HYPOXIC PRECONDITIONING OF STEM CELLS AS A NEW APPROACH TO INCREASE THE EFFICACY OF CELL THERAPY FOR MYOCARDIAL INFARCTION

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Abstract

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.

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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
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 Россия

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
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 Россия

A. G. Portnichenko

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

Email: port@serv.biph.kiev.ua
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 Украина

A. V. Naumova

Department of Radiology, University of Washington, Seattle, USA

Email: anabella1710@gmail.com
MD, research scientist of the Department of Radiology, Washington University. Address: Seattle, USA США

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