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Author Notes:

Correspondence: Shan P. Yu, M.D., PhD, 101 Woodruff Circle, Woodruff Memorial Research Building, Suite 620, Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA; Email: spyu@emory.edu; Tel. 404-712-8678; Fax: 404-727-6300


Research Funding:

This work was supported by NIH grants NS058710 (LW), NS062097 (LW), NS075338 (LW), NS057255 (SPY), NS073378 (SPY) and the American Heart Association Established Investigator Award (LW).

It was also supported by the NIH grant NS055077 to the ENNCF (Emory Neurology-NINDS Core Facility).


  • hypoxic preconditioning
  • bone marrow mesenchymal stem cell
  • transplantation
  • angiogenesis
  • neurogenesis

Transplantation of Hypoxia Preconditioned Bone Marrow Mesenchymal Stem Cells Enhances Angiogenesis and Neurogenesis after Cerebral Ischemia in Rats


Journal Title:

Neurobiology of Disease


Volume 46, Number 3


, Pages 635-645

Type of Work:

Article | Post-print: After Peer Review


Hypoxic preconditioning of stem cells and neural progenitor cells has been tested for promoting cell survival after transplantation. The present investigation examined the hypothesis that hypoxic preconditioning of bone marrow mesenchymal stem cells (BMSCs) could not only enhance their survival but also reinforce regenerative properties of these cells. BMSCs from eGFP engineered rats or pre-labeled with BrdU were pre-treated with normoxia (20% O2, N-BMSCs) or sublethal hypoxia (0.5% O2. H-BMSCs). The hypoxia exposure up-regulated HIF-1α and trophic/growth factors in BMSCs, including brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF) and its receptor FIK-1, erythropoietin (EPO) and its receptor EPOR, stromal derived factor-1 (SDF-1) and its CXC chemokine receptor 4 (CXCR4). Meanwhile, many pro-inflammatory cytokines/chemokines were downregulated in H-BMSCs. N-BMSCs or H-BMSCs were intravenously injected into adult rats 24 hrs after 90-min middle cerebral artery occlusion. Comparing to N-BMSCs, transplantation of H-BMSCs showed greater effect of suppressing microglia activity in the brain. Significantly more NeuN-positive and Glut1-positive cells were seen in the ischemic core and peri-infarct regions of the animals received H-BMSC transplantation than that received N-BMSCs. Some NeuN-positive and Glut-1-positive cells showed eGFP or BrdU immunoflourescent reactivity, suggesting differentiation from exogenous BMSCs into neuronal and vascular endothelial cells. In Rota-rod test performed 15 days after stroke, animals received H-BMSCs showed better locomotion recovery compared with stroke control and N-BMSC groups. We suggest that hypoxic preconditioning of transplanted cells is an effective means of promoting their regenerative capability and therapeutic potential for the treatment of ischemic stroke.

Copyright information:

© 2012 Elsevier Inc. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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