Transplantation of Pre-conditioned Bone Marrow Mesenchymal Stem Cells after Ische

描述（由申请人提供）：虽然缺血性中风后的干细胞移植作为一种可能的治疗方法已在成年动物中进行了广泛的测试，但很少有研究来评估新生儿的干细胞移植。在不同类型的干细胞中，骨髓间充质干细胞（BMSC）因其多能性潜力和自体移植能力而独一无二。 BMSCs能够穿过血脑屏障并归巢至缺血区域。然而，移植的骨髓间充质干细胞（或一般干细胞）的低存活率严重阻碍了它们在中风治疗中的有效性和应用。利用我们独特的新生儿桶状皮层缺血性中风模型，我们将寻求新的方法来提高 BMSC 的活力和再生能力。具体目标 1 将检验以下假设：移植经过低氧预处理 (HP) 预处理的 BMSC 会比未经处理的 BMSC 在修复缺血损伤的皮质方面产生显着更大的功能益处。通过骨髓间充质干细胞移植后的目标特异性物理治疗的丰富环境，将进一步改善功能益处。具体目标 2 将检验以下假设：BMSC 的 HP 预处理可显着提高其移植到新生儿缺血脑后的存活率。将在移植后 1 至 30 天比较归巢于缺血皮质的 BMSC 的细胞死亡和神经分化程度。具体目标 3 将检查移植的 BMSC 对缺血后大脑血管生成的影响。我们将具体测试新的假设，即 HP 增加的 BMSC 中 VEGF 表达是内源性血管生成、神经发生的有效刺激剂，因此可有效治疗缺血性中风。 BMSC治疗后局部脑血流量（LCBF）和桶功能的恢复将与血管生成和形态变化相关。 我们期望这种新颖的治疗干预结合 1) HP-BMSCs 的管理和 2) 丰富的环境，将产生协同有益效果；如果是这样，这一策略可能会提高骨髓间充质干细胞移植治疗成人和新生儿中风的疗效和效率。

DESCRIPTION (provided by applicant): Although stem cell transplantation after ischemic stroke has been extensively tested as a possible therapy in adult animals, little research has been done to evaluate stem cell transplantation in neonates. Among the different types of stem cells, bone marrow mesenchymal stem cells (BMSCs) are unique in their potential for multipotentcy and their autograft capability. BMSCs are capable of passing through the blood brain barrer and homing to the ischemic region. The low survival rate of transplanted BMSCs, or stem cells in general, however, has significantly hampered their effectiveness and application in stroke therapy. Making use of our unique barrel cortex ischemic stroke model in the neonate, we will pursue novel approaches to improve both the viability and regenerative capacity of BMSCs. Specific Aim 1 will test the hypothesis that transplantation of BMSCs pre-treated with hypoxic preconditioning (HP) will result in significantly greater functional benefits in the repair of the ischemia- damaged cortex than non-treated BMSCs. Further improvement of functional benefits will be achieved through an enriched environment of target specific physical therapy following BMSC transplantation. Specific Aim 2 will examine the hypothesis that HP-pretreatment of BMSCs significantly enhances their survival after transplantation into the neonatal ischemic brain. The extent of cell death and neural differentiation of BMSCs that home to the ischemic cortex will be compared at 1 to 30 days after transplantation. Specific Aim 3 will examine the effect of transplanted BMSCs on angiogenesis in the post-ischemic brain. We will specifically test the novel hypothesis that HP-increased VEGF expression in BMSCs is a potent stimulator of endogenous angiogenesis, neurogenesis and therefore is effective in the treatment of ischemic stroke. Recovery of local cerebral blood flow (LCBF) and barrel functions after BMSC treatment will be correlated with both angiogenesis and morphological changes. We expect that this novel therapeutic intervention combining 1) administation of HP-BMSCs with 2) an enriched environment, will result in synergistic beneficial effects; if so, this strategy will likely improve the efficacy and efficiency of BMSC transplantation therapy in the treatment of stroke in adults as well as in neonates.