Hicks Anna U, MacLellan Crystal L, Chernenko Garry A, Corbett Dale
BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
Brain Res. 2008 Sep 22;1231:103-12. doi: 10.1016/j.brainres.2008.07.041. Epub 2008 Jul 19.
The potential for using stem cells to treat stroke has garnered much interest, but stem cell therapies must be rigorously tested in animal models before transplantation studies progress to clinical trials. An enriched environment enhances transplanted subventricular zone (SVZ) cell migration and functional benefit following stroke in rats. However, the ability of SVZ cells to survive, migrate, differentiate and promote functional recovery at protracted survival times (e.g., 3 months) has not been investigated. The vasoconstrictive peptide endothelin-1 was injected adjacent to the middle cerebral artery to produce focal ischemia. Seven days later, cells derived from the SVZ of adult mice (800,000 cells/rat or vehicle injection) were transplanted into the sensory-motor cortex and striatum, and rats were then housed in enriched or standard conditions. Rats in enriched housing had access to running wheels once per week. Recovery was assessed in the forelimb-use asymmetry task (cylinder) at 1, 2, or 3 months after transplantation immediately prior to euthanasia. Transplanted cell survival and migration were quantified using stereology. Cell phenotype was determined with immunohistochemistry and confocal microscopy. Enriched housing did not enhance survival or migration of transplanted SVZ cells at protracted survival times, and the majority (~99%) of cells died within 2 months of transplantation. Cell survival was significantly, and negatively, correlated with microglial activation. Many surviving cells expressed an astrocytic phenotype. Functional recovery was not improved at any time. Therapies involving transplantation of SVZ cells following stroke must be further optimized in order to enhance long-term cell survival and thereby maximize functional benefit.
利用干细胞治疗中风的潜力已引起广泛关注，但在移植研究进入临床试验之前，干细胞疗法必须在动物模型中进行严格测试。丰富的环境可增强大鼠中风后移植的脑室下区（SVZ）细胞的迁移及功能效益。然而，尚未研究SVZ细胞在延长存活时间（如3个月）时的存活、迁移、分化及促进功能恢复的能力。在大脑中动脉附近注射血管收缩肽内皮素-1以产生局灶性缺血。7天后，将成年小鼠SVZ来源的细胞（800,000个细胞/大鼠或注射溶剂）移植到感觉运动皮层和纹状体，然后将大鼠饲养在丰富或标准条件下。饲养在丰富环境中的大鼠每周可使用一次跑步轮。在移植后1、2或3个月，即在安乐死之前，通过前肢使用不对称任务（圆筒试验）评估恢复情况。使用体视学方法对移植细胞的存活和迁移进行定量分析。通过免疫组织化学和共聚焦显微镜确定细胞表型。在延长存活时间时，丰富的环境并未增强移植的SVZ细胞的存活或迁移，并且大多数（约99%）细胞在移植后2个月内死亡。细胞存活与小胶质细胞活化呈显著负相关。许多存活细胞表达星形胶质细胞表型。在任何时间点，功能恢复均未得到改善。中风后涉及SVZ细胞移植的疗法必须进一步优化，以提高细胞的长期存活率，从而最大程度地发挥功能效益。
