Astrocytic reprogramming combined with rehabilitation strategy improves recovery from spinal cord injury.

After spinal cord injury (SCI), the irreversible loss of neurons and the dense glial scar are two of the leading causes of axon regeneration failure. The adult mammalian spinal cord lacks the ability to spontaneously produce new neurons, making it a key challenge to provide new neurons for spinal cord regeneration. Additionally, the dual role of the glial scar (both inhibitory and protective) makes it difficult to manipulate it for therapeutic purposes. In this study, using a single transcription factor Sry-related HMG-box 2 (Sox2) delivered by adeno-associated virus (AAV), we reprogrammed some of the astrocytes targeted by the viral vectors in the glial scar into neurons in a severe SCI model. We show that this astrocytic reprogramming alone can propel axon regeneration by not only replenishing the lost neurons, but also moderately reducing the density of the glial scar without interrupting its integrity. Beyond that, astrocytic reprogramming can significantly improve functional recovery when combined with running wheel rehabilitation, which provides use-dependent plasticity. These findings may provide us with a new idea for how to manipulate the glial scar and a promising therapeutic strategy that combines biological intervention with a rehabilitation strategy.