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

描述(申请人提供)：尽管缺血性中风后的干细胞移植已经作为一种可能的治疗方法在成年动物中进行了广泛的测试，但对新生儿干细胞移植的评估研究还很少。在不同类型的干细胞中，骨髓间充质干细胞(BMSCs)具有独特的多能性和自体移植能力。骨髓间充质干细胞能够通过血脑屏障并归巢到缺血区。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。利用我们在新生儿中独特的桶状皮质缺血性卒中模型，我们将寻求新的方法来提高BMSCs的活力和再生能力。特定目的1将验证这样一种假设，即经低氧预适应(HP)处理的BMSCs移植在修复脑缺血损伤的皮质方面将比未处理的BMSCs产生显著更大的功能益处。在骨髓间充质干细胞移植后，通过丰富的靶向特异性物理治疗环境，将进一步改善功能益处。具体目标2将检验这样一种假设，即骨髓间充质干细胞经HP预处理后，在移植到新生儿缺血脑中后显著提高其存活率。移植后1至30天，将比较植入缺血皮质的骨髓间充质干细胞的细胞死亡和神经分化的程度。具体目标3将检测移植的骨髓间充质干细胞对脑缺血后血管生成的影响。我们将专门测试这一新的假说，即幽门螺杆菌增加的BMSCs中血管内皮生长因子的表达是内源性血管生成和神经再生的有力刺激因素，因此在治疗缺血性中风方面是有效的。骨髓间充质干细胞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有关。我们期待这种新的治疗干预措施结合1)HP-BMSCs的应用和2)丰富的环境，将产生协同的有益效果；如果是这样的话，这一策略可能会提高BMSC移植治疗成人和新生儿卒中的疗效和效率。 公共卫生相关性：将测试一种组合策略，以提高新生大鼠缺血性中风后移植的骨髓间充质干细胞(BMSCs)的细胞生存质量和再生能力。我们将解决BMSC移植中的三个关键问题：1)促进BMSCs移植后的存活；2)促进内源性再生反应；3)引导和改善BMSC移植后胡须桶途径的修复过程和功能恢复。

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. PUBLIC HEALTH RELEVANCE: A combination strategy will be tested to improve the cell survival quality and regenerative capacities of transplanted bone marrow mesenchymal stem cells (BMSCs) after rat neonatal ischemic stroke. We will address three key issues in BMSC transplantation: 1) to promote survival of BMSCs after transplantation; 2) to promote endogenous regenerative responses; 3) to guide and improve the repair process and functional recovery in the whisker-barrel pathway after BMSC transplantation.