Cellular Dynamics and Regulatory Pathways for Successful Regeneration

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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.