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J Thorac Cardiovasc Surg 2008;135:799-808
© 2008 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis

Xinyang Hu, MDa,c, Shan Ping Yu, MD, PhDc,d, Jamie L. Fraser, BAc, Zhongyang Lu, MD, PhDc, Molly E. Ogle, BSc, Jian-An Wang, MD, PhDb, Ling Wei, MDc,*

a Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University, College of Medicine, Hangzhou, China
b Department of Cardiology, Second Affiliated Hospital, Zhejiang University, College of Medicine, Hangzhou, China
c Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC
d Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, SC

Received for publication April 19, 2007; revisions received July 3, 2007; accepted for publication July 9, 2007.

* Address for reprints: Ling Wei, MD, Department of Pathology and Laboratory Medicine, 165 Ashley Ave, Medical University of South Carolina, Charleston, SC 29425. (Email: weil{at}musc.edu).

Objectives: This study explored the novel strategy of hypoxic preconditioning of bone marrow mesenchymal stem cells before transplantation into the infarcted heart to promote their survival and therapeutic potential of mesenchymal stem cell transplantation after myocardial ischemia.

Methods: Mesenchymal stem cells from green fluorescent protein transgenic mice were cultured under normoxic or hypoxic (0.5% oxygen for 24 hours) conditions. Expression of growth factors and anti-apoptotic genes were examined by immunoblot. Normoxic or hypoxic stem cells were intramyocardially injected into the peri-infarct region of rats 30 minutes after permanent myocaridal infarction. Death of mesenchymal stem cells was assessed in vitro and in vivo after transplantation. Angiogenesis, infarct size, and heart function were measured 6 weeks after transplantation.

Results: Hypoxic preconditioning increased expression of pro-survival and pro-angiogenic factors including hypoxia-inducible factor 1, angiopoietin-1, vascular endothelial growth factor and its receptor, Flk-1, erythropoietin, Bcl-2, and Bcl-xL. Cell death of hypoxic stem cells and caspase-3 activation in these cells were significantly lower compared with that in normoxic stem cells both in vitro and in vivo. Transplantation of hypoxic versus normoxic mesenchymal stem cells after myocardial infarctiion resulted in an increase in angiogenesis, as well as enhanced morphologic and functional benefits of stem cell therapy.

Conclusions: Hypoxic preconditioning enhances the capacity of mesenchymal stem cells to repair infarcted myocardium, attributable to reduced cell death and apoptosis of implanted cells, increased angiogenesis/vascularization, and paracrine effects.

Abbreviations and Acronyms dp/dt = rate of pressure rise; EPO = erythropoietin; EPOR = cognate receptor of erythropoietin; GFP = green fluorescent protein; HIF-1{alpha} = hypoxia-inducible factor-1{alpha}; H-MSC = hypoxic mesenchymal stem cell; HP = hypoxic preconditioning; LVEDP = left ventricular end-diastolic pressure; LVSP = left ventricular systolic pressure; MI = myocardial infarction; MSC = mesenchymal stem cell; N-MSC = normoxic mesenchymal stem cell; PBS = phosphate-buffered saline solution; TUNEL = terminal deoxynucleotidyl transferase biotin-dUPT nick end labeling; VEGF = vascular endothelial growth factor




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I. Rosova, M. Dao, B. Capoccia, D. Link, and J. A. Nolta
Hypoxic Preconditioning Results in Increased Motility and Improved Therapeutic Potential of Human Mesenchymal Stem Cells
Stem Cells, August 1, 2008; 26(8): 2173 - 2182.
[Abstract] [Full Text] [PDF]


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