Cell-based therapies have shown enormous promise in reducing neurological deficits associated with stroke. One of the most effective of these therapies is bone 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 MSC treatment of stroke promotes neurite remodeling of brain. We propose that when administered after stroke, MSCs activate tissue plasminogen activator (tPA) within parenchymal cells, and tPA mediates neurite remodeling leading to improvement in neurological function. Therefore, the following three hypotheses are tested: Hypothesis 1: a) MSCs increase tPA activity in parenchymal cells;b) Increased tPA activity increases neurite remodeling;c) Increased neurite remodeling contributes to improvement of functional outcome after stroke. Hypothesis 2: a) MSCs up-regulate tPA activity in astrocytes, neurons and endothelial cells via the Shh signaling pathway;b) MSCs down-regulate TGF-?1/PAI-1 via the Shh signaling pathway and thereby increase tPA activity. Hypothesis 3: tPA activity increased by MSCs promotes neurite remodeling via plasmin-dependent proteolytic cleavage of pro-neurotrophins: pro-nerve growth factor (pro-NGF) to NGF, pro-brain derived neurotrophic factor (pro-BDNF) to BDNF These hypotheses dissect the interactions of exogenous MSCs and endogenous parenchymal cells and their affect on tPA activity, neurite remodeling and neurological function after stroke. Our studies employ genetically modified tPA-/-, Plg-/-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 activity as a key unifying factor to amplify beneficial actions of exogenous cells in the CNS. This project is a coherent and highly interwoven effort to elucidate the molecular and cellular pathways by which injured brain can be remodeled by cell-based therapies. Our ultimate goal is to delineate the mechanistic underpinnings of cell-based therapy in the restorative treatment of stroke. The therapeutic implications of our studies for all neurological disease and injury are evident.

Public Health Relevance

Our study will provide essential insight into how the injured brain is remodeled and neurological function improved using a cell-based therapy. Restorative therapy using exogenously administered cells is not limited by a narrow therapeutic window and can be administered to all stroke patients. Our goal to identify how these administered cells interact with the endogenous brain cells will likely bring to fruition restorative cell-based therapy for the treatment of stroke and neural injury.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG037506-03
Application #
8450131
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Wise, Bradley C
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2013-05-15
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$283,807
Indirect Cost
$90,082
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Zhang, Li; Chopp, Michael; Zhang, Yanlu et al. (2016) Diabetes Mellitus Impairs Cognitive Function in Middle-Aged Rats and Neurological Recovery in Middle-Aged Rats After Stroke. Stroke 47:2112-8
Li, Lian; Chopp, Michael; Ding, Guangliang et al. (2016) Diffusion-Derived Magnetic Resonance Imaging Measures of Longitudinal Microstructural Remodeling Induced by Marrow Stromal Cell Therapy after Traumatic Brain Injury. J Neurotrauma :
Zhang, Jing; Zhang, Zheng Gang; Li, Yi et al. (2016) Thymosin beta4 promotes oligodendrogenesis in the demyelinating central nervous system. Neurobiol Dis 88:85-95
Liu, Zhongwu; Chopp, Michael (2016) Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke. Prog Neurobiol 144:103-20
Cui, Xu; Chopp, Michael; Zacharek, Alex et al. (2016) D-4F Decreases White Matter Damage After Stroke in Mice. Stroke 47:214-20
Jiang, Quan; Zhang, Li; Ding, Guangliang et al. (2016) Impairment of the glymphatic system after diabetes. J Cereb Blood Flow Metab :
Chen, Jieli; Ning, Ruizhuo; Zacharek, Alex et al. (2016) MiR-126 Contributes to Human Umbilical Cord Blood Cell-Induced Neurorestorative Effects After Stroke in Type-2 Diabetic Mice. Stem Cells 34:102-13
Ding, Guangliang; Chen, Jieli; Chopp, Michael et al. (2016) Cell Treatment for Stroke in Type Two Diabetic Rats Improves Vascular Permeability Measured by MRI. PLoS One 11:e0149147
Wang, Lei; Chopp, Michael; Jia, Longfei et al. (2015) Therapeutic Benefit of Extended Thymosin β4 Treatment Is Independent of Blood Glucose Level in Mice with Diabetic Peripheral Neuropathy. J Diabetes Res 2015:173656
Yan, Tao; Chopp, Michael; Chen, Jieli (2015) Experimental animal models and inflammatory cellular changes in cerebral ischemic and hemorrhagic stroke. Neurosci Bull 31:717-34

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