Although stem cell transplantation after ischemic stroke has been extensively tested as a possible therapy in adult animals, little research has been done to evaluate stem cell transplantation in neonates. Among the different types of stem cells, bone marrow mesenchymal stem cells (BMSCs) are unique in their potential for multipotentcy and their autograft capability. BMSCs are capable of passing through the blood brain barrer and homing to the ischemic region. The low survival rate of transplanted BMSCs, or stem cells in general, however, has significantly hampered their effectiveness and application in stroke therapy. Making use of our unique barrel cortex ischemic stroke model in the neonate, we will pursue novel approaches to improve both the viability and regenerative capacity of BMSCs.
Specific Aim 1 will test the hypothesis that transplantation of BMSCs pre-treated with hypoxic preconditioning (HP) will result in significantly greater functional benefits in the repair of the ischemia- damaged cortex than non-treated BMSCs. Further improvement of functional benefits will be achieved through an enriched environment of target specific physical therapy following BMSC transplantation.
Specific Aim 2 will examine the hypothesis that HP-pretreatment of BMSCs significantly enhances their survival after transplantation into the neonatal ischemic brain. The extent of cell death and neural differentiation of BMSCs that home to the ischemic cortex will be compared at 1 to 30 days after transplantation.
Specific Aim 3 will examine the effect of transplanted BMSCs on angiogenesis in the post-ischemic brain. We will specifically test the novel hypothesis that HP-increased VEGF expression in BMSCs is a potent stimulator of endogenous angiogenesis, neurogenesis and therefore is effective in the treatment of ischemic stroke. Recovery of local cerebral blood flow (LCBF) and barrel functions after BMSC treatment will be correlated with both angiogenesis and morphological changes. We expect that this novel therapeutic intervention combining 1) administation of HP-BMSCs with 2) an enriched environment, will result in synergistic beneficial effects;if so, this strategy will likely improve the efficacy and efficiency of BMSC transplantation therapy in the treatment of stroke in adults as well as in neonates.

Public Health Relevance

A combination strategy will be tested to improve the cell survival quality and regenerative capacities of transplanted bone marrow mesenchymal stem cells (BMSCs) after rat neonatal ischemic stroke. We will address three key issues in BMSC transplantation: 1) to promote survival of BMSCs after transplantation;2) to promote endogenous regenerative responses;3) to guide and improve the repair process and functional recovery in the whisker-barrel pathway after BMSC transplantation.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Owens, David F
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Emory University
Schools of Medicine
United States
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Lee, Jin Hwan; Wei, Ling; Gu, Xiaohuan et al. (2014) Therapeutic effects of pharmacologically induced hypothermia against traumatic brain injury in mice. J Neurotrauma 31:1417-30
Wang, Li-Li; Chen, Dongdong; Lee, Jinhwan et al. (2014) Mobilization of endogenous bone marrow derived endothelial progenitor cells and therapeutic potential of parathyroid hormone after ischemic stroke in mice. PLoS One 9:e87284
Wei, Ning; Yu, Shan-Ping; Gu, Xiao-Huan et al. (2013) The involvement of autophagy pathway in exaggerated ischemic brain damage in diabetic mice. CNS Neurosci Ther 19:753-63
Mohamad, Osama; Yu, Shan Ping; Chen, Dongdong et al. (2013) Efficient neuronal differentiation of mouse ES and iPS cells using a rotary cell culture protocol. Differentiation 86:149-58
Yu, Shan Ping; Wei, Zheng; Wei, Ling (2013) Preconditioning strategy in stem cell transplantation therapy. Transl Stroke Res 4:76-88
Mohamad, Osama; Drury-Stewart, Danielle; Song, Mingke et al. (2013) Vector-free and transgene-free human iPS cells differentiate into functional neurons and enhance functional recovery after ischemic stroke in mice. PLoS One 8:e64160
Wei, Ning; Yu, Shan Ping; Gu, Xiaohuan et al. (2013) Delayed intranasal delivery of hypoxic-preconditioned bone marrow mesenchymal stem cells enhanced cell homing and therapeutic benefits after ischemic stroke in mice. Cell Transplant 22:977-91
Wei, S; Sun, J; Li, J et al. (2013) Acute and delayed protective effects of pharmacologically induced hypothermia in an intracerebral hemorrhage stroke model of mice. Neuroscience 252:489-500
Espinera, A R; Ogle, M E; Gu, X et al. (2013) Citalopram enhances neurovascular regeneration and sensorimotor functional recovery after ischemic stroke in mice. Neuroscience 247:1-11
Li, W-L; Yu, S P; Chen, D et al. (2013) The regulatory role of NF-*B in autophagy-like cell death after focal cerebral ischemia in mice. Neuroscience 244:16-30

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