激活的星形胶质细胞增生过程中对称和不对称分裂与肥大过程极化特征的关联研究

Brain injury is the major cause for brain dysfunctions with high mortality, disability and slow recovery. Astrocytes are the greatest population among all brain cells and playing vital roles in CNS functions. They can be reactivated in various injuries and diseases to form scar and plaques. This process is also known as astrogliosis which features a trilogy of reactive astrocytes: hypertrophy, GFAP upregulation and hyperplasia. Our previous studies have unraveled some detailed mechanisms involved in the first two phases. The current project would extend our astrogliosis study into the hyperplastic phase, aiming to investigate whether our observation of cell polarity in the aspect of Ca2+ signal, changes of pH and macropinocytosis, etc. during the hypertrophic phase are related to the symmetrical or asymmetrical cell divisions during hyperplasia. The results from this study will further our knowledge on astrogliosis, thus would allow us to manipulate the mechanisms to derive means of modulating scar formation. Most important of all, our result might be able to clarify whether the asymmetrical cell division under hyperplasia in these injured astrocytes would be the source of stem cells as observed in many studies indicating astrocytes might be one of the origins of stem cells in injured brains. The current study would thus provide evidence for brain injury repair via an internal intrinsic way.

脑损伤具有致死、致残率高，恢复缓慢的特点。星形胶质细胞（AS）是中枢神经系统脑细胞中比例最多的细胞。 近年发现，AS在神经系统的生理和病理功能中均扮演不可取代的角色。本实验室一直以来研究AS在脑损伤和病变中的激活机制。激活的AS在受损处发生胶质化三部曲 - 细胞肥大，GFAP上调及细胞增生。本实验室已对在前两阶段进行了深入系统的研究。以此为基础，本项目将扩展AS胶质化的研究到第三阶段AS增生的发生机制。我们发现增生中存在对称和不对称两种细胞分裂。本项目将从细胞肥大早期观察到的细胞内部和膜上的多个极性表现包括钙信号、pH值、巨胞饮等的结果跟踪、阐明这些现象是否与后续增生过程细胞对称或不对称分裂的命运有特异性关联，并试图澄清增生过程中是否有神经干细胞的产生。本项目将对AS胶质化第三部曲的机理作系统研究，更可能为神经系统损伤中干细胞的来源之谜找出答案，为实现脑损伤的修复提供依据。

本项目成功建立了细胞周期同步化的原代星形胶质细胞划伤模型，以此为基础创造了一套研究大脑皮层星形胶质细胞机械损伤条件下发生分裂过程的有效研究系统。通过对细胞损伤即细胞分裂前期细胞各种基因、蛋白、以及相关通路情况的评估，到细胞分裂期极性建立、分裂的发生比例、方式、方向、子细胞活跃程度，再到细胞分裂后子细胞中标志性蛋白的表达情况的研究，明确了大脑皮层星形胶质细胞在损伤情况下发生不对称分裂并可能向干细胞去分化的比例，揭示了星形胶质细胞不对称分裂比例和分裂方式等因素可能的内在联系；发现了核转录因子Dream很可能是决定子代细胞命运的关键分子之一。总之，本项目的完成对星形胶质细胞是否可以成为神经干细胞的一个来源给予了解答。这为深入了解激活的AS 胶质化、诠释其在损伤修复中的积极作用提供了坚实的理论支持。