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.