Cell transplantation has shown promise in reducing neurological deficits associated with stroke. One of the most effective of these therapies is marrow stromal cells (MSCs), that has been demonstrated to be highly neurorestorative. In this application, we will investigate the mechanisms by which MSCs produce this neurorestorative effect. Our preliminary data strongly indicate that there is extensive axonal remodeling in both brain and spinal cord in response to MSC treatment which highly correlates with improvement of neurological function. Given these robust preliminary data, and the fact that the field of white matter changes after stroke is understudied, and that there are no investigations on the effect of cell-based therapies for stroke on spinal cord remodeling, we propose the following two specific aims:
In Aim 1, we will test the effects of MSC treatment of stroke on axonal outgrowth in the brain and the spinal cord. We hypothesize that recovery of limb motor function after stroke depends on axonal remodeling of the corticospinal tract (CST). CST axons emanating from the ischemic boundary in the ipsilateral hemisphere and from the intact contralateral hemisphere sprout and extend to the denervated spinal neurons. MSCs enhance such axonal restructuring to promote functional recovery.
In Aim 2, we will investigate the cellular and molecular mechanisms by which MSC treatment promotes neuronal remodeling after stroke. We hypothesize that neuronal remodeling in the central nervous system (CNS) after stroke with MSC treatment is mediated by astrocytes, the most numerous cells and the major endogenous repair mediators in the adult CNS. Neurite outgrowth after stroke is enhanced by MSC treatment via astrocytic increase in the net activity of tissue plasminogen activator (tPA) via modifying the balance of tPA/plasminogen activator inhibitor-1(PAI-1) level. In this application, we employ genetically modified CST-YFP mice in which the CST is specifically and completely labeled with yellow fluorescent protein (YFP) and tPA knockout (tPA-/-)mice, as well as an array of novel and well-established experimental techniques in our laboratory. To our knowledge, our work is the first to investigate tPA as amplifying neurite remodeling and thereby mediating the beneficial actions of exogenous cells in the CNS. This project elucidates the interaction between MSCs and parenchymal cells that lead to white matter changes in the brain and spinal cord by which the injured CNS can be remodeled. Our ultimate goal is to delineate the mechanistic underpinnings of cell-based therapy in the restorative treatment of stroke. The proposed studies have high translational significance and will advance the field of stroke recovery.

Public Health Relevance

This proposal will investigate the mechanism by which MSCs interact with parenchymal cells to promote neurite remodeling and functional benefit after stroke. Elucidating these cellular and molecular mechanisms will lead to improved restorative treatments for stroke and other forms of neural injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS066041-03
Application #
8247006
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2010-04-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$314,059
Indirect Cost
$99,684
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Liu, Zhongwu; Li, Yi; Cui, Yisheng et al. (2014) Beneficial effects of gfap/vimentin reactive astrocytes for axonal remodeling and motor behavioral recovery in mice after stroke. Glia 62:2022-33
Li, Yi; Liu, Zhongwu; Xin, Hongqi et al. (2014) The role of astrocytes in mediating exogenous cell-based restorative therapy for stroke. Glia 62:1-16
Feng, Yuliang; Huang, Wei; Meng, Wei et al. (2014) Heat shock improves Sca-1+ stem cell survival and directs ischemic cardiomyocytes toward a prosurvival phenotype via exosomal transfer: a critical role for HSF1/miR-34a/HSP70 pathway. Stem Cells 32:462-72
Liu, Zhongwu; Li, Yi; Qian, Jianyong et al. (2014) Plasminogen deficiency causes reduced corticospinal axonal plasticity and functional recovery after stroke in mice. PLoS One 9:e94505
Ding, Xiaoshuang; Li, Yi; Liu, Zhongwu et al. (2013) The sonic hedgehog pathway mediates brain plasticity and subsequent functional recovery after bone marrow stromal cell treatment of stroke in mice. J Cereb Blood Flow Metab 33:1015-24
Xin, Hongqi; Li, Yi; Liu, Zhongwu et al. (2013) MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cells 31:2737-46
Liu, Zhongwu; Chopp, Michael; Ding, Xiaoshuang et al. (2013) Axonal remodeling of the corticospinal tract in the spinal cord contributes to voluntary motor recovery after stroke in adult mice. Stroke 44:1951-6
Xin, Hongqi; Li, Yi; Cui, Yisheng et al. (2013) Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab 33:1711-5
Xin, Hongqi; Chopp, Michael; Shen, Li Hong et al. (2013) Multipotent mesenchymal stromal cells decrease transforming growth factor ?1 expression in microglia/macrophages and down-regulate plasminogen activator inhibitor 1 expression in astrocytes after stroke. Neurosci Lett 542:81-6
Liu, Zhongwu; Li, Yi; Zhang, Li et al. (2012) Subacute intranasal administration of tissue plasminogen activator increases functional recovery and axonal remodeling after stroke in rats. Neurobiol Dis 45:804-9

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