INTRODUCTION Clinically, significant stroke injury results from ischemia-reperfusion (IR), which induces a deleterious biphasic opening of the blood-brain barrier (BBB). Tissue plasminogen activator (tPA) remains the sole pharmacological agent to treat ischemic stroke. However, major limitations of tPA treatment include a narrow effective therapeutic window of 4.5 h in most patients after initial stroke onset and off-target non-thrombolytic effects (e.g., the risk of increased IR injury). We hypothesized that ameliorating BBB damage with exogenous human neural stem cells (hNSCs) would improve stroke outcome to a greater extent than treatment with delayed tPA alone in aged stroke mice. METHODS We employed middle cerebral artery occlusion to produce focal ischemia with subsequent reperfusion (MCAO/R) in aged mice and administered tPA at a delayed time point (6 h post-stroke) via tail vein. We transplanted hNSCs intracranially in the subacute phase of stroke (24 h post-stroke). We assessed the outcomes of hNSC transplantation on pathophysiological markers of stroke 48 h post-stroke (24 h post-transplant). RESULTS Delayed tPA treatment resulted in more extensive BBB damage and inflammation relative to MCAO controls. Notably, transplantation of hNSCs ameliorated delayed tPA-induced escalated stroke damage; decreased expression of proinflammatory factors (tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6), decreased the level of matrix metalloprotease-9 (MMP-9), increased the level of brain-derived neurotrophic factor (BDNF), and reduced BBB damage. CONCLUSIONS Aged stroke mice that received delayed tPA treatment in combination with hNSC transplantation exhibited reduced stroke pathophysiology in comparison to non-transplanted stroke mice with delayed tPA. This suggests that hNSC transplantation may synergize with already existing stroke therapies to benefit a larger stroke patient population.

中文翻译：

---

人类神经干细胞可改善经延迟组织纤溶酶原激活剂治疗的老年中风大脑的早期中风结果。


简介 临床上，严重的中风损伤是由缺血再灌注（IR）引起的，它会引起血脑屏障（BBB）的有害双相开放。组织纤溶酶原激活剂（tPA）仍然是治疗缺血性中风的唯一药物。然而，tPA 治疗的主要局限性包括大多数患者在初次卒中发作后的 4.5 小时有效治疗窗狭窄，以及脱靶非溶栓效应（例如，IR 损伤的风险增加）。我们假设，在老年中风小鼠中，使用外源性人类神经干细胞 (hNSC) 改善血脑屏障损伤，比单独使用延迟 tPA 治疗能在更大程度上改善中风结果。方法我们采用大脑中动脉闭塞在老年小鼠中产生局灶性缺血并随后再灌注（MCAO/R），并在延迟时间点（中风后 6 小时）通过尾静脉给予 tPA。我们在中风亚急性期（中风后 24 小时）颅内移植 hNSC。我们在中风后 48 小时（移植后 24 小时）评估了 hNSC 移植对中风病理生理标志物的结果。结果 与 MCAO 对照相比，延迟 tPA 治疗导致更广泛的 BBB 损伤和炎症。值得注意的是，hNSC 移植可改善延迟性 tPA 诱导的中风损伤升级；促炎因子（肿瘤坏死因子-α (TNF-α) 和白细胞介素 (IL)-6）表达减少，基质金属蛋白酶 9 (MMP-9) 水平降低，脑源性神经营养因子 (BDNF) 水平增加），并减少 BBB 损伤。结论 与接受延迟 tPA 的非移植中风小鼠相比，接受延迟 tPA 治疗联合 hNSC 移植的老年中风小鼠表现出中风病理生理学的减轻。 这表明 hNSC 移植可能与现有的中风疗法产生协同作用，使更多的中风患者群体受益。