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

Ische后预条件化骨髓间充质干细胞的移植

• 批准号: 8415576
• 负责人: LING WEI
• 金额: $ 32.07万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8415576
• 关键词: Address; Adult; Angiogenic Factor; Animals; Antibodies; Autologous Transplantation; Behavior; Biological Assay; Blood; Blood - brain barrier anatomy; Bone Marrow; Bone Marrow Stem Cell; Bone Marrow Transplantation; Brain; Brain region; Cardiovascular Surgical Procedures; Cell Death; Cell Survival; Cells; Central Nervous System Diseases; Cerebrovascular Circulation; Data; Effectiveness; Environment; Enzyme-Linked Immunosorbent Assay; Ethical Issues; Exhibits; Exposure to; Future; Goals; Graft Rejection; Grant; Home environment; Homing; Hypoxia; In Vitro; Investigation; Ischemia; Ischemic Stroke; Journals; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Modeling; Neonatal; Neurologic; Outcome; Paper; Pathway interactions; Physical therapy; Process; Published Comment; Publishing; Rattus; Recovery; Recovery of Function; Research; Research Personnel; Sensorimotor functions; Signal Transduction; Staining method; Stains; Stem cell transplant; Stem cells; Stroke; Survival Rate; Testing; Therapeutic; Thoracic Surgical Procedures; Transplantation; Vascular Endothelial Growth Factors; Vascularization; Vibrissae; Western Blotting; Work; Writing; angiogenesis; barrel cortex; cell type; editorial; effective therapy; functional improvement; improved; in vivo; mature animal; mortality; neonatal human; neonate; neurogenesis; novel; novel strategies; novel therapeutic intervention; optical imaging; preconditioning; public health relevance; regenerative; relating to nervous system; repaired; response; stroke therapy; tissue repair

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.

描述（由申请人提供）：尽管缺血性中风后的干细胞移植已被广泛测试是成年动物的一种可能的治疗，但几乎没有研究用于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）在多振体和自体移植能力方面是独一无二的。 BMSC能够穿过血脑室桶并将其归居到缺血区域。然而，移植的BMSC或干细胞的生存率低，但总体上严重阻碍了其在中风治疗中的有效性和应用。利用我们在新生儿中使用独特的桶形缺血性中风模型，我们将采用新颖的方法来提高BMSC的生存能力和再生能力。具体目标1将检验以下假设：预先处理的BMSC进行缺氧预处理（HP）将导致缺血损坏的皮质的修复比未经处理的BMSC的功能益处明显更大。 BMSC移植后，通过富集的特定物理治疗环境来进一步改善功能益处。具体目标2将研究以下假设：BMSC的HP预测在移植到新生儿缺血大脑中后会显着增强其存活率。在移植后1至30天，将比较BMSC的细胞死亡和神经分化的程度。具体目标3将检查移植BMSC对缺血后大脑血管生成的影响。我们将特别检验新的假设，即BMSC中HP增强的VEGF表达是内源性血管生成，神经发生的有效刺激剂，因此有效地治疗缺血性中风。 BMSC治疗后局部脑血流量（LCBF）和枪管功能的恢复将与血管生成和形态学变化相关。 我们预计，这种新型的治疗干预措施结合1）HP-BMSC和2）富集的环境将产生协同的有益效果；如果是这样，该策略可能会提高BMSC移植疗法在成人和新生儿中卒中治疗中的疗效和效率。