Blood-Brain Barrier Repair in Cell Therapy for Stroke

描述(申请人提供)：本提案提出了“你弄坏它，我们修理它”的格言。认识到血脑屏障(BBB)的破坏会对卒中后中枢神经系统(CNS)的再生过程产生负面影响，我们建议在急性和亚急性卒中环境下从结构和功能上恢复BBB。我们的初步数据表明，静脉注射含有干细胞或祖细胞的异种细胞群在卒中动物模型中显示出好处。最近，我们能够将移植卒中动物的功能恢复归因于移植细胞群体中内皮祖细胞的存在。虽然基于细胞的技术在很大程度上是为了绕过血脑屏障，将细胞或药物从外周输送到大脑，但在这里，我们正在采用一种新的方法来修复中风中的血脑屏障损伤。我们还认识到，缺血性卒中的治疗仅限于丝氨酸蛋白酶组织型纤溶酶原激活剂(TPA)。然而，只有不到3%的缺血性中风患者从tPA治疗中受益，这是因为该药物的3小时治疗窗口很窄，而且它的有害副作用，特别是该药物加剧了中风引起的血脑屏障损害。1)中风伴随着血脑屏障损害，2)tPA对血脑屏障损害有不利影响，3)细胞疗法可以提供血脑屏障修复，这构成了我们总体假设的基础。我们认为，任何针对减轻卒中缺陷的治疗方案都应该考虑血脑屏障修复的关键作用，以维持中枢神经系统的动态平衡，促进神经元再生。EPC修复受损血脑屏障的再生机制是卒中细胞治疗成功的关键，也应该延长治疗窗口，提高tPA治疗卒中的功能效益。

DESCRIPTION (provided by applicant): 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.