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

描述（由申请人提供）：尽管干细胞移植在缺血性中风后作为一种可能的治疗方法已经在成年动物中进行了广泛的测试，但很少有研究评估干细胞移植在新生儿中的应用。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身移植能力。骨髓间充质干细胞能够穿过血脑屏障，回到缺血区域。然而，移植骨髓间充质干细胞或干细胞的低存活率极大地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脑桶皮质缺血性中风模型，我们将寻求新的方法来提高骨髓间充质干细胞的生存能力和再生能力。特异性目的1将验证经过缺氧预处理（HP）处理的骨髓间充质干细胞移植在修复缺血损伤的皮层方面比未处理的骨髓间充质干细胞具有更大的功能益处。通过BMSC移植后靶向特异性物理治疗的丰富环境，进一步改善功能益处。特异性目的2将检验hp预处理骨髓间充质干细胞移植到新生儿缺血性脑后显著提高其存活率的假设。移植后1至30天，将比较缺血皮质的骨髓间充质干细胞的细胞死亡程度和神经分化程度。特异性目的3将研究移植骨髓间充质干细胞对缺血后脑血管生成的影响。我们将特别验证一个新的假设，即hp增加的骨髓间充质干细胞中VEGF表达是内源性血管生成和神经发生的有力刺激物，因此对缺血性中风的治疗有效。BMSC治疗后局部脑血流（LCBF）和脑桶功能的恢复与血管生成和形态学改变相关。我们期望这种新的治疗干预结合1)给药HP-BMSCs和2)丰富的环境，将产生协同有益的效果；如果是这样，该策略可能会提高BMSC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. 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.