In vivo reprogramming of NG2 glia for neurogenesis

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Neuron loss is a frequent result of neural injury or degeneration. A fundamental but unresolved challenge is how to restore the lost neurons and repair the neural circuits in the adult central nervous system. Stem cell-based transplantation has limitations on immune compatibility, neuronal survival, and functional integration; and it has the potential for tumorigenesis. The long-term goal of this proposal is to define innovative regenerative strategies by using a patient’s own scar-forming cells without cell transplantation. In response to injury or neural degeneration, glial cells become reactive, proliferate, and form scars. Scar formation is initially beneficial by restricting damage but ultimately detrimental to neural regeneration through acting as a physical and chemical barrier to axonal regeneration and growth. Our prior research showed that reactive astrocytes can be in vivo reprogrammed to expandable neural progenitors, which can further produce mature neurons in the adult central nervous system. The current proposal will focus on NG2 glia, another major component of the glial scar. Our preliminary data indicate that they can be in vivo reprogrammed to become neurogenic. We here propose to determine the molecular and cellular mechanisms underlying the reprogramming process of NG2 glia in adult mouse. We will also examine the excitability and synaptic integrations of the induced neurons from NG2 glia. Finally, we will investigate the biological function of these newly generated neurons in a mouse model of neural injury. Results from this work may lead to paradigm-shifting regeneration-based therapeutic strategies for neural injury and degeneration.