EXCEED THE SPACE PROVIDED. Stroke is a major cause of morbidity and disability and the functional recovery is slow and uncertain. Our data demonstrate that intravenously transplanted bone marrow stromal cells (MSCs), including mesenchymal stem or progenitor cells which possess multilineage developmental potential, migrate to the damaged brain tissue, and improve functional recovery. This research proposal is concerned with understanding the cellular and molecular mechanisms responsible for the therapeutic effect of MSC therapy of stroke. The major hypothesis being tested in vivo is that the MSCs delivered to the brain after stroke provide neuroprotection by reducing apoptotic cell death of neurons, promote angiogenesis, and induce structural changes in neurons (neuronal remodeling), including axonal and dendritic sprouting and synapse formation in the penumbral region. To determine whether MSCs differentiate into neural cells and integrate into the cerebral tissue and form connections, ultrastruetural (electron microscopy) and electrophysiological measurements will be performed on MSCs that have been labeled prior to transplantation with green fluorescent protein (GFP) and gold particles using gene gun technology. We will test the hypothesis that the microenvironment of the ischcmic brain tissue induces in MSCs and astrocytes the production of angiogenic and neurotrophic growth factors (VEGF, bFGF, BDNF, NGF), which mediate the beneficial effects of MSC treatment. Using appropriate in vitro model systems, detailed functional characterization of MSC and astrocyte secreted products will be performed to assess the antiapoptotic, angiogenic, and neurogenic activities of these molecules. In addition, we will test whether ncurotrophic factors alter the growth and differentiation pathways of MSCs to become neural cells (glia and neurons). Thus, the studies in this proposal will provide insight into the cellular and molecular mechanisms underlying the therapeutic benefit provided by MSC cellular therapy of stroke. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045041-03
Application #
6823283
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Owens, David F
Project Start
2002-12-15
Project End
2006-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
3
Fiscal Year
2005
Total Cost
$305,663
Indirect Cost
Name
Henry Ford Health System
Department
Neurology
Type
Schools of Medicine
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Shen, L H; Li, Y; Chopp, M (2010) Astrocytic endogenous glial cell derived neurotrophic factor production is enhanced by bone marrow stromal cell transplantation in the ischemic boundary zone after stroke in adult rats. Glia 58:1074-81
Zhang, Jing; Chen, Jieli; Li, Yi et al. (2008) Niaspan treatment improves neurological functional recovery in experimental autoimmune encephalomyelitis mice. Neurobiol Dis 32:273-80
Zhang, Jing; Li, Yi; Zheng, Xuguang et al. (2008) Bone marrow stromal cells protect oligodendrocytes from oxygen-glucose deprivation injury. J Neurosci Res 86:1501-10
Chopp, Michael; Li, Yi; Zhang, Jing (2008) Plasticity and remodeling of brain. J Neurol Sci 265:97-101
Shen, Li Hong; Li, Yi; Gao, Qi et al. (2008) Down-regulation of neurocan expression in reactive astrocytes promotes axonal regeneration and facilitates the neurorestorative effects of bone marrow stromal cells in the ischemic rat brain. Glia 56:1747-54
Gao, Q; Li, Y; Shen, L et al. (2008) Bone marrow stromal cells reduce ischemia-induced astrocytic activation in vitro. Neuroscience 152:646-55
Shen, Li Hong; Li, Yi; Chen, Jieli et al. (2007) One-year follow-up after bone marrow stromal cell treatment in middle-aged female rats with stroke. Stroke 38:2150-6
Qu, Runjiang; Li, Yi; Gao, Qi et al. (2007) Neurotrophic and growth factor gene expression profiling of mouse bone marrow stromal cells induced by ischemic brain extracts. Neuropathology 27:355-63
Liu, Zhongwu; Li, Yi; Qu, Runjiang et al. (2007) Axonal sprouting into the denervated spinal cord and synaptic and postsynaptic protein expression in the spinal cord after transplantation of bone marrow stromal cell in stroke rats. Brain Res 1149:172-80
Shen, Li Hong; Li, Yi; Chen, Jieli et al. (2007) Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. J Cereb Blood Flow Metab 27:6-13

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