Stem cell therapy offers great promise in treating stroke. Extensive injury from stroke results from ischemia‐reperfusion (IR), which damages the blood‐brain barrier (BBB), promotes inflammation and loss of cerebral parenchyma. Presently, tissue plasminogen activator (tPA) is the sole FDA‐approved antithrombotic treatment available for stroke. tPA has a narrow time window (<4.5hour) and delayed tPA (>5h) can exacerbate BBB damage and increase hemorrhagic complications. Our long‐term goal is to limit early‐stage BBB injuries, an outcome that would protect against the second phase of stroke damage. Aging is a strong risk factor for stroke but the harmful effects of delayed tPA (>4.5h), particularly on aged stroke animals, have not been well studied. We utilized a mouse model of stroke with middle cerebral artery occlusion (MCAO) to induce focal ischemia followed by reperfusion. We injected human neural stem cells (hNSCs) 24h after MCAO to correspond to the upregulation of endogenous proinflammatory cytokines. Previously, we reported that intracranial transplantation of hNSCs rapidly ameliorates BBB damage caused by ischemic stroke in young adult mice. In this study, we employed aged mice to test the effect of delayed tPA‐induced IR injury. We tested the hypothesis that hNSCs ameliorate pathophysiology of aged stroke mice after delayed tPA administration (6h post‐MCAO). We found that delayed tPA administration exacerbates BBB damage, upregulates inflammatory cytokines, and increases mortality. Engrafted hNSCs reduced BBB disruption, rapidly ameliorated symptomatic inflammation, and decreased mortality within 24h post‐transplantation (48h post‐MCAO). Our data demonstrate clear benefits of hNSCs during the early stage of ischemic stroke in aged stroke mice. Support or Funding Information 1. Louisiana Clinical and Translational Science Center (LA CaTs), Pilot Grant, to J‐P. L. 2. Carol Lavin Bernick Faculty Grant to J‐P. L, Tulane University.
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