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

描述（由申请人提供）：虽然缺血性卒中后干细胞移植已被广泛测试为成年动物的可能治疗方法，但很少有研究评估新生儿干细胞移植。骨髓间充质干细胞（BMSCs）是目前研究较多的一类干细胞，具有多向分化潜能和自体移植能力。骨髓间充质干细胞能够穿过血脑屏障并归巢到缺血区域。然而，移植的BMSCs或干细胞的低存活率显著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皮质缺血性中风模型，我们将寻求新的方法来提高BMSCs的活力和再生能力。具体目标1将检验以下假设：与未处理的BMSC相比，经低氧预处理（HP）预处理的BMSC的移植将在缺血损伤皮质的修复中产生显著更大的功能益处。通过BMSC移植后目标特异性物理治疗的丰富环境，将实现功能益处的进一步改善。具体目标2将检查HP预处理的BMSC移植到新生儿缺血脑后显著提高其存活率的假设。在移植后1至30天比较归巢至缺血皮质的BMSC的细胞死亡和神经分化的程度。具体目标3将检查移植的BMSC对缺血后脑中血管生成的影响。我们将专门测试新的假设，即HP增加的VEGF在BMSCs中的表达是内源性血管生成、神经发生的有效刺激物，因此在缺血性卒中的治疗中是有效的。BMSC治疗后局部脑血流量（LCBF）和桶功能的恢复与血管生成和形态学变化相关。 我们期望这种新的治疗干预结合1）HP-BMSC的施用与2）富集环境，将产生协同有益作用;如果是这样，这种策略将可能提高BMSC移植疗法在治疗成人以及新生儿中风中的功效和效率。

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.