The present proposal advances the motto you break it, we repair it. Recognizing that blood-brain barrier (BBB) breakdown could negatively influence central nervous system (CNS) regenerative processes after stroke, we propose to structurally and functionally restore the BBB in an acute and sub-acute stroke setting. Our preliminary data demonstrate that intravenous administration of a heterogeneous cell population containing stem or progenitor cells shows benefit in animal models of stroke. More recently, we are able to ascribe the functional recovery in transplanted stroke animals to the presence of endothelial progenitor cells (EPC) in the grafted cell population. Whereas cell-based technologies are largely designed to circumvent the BBB for delivery of cells or drugs from the periphery into the brain, we are taking here a novel approach of repairing the BBB damage in stroke. We are also cognizant that the treatment of ischemic stroke is limited to the serine protease tissue-type plasminogen activator (tPA). However, less than 3 percent of ischemic stroke patients benefit from tPA treatment, due to the drug's narrow 3-hour therapeutic window and its detrimental side effects in particular the drug's exacerbation of stroke-induced BBB damage. That 1) stroke is accompanied by BBB damage, 2) tPA adversely contributes to this BBB damage, and 3) cell therapy can afford BBB repair, form the basis of our overarching hypothesis. We posit that any treatment regimen directed at attenuating stroke deficits should consider the pivotal role of BBB repair in order to maintain CNS homeostasis and enhance neuronal regeneration. A regenerative mechanism involving the repair of the damaged BBB by EPC is critical to the successful outcome of cell therapy in stroke, and should also extend the therapeutic window, as well as improve the functional benefits of tPA treatment in stroke.

Public Health Relevance

Blood-brain barrier (BBB) breakdown accompanies stroke and may be exacerbated by tissue-type plasminogen activator (tPA). To date, most stroke therapies have not considered the repair of this BBB damage after stroke. If BBB restoration via endothelial progenitor cell (EPC) transplantation alone or in combination with tPA is proven effective, we believe that direct clinical application of this cell therapy will be far reaching as the proposed treatment could help a large population of ischemic stroke patients who otherwise would have missed the limited 3-hour tPA window. In addition, we envision that this EPC transplantation can supplement other stroke therapeutics that require BBB manipulation in order to afford beneficial effects, and can be extended to other neurological disorders characterized by BBB breakdown.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS071956-05
Application #
8862545
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Bosetti, Francesca
Project Start
2011-07-01
Project End
2017-06-30
Budget Start
2015-07-01
Budget End
2017-06-30
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of South Florida
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612
Liska, Grant M; Lippert, Trenton; Russo, Eleonora et al. (2018) A Dual Role for Hyperbaric Oxygen in Stroke Neuroprotection: Preconditioning of the Brain and Stem Cells. Cond Med 1:151-166
Dewan, Shyam; Schimmel, Samantha; Borlongan, Cesar V (2018) Treating childhood traumatic brain injury with autologous stem cell therapy. Expert Opin Biol Ther 18:515-524
Shojo, Hideki; Borlongan, Cesario V; Mabuchi, Tadashi (2017) Genetic and Histological Alterations Reveal Key Role of Prostaglandin Synthase and Cyclooxygenase 1 and 2 in Traumatic Brain Injury-Induced Neuroinflammation in the Cerebral Cortex of Rats Exposed to Moderate Fluid Percussion Injury. Cell Transplant 26:1301-1313
Liska, Michael G; Crowley, Marci G; Borlongan, Cesar V (2017) Regulated and Unregulated Clinical Trials of Stem Cell Therapies for Stroke. Transl Stroke Res 8:93-103
Acosta, Sandra A; Mashkouri, Sherwin; Nwokoye, Diana et al. (2017) Chronic inflammation and apoptosis propagate in ischemic cerebellum and heart of non-human primates. Oncotarget 8:102820-102834
Garbuzova-Davis, Svitlana; Haller, Edward; Lin, Roger et al. (2017) Intravenously Transplanted Human Bone Marrow Endothelial Progenitor Cells Engraft Within Brain Capillaries, Preserve Mitochondrial Morphology, and Display Pinocytotic Activity Toward Blood-Brain Barrier Repair in Ischemic Stroke Rats. Stem Cells 35:1246-1258
Marcet, Paul; Santos, Nicole; Borlongan, Cesar V (2017) When friend turns foe: central and peripheral neuroinflammation in central nervous system injury. Neuroimmunol Neuroinflamm 4:82-92
Tajiri, Naoki; Quach, David M; Kaneko, Yuji et al. (2017) NSI-189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats. J Cell Physiol 232:2731-2740
Napoli, Eleonora; Borlongan, Cesar V (2017) Stem Cell Recipes of Bone Marrow and Fish: Just What the Stroke Doctors Ordered. Stem Cell Rev 13:192-197
Stonesifer, Connor; Corey, Sydney; Ghanekar, Shaila et al. (2017) Stem cell therapy for abrogating stroke-induced neuroinflammation and relevant secondary cell death mechanisms. Prog Neurobiol 158:94-131

Showing the most recent 10 out of 98 publications