Generation of induced neurons by direct conversion of microglia and related cells

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Microglia are myeloid cells with ubiquitous distribution throughout the central nervous system and constant self-regeneration. The natural behavior of microglia to home to injury sites could be used for targeted therapies in multifocal neurological pathologies and neuroregenerative approaches.The proposed study aims to explore the potential of microglia as a source cell for direct lineage conversion towards a neuronal fate. Based on the finding that depleted endogenous microglia can be exogenously repopulated by cells of hematopoietic origin, direct neuronal reprogramming potential of such microglia-like cells and preceding hematopoietic cells is investigated as well. A further aim of this research proposal is to develop a model to systemically access the central nervous system with genetically modified cells and provoke wide-spread in vivo neurogenesis. Additionally, application of this approach for targeted neuroregeneration at lesion sites will be evaluated.Microglia and related cells will be genetically modified and in vitro screening for suitable and effective transcription factors for neuronal reprogramming will be conducted. Resulting cells will be evaluated regarding molecular and functional properties employing immunohistological and electrophysiological methods as well as gene expression profiling. Cells transduced with identified proneural transcription factors under the control of an inducible operator will be used to replace diminished microglia and neuronal conversion will be induced in vivo. This approach will then be applied in a model of acute cerebral injury.This project will provide additional insight into the mechanisms of direct neuronal reprogramming as well as improve the understanding of the nature of microglia and characteristics of in vivo induced neuronal cells. Direct in vivo cellular reprogramming could proof as a valuable translational technique for the development of regenerative therapies.