Neuroprotective and behavioral efficacy of nerve growth factor-transfected hippocampal progenitor cell transplants after experimental traumatic brain injury.
Neuroprotective and behavioral efficacy of nerve growth factor-transfected hippocampal progenitor cell transplants after experimental traumatic brain injury.
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DOI：
10.3171/jns.2001.94.5.0765
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发表时间：
2001-05
影响因子：
4.1
通讯作者：
M. Philips;Gustav Mattiasson;T. Wieloch;A. Björklund;B. Johansson;G. Tomasevic;A. Martínez-Serrano;P. Lenzlinger;G. Sinson;M. Grady;T. Mcintosh
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文献类型：
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作者：
M. Philips;Gustav Mattiasson;T. Wieloch;A. Björklund;B. Johansson;G. Tomasevic;A. Martínez-Serrano;P. Lenzlinger;G. Sinson;M. Grady;T. Mcintosh
用小鼠神经生长因子（NGF）基因离体转导来自胚胎大鼠海马（HiB 5）的永生化神经祖细胞，以2ng/hr/10（5）个培养细胞分泌NGF（NGF-HiB 5）。方法雄性Wistar大鼠59只，体重300 ~ 370 g，戊巴比妥钠60 mg/kg麻醉，造成中度侧位液压脑损伤（2.3-2.4 atm，34只）或假损伤（25只）。在损伤后24小时，将2 μ l（150，000个细胞/μ l）的[3 H]胸苷标记的NGF-HiB 5细胞立体定向地移植到邻近损伤部位的大脑皮层中的三个单独部位（14只大鼠）。脑损伤大鼠的单独组接受未转染的（幼稚[n]）-HiB 5细胞（12只动物）或细胞悬浮载体（8只动物）。损伤后一周，动物进行运动功能和认知（Morris水迷宫）的神经学评价，并处死进行组织学、放射自显影和免疫细胞化学分析。在所有动物中鉴定出活的HiB 5细胞移植物，以及位于整个损伤周围实质和移植物中的反应性小胶质细胞和巨噬细胞（OX-42免疫组织化学）。与接受单独微注射载体的脑损伤动物相比，移植NGF-HiB 5或n-HiB 5细胞的脑损伤动物显示出显著改善的神经运动功能（p <0.05）和空间学习行为（p < 0.005）。与接受n-HiB 5细胞或载体的那些相比，在接受NGF-HiB 5细胞移植的脑损伤动物中观察到海马CA 3细胞死亡的显著减少（p < 0.025）。结论：本研究表明，永生化神经干细胞已被逆转录病毒转导产生神经生长因子，可显着改善认知和神经运动功能，并拯救海马CA 3神经元移植到急性创伤后时期的损伤脑。
OBJECT Immortalized neural progenitor cells derived from embryonic rat hippocampus (HiB5), were transduced ex vivo with the gene for mouse nerve growth factor (NGF) to secrete NGF (NGF-HiB5) at 2 ng/hr/10(5) cells in culture. METHODS Fifty-nine male Wistar rats weighing 300 to 370 g each were anesthetized with 60 mg/kg sodium pentobarbital and subjected to lateral fluid-percussion brain injury of moderate severity (2.3-2.4 atm, 34 rats) or sham injury (25 rats). At 24 hours postinjury, 2 microl (150,000 cells/microl) of [3H]thymidine-labeled NGF-HiB5 cells were transplanted stereotactically into three individual sites in the cerebral cortex adjacent to the injury site (14 rats). Separate groups of brain-injured rats received nontransfected (naive [n])-HiB5 cells (12 animals) or cell suspension vehicle (eight animals). One week postinjury, animals underwent neurological evaluation for motor function and cognition (Morris water maze) and were killed for histological, autoradiographic, and immunocytochemical analysis. Viable HiB5 cell grafts were identified in all animals, together with reactive microglia and macrophages located throughout the periinjured parenchyma and grafts (OX-42 immunohistochemistry). Brain-injured animals transplanted with either NGF-HiB5 or n-HiB5 cells displayed significantly improved neuromotor function (p < 0.05) and spatial learning behavior (p < 0.005) compared with brain-injured animals receiving microinjections of vehicle alone. A significant reduction in hippocampal CA3 cell death was observed in brain-injured animals receiving transplants of NGF-HiB5 cells compared with those receiving n-HiB5 cells or vehicle (p < 0.025). CONCLUSIONS This study demonstrates that immortalized neural stem cells that have been retrovirally transduced to produce NGF can markedly improve cognitive and neuromotor function and rescue hippocampal CA3 neurons when transplanted into the injured brain during the acute posttraumatic period.