Blood-Brain Barrier Repair in Cell Therapy for Stroke

描述（由申请人提供）：本提案提出的座右铭是“你打破它，我们修复它”。认识到血脑屏障（BBB）的破坏可能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中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质细胞群在中风动物模型中显示出益处。最近，我们能够归因于移植的中风动物的功能恢复的内皮祖细胞（EPC）在移植的细胞群体中的存在。虽然基于细胞的技术在很大程度上是为了绕过BBB，将细胞或药物从外周输送到大脑中，但我们在这里采用了一种修复中风中BBB损伤的新方法。我们也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，不到3%的缺血性卒中患者受益于tPA治疗，这是由于该药物的3小时治疗窗狭窄及其有害的副作用，特别是该药物加重了卒中引起的BBB损伤。1）中风伴随着BBB损伤，2）tPA对这种BBB损伤有不利影响，3）细胞疗法可以提供BBB修复，这些构成了我们总体假设的基础。我们认为，任何旨在减轻卒中缺陷的治疗方案都应考虑BBB修复的关键作用，以维持CNS稳态并增强神经元再生。涉及通过EPC修复受损BBB的再生机制对于中风中细胞治疗的成功结果至关重要，并且还应该延长治疗窗，以及改善tPA治疗中风的功能益处。

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.