Regeneration and cell replacement therapy for ischemic brain injury Approach from endogenous neural progenitors

缺血性脑损伤的再生和细胞替代疗法来自内源性神经祖细胞的方法

基本信息

批准号：
13470285
负责人：
KAWAHARA Nobutaka
金额：
$ 9.09万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

Regeneration or cell replacement therapy has become one of the main topics in the field of cell biology due to remarkable advance of research in this field over the past decade. In particular, existence of endogenous neural stem cell or progenitors has been found in mature mammalian adult brain, which led to new approach to reconstruct lost neuronal network incurred by various insults through induction of neuronal regeneration from endogenous progenitors. In line with this concept, we addressed question whether neuronal regeneration can be induced in the hippocampal CA1 sector, a region supposed to be non-neurogenic, following ischemic neuronal death in rats. We found that neuronal progenitors exist in the periventricular region adjacent to CA1 sector, which respond to ischemia. Following administration of EGF and FGF-2 intraventricularly for 3 days after ischemia, we could successfully induce proliferation, migration and differentiation of neural progenitors in this region, resulting … More in 40% recovery of neuronal population. In addition, these neurons displayed mature phenotype and extended dendrites and long axons. They finally re-established electrophysiological activity demonstrated by recovery of long-term potentiation, as well as improvement of cognitive function by assessing Marris Water Maze test. These findings imply that "non-neurogenic regions" still retain capacity for regeneration when stimulated by some factors after brain insults, and would open a new approach for various central nervous system disorders.We also tried to establish an in vivo model of consistent ischemic neuronal injury in hippocampal CA1 in mice to explore molecular mechanisms of neuronal regeneration, since several gene modified animals are available in mice. In BL6 strain, we could produce this model by subjecting them to 14 minute ischemia through temporary occlusion of three vessels in the neck. This model would contribute greatly to understating of molecular control of progenitors in situ in the future research. Less

由于过去十年中该领域的显着发展，再生或细胞替代疗法已成为细胞生物学领域的主要主题之一。特别是，在成熟的哺乳动物大脑中发现了内源性神经元干细胞或祖细胞的存在，这导致了通过内源性祖细胞诱导神经元再生而引起的各种损伤产生的新方法，从而重建了丧失的神经元网络。与这个概念一致，我们提出了疑问，在大鼠缺血性神经元死亡之后，海马CA1部门是否可以诱导神经元再生。我们发现，神经元祖细胞存在于与CA1部门相邻的周围区域，对缺血作出反应。在缺血后3天内进行EGF和FGF-2静脉注射后，我们可以成功诱导该地区神经元祖细胞的增殖，迁移和分化，从而产生了40％的神经元种群的恢复40％。另外，这些神经元显示出成熟的表型和延伸的树突和长轴突。他们最终通过恢复长期潜力的恢复以及通过评估Marris水迷宫检验来改善认知功能来重新建立的电生理活性。这些发现表明，当脑损伤后某些因素刺激某些因素时，“非神经生成区域”仍然保留了再生能力，并将为各种中枢神经系统疾病打开一种新方法。我们还试图建立一种在小鼠中探索分子机制的小鼠中的海马CA1的一致性缺血性神经元损伤的体内模型。在BL6菌株中，我们可以通过在颈部临时阻塞三只容器来使其遭受14分钟的缺血来产生这种模型。该模型将在将来的研究中低估对祖细胞的分子控制。较少的