Stroke is the leading cause of adult disability with few treatment options for stroke survivors. Astrocytereprogramming to neurons enables the targeted in vivo generation of new cells at the site of injury andrepresents a novel approach for brain repair. A number of studies have demonstrated successfulconversion of astrocytes to neurons in various models of brain injury and disease; however, the impact ofthis strategy on tissue and functional outcome following stroke is not well established. Using AAV deliveryof the transcription factor NeuroD1, we reprogrammed astrocytes 7 days after endothelin-1 inducedcortical stroke, and studied the long-term cellular and functional outcomes. We found that by 63 dayspost-stroke, 20% of neurons in the perilesional cortex were reprogrammed. Furthermore, reprogrammedneurons had matured into regionally appropriate neuronal subtypes. Importantly, this treatment wasassociated with improved functional outcome using the foot fault test and gait analysis. Together, ourfindings indicate that in vivo reprogramming is a promising regenerative approach for stroke repair.

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