A., Hu X. et al. Anoxic preconditioning: a way to enhance the cardioprotection of mesenchymal stem cells. Int. J. Cardiol. 2009; 133 (3): 410-412.
  61. Wang Y., Luther K. Genetically manipulated progenitor/stem cells restore function to the infarcted heart via the SDF-1α/CXCR4 signaling pathway. Prog. Mol. Biol. Transl. Sci. 2012; 111: 265-284.
  62. Liu H., Xue W., Ge G. et al. Hypoxic preconditioning advances CXCR4 and CXCR7 expression by activating HIF-1α in MSCs. Biochem. Biophys. Res. Commun. 2010; 401 (4): 509-515.
  63. Wei L., Fraser J.L., Lu Z.Y., Hu X., Yu S.P. Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and neurogenesis after cerebral ischemia in rats. Neurobiol. Dis. 2012; 46 (3): 635-645.
  64. Liu H., Liu S., Li Y. et al. The role of SDF-1-CXCR4/CXCR7 axis in the therapeutic effects of hypoxia-preconditioned mesenchymal stem cells for renal ischemia/reperfusion injury. PLoS One. 2012; 7 (4): e34608.
  65. Liu H., Yu X.F., Teng J. et al. Effects of hypoxic preconditioning on the migration of bone marrow derived mesenchymal stem cells. Zhonghua Yi Xue Za Zhi. 2012; 92 (10): 709-713.
  66. Kim H.W., Haider H.K., Jiang S., Ashraf M. Ischemic preconditioning augments survival of stem cells via miR-210 expression by targeting caspase-8-associated protein 2. J. Biol. Chem. 2009; 284 (48): 33161-33168.
  67. Kim H.W., Mallick F., Durrani S. et al. Concomitant activation of miR-107/PDCD10 and Hypoxamir-210/Casp8ap2 and their role in cytoprotection during ischemic preconditioning of stem cells. Antioxid. Redox Signal. 2012; 17 (8): 1053-1065.
  68. Chacko S.M., Ahmed S., Selvendiran K. et al. Hypoxic preconditioning induces the expression of prosurvival and proangiogenic markers in mesenchymal stem cells. Am. J. Physiol. Cell Physiol. 2010; 299 (6): C1562-C1570.
  69. Peterson K.M., Aly A., Lerman A. et al. Improved survival of mesenchymal stromal cell after hypoxia preconditioning: role of oxidative stress. Life Sci. 2011; 88 (1-2): 65-73.
  70. Koopman G., Reutelingsperger C.P., Kuijten G.A. et al. Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood. 1994; 84 (5): 1415-1420.
  71. Sah N.K., Khan Z., Khan G.J., Bisen P.S. Structural, functional and therapeutic biology of survivin. Cancer Lett. 2006; 244 (2): 164-171.
  72. Men'shchikova E.B., Lankin V.Z., Zenkov N.K. etc. Okislitel'nyi stress. Prooksidanty i antioksidanty [Oxidative Stress. Prooxidants and Antioxidants]. Moscow, Firma «Slovo», 2006. 556 p.
  73. Efimenko A., Starostina E., Kalinina N., Stolzing A. Angiogenic properties of aged adipose derived mesenchymal stem cells after hypoxic conditioning. J. Transl. Med. 2011; 9: 10.
  74. Hollenbeck S.T., Senghaas A., Komatsu I. et al. Tissue engraftment of hypoxic-preconditioned adipose-derived stem cells improves flap viability. Wound Repair Regen. 2012; 20(6): 872-878.
  75. Zhu H., Chen X., Deng L. Effects of hypoxic preconditioning on glucose metabolism of rat bone marrow mesenchymal stem cells. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2011; 25(8): 1004-1007.
  76. Sen G.L., Wehrman T.S., Blau H.M. mRNA translation is not a prerequisite for small interfering RNA-mediated mRNA cleavage. Differentiation. 2005; 73(6): 287-293.
  77. Ong L.L., Li W., Oldigs J.K. et al. Hypoxic/normoxic preconditioning increases endothelial differentiation potential of human bone marrow CD133+ cells. Tissue Eng. Part C Methods. 2010; 16 (5): 1069-1081.
  78. Horn P.A., Tesch H., Staib P. et al. Expression of AC133, a novel hematopoietic precursor antigen, on acute myeloid leukemia cells". Blood. 1999; 93 (4): 1435-1437.
  79. Peichev M., Naiyer A.J., Pereira D. et al. Expression of VEGFR-2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors. Blood. 2000; 95(3): 952-958.
  80. Sanai N., Alvarez-Buylla A., Berger M.S. Neural stem cells and the origin of gliomas. N. Engl. J. Med. 2005; 353 (8): 811-822.
  81. Oh J.S., Ha Y., An S.S. et al. Hypoxia-preconditioned adipose tissue-derived mesenchymal stem cell increase the survival and gene expression of engineered neural stem cells in a spinal cord injury model. Neurosci. Lett. 2010; 472 (3): 215-219.
  82. De Barros S., Dehez S., Arnaud E., et al. Aging-related decrease of human ASC angiogenic potential is reversed by hypoxia preconditioning through ROS production. Mol. Ther. 2013; 21 (2): 399-408.
  83. Stubbs S.L., Hsiao S.T., Peshavariya H.M. et al. Hypoxic preconditioning enhances survival of human adipose-derived stem cells and conditions endothelial cells in vitro. Stem. Cells Dev. 2012; 21 (11): 1887-1896.
  84. Jaussaud J., Biais M., Calderon J. et al. Hypoxia-preconditioned mesenchymal stromal cells improve cardiac function in a swine model of chronic myocardial ischaemia. Eur. J. Cardiothorac. Surg. 2013; 43 (5): 1050-1057.
  85. Beltrami A.P., Barlucchi L., Torella D. et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell. 2003; 114 (6): 763-776.
  86. Messina E., De Angelis L., Frati G. et al. Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ. Res. 2004; 95(9): 911-921.
  87. Dawn B., Stein A.B., Urbanek K. et al. Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function. Proc. Natl. Acad. Sci. USA. 2005; 102 (10): 3766-3771.
  88. Davis D.R., Zhang Y., Smith R.R. et al. Validation of the cardiosphere method to culture cardiac progenitor cells from myocardial tissue. PLoS One. 2009; 4 (9): 7195.
  89. Yan F., Yao Y., Chen L. et al. Hypoxic preconditioning improves survival of cardiac progenitor cells: role of stromal cell derived factor-1α-CXCR4 axis. PLoS One. 2012; 7 (7): 37948.
  90. Makkar R.R., Smith R.R., Cheng K. et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet. 2012; 379 (9819): 895-904.
  91. Bolli R., Chugh A.R., D'Amario D. et al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet. 2011; 378 (9806): 1847-1857.



Abstract - 271

PDF (Russian) - 257




Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies