Cellular Dynamics and Regulatory Pathways for Successful Regeneration

不同类型的脑损伤后神经功能的恢复是最常见的医疗挑战之一，但尚无成功的治疗方法。损伤所致的胶质瘢痕不仅干扰了沉积部位脑区的功能，而且阻碍了新神经元的整合，是导致神经功能恢复不佳的主要原因。与哺乳动物相比，斑马鱼可以限制胶质瘢痕的形成，激活神经胶质细胞的神经发生潜力，以无疤痕的方式生成新的神经元和再生神经组织。因此，我们建议进行一种新的跨物种比较(斑马鱼和小鼠)，利用单细胞转录本来确定定义斑马鱼和小鼠脑中神经胶质反应的细胞轨迹，目的是消除其有害影响，同时不妨碍神经胶质细胞在伤口愈合中最初的有益作用。此外，这种比较将使我们能够识别易于将神经胶质细胞直接重编程为神经元的细胞状态，作为哺乳动物大脑功能再生的一种手段。第二组实验旨在确定神经炎性细胞(小胶质细胞和星形胶质细胞)和移植或原位重编程神经元之间可能的细胞相互作用，以此作为提高其存活率并分化为功能恢复所需的适当神经元亚型的手段。

The recovery of neuronal functions after different types of brain injuries is one of the most common healthcare challenges, yet without successful therapies. Injury induced glial scar is the prime reason for the poor recovery, as the scar does not only interfere with the function of the brain area at the site of its deposition, but also hampers integration of new neurons. In contrast to mammals, zebrafish can restrict glial scar formation, activate neurogenic potential of glial cells to generate new neurons and regenerate neural tissue in a scarless manner. Therefore, we propose to pursue a novel trans-species comparison (zebrafish and mouse) using single cell transcriptomes to identify the cellular trajectories defining the glial reaction in zebrafish and mouse brain, with the goal of eliminating its detrimental effects, while at the same time not hampering the initial beneficial role of glial cells in wound healing. Moreover, this comparison will allow us to identify the cellular states prone for direct reprogramming of glial cells to neurons, as a mean for functional regeneration in the mammalian brain. The second set of experiments will aim at identification of cellular possible cellular interactions of the neuroinflammatory cells (microglia and astrocytes) and transplanted or in situ reprogrammed neurons as a mean to improve their survival and differentiation into proper neuronal subtypes necessary for the functional recovery.