Ectopic Expression of Neurod1 Is Sufficient for Functional Recovery following a Sensory-Motor Cortical Stroke

Biomedicines. 2024 Mar 15;12(3):663. doi: 10.3390/biomedicines12030663.


Stroke is the leading cause of adult disability worldwide. The majority of stroke survivors are left with devastating functional impairments for which few treatment options exist. Recently, a number of studies have used ectopic expression of transcription factors that direct neuronal cell fate with the intention of converting astrocytes to neurons in various models of brain injury and disease. While there have been reports that question whether astrocyte-to-neuron conversion occurs in vivo, here, we have asked if ectopic expression of the transcription factor Neurod1 is sufficient to promote improved functional outcomes when delivered in the subacute phase following endothelin-1-induced sensory-motor cortex stroke. We used an adeno-associated virus to deliver Neurod1 from the short GFAP promoter and demonstrated improved functional outcomes as early as 28 days post-stroke and persisting to at least 63 days post-stroke. Using Cre-based cell fate tracking, we showed that functional recovery correlated with the expression of neuronal markers in transduced cells by 28 days post-stroke. By 63 days post-stroke, the reporter-expressing cells comprised ~20% of all the neurons in the perilesional cortex and expressed markers of cortical neuron subtypes. Overall, our findings indicate that ectopic expression of Neurod1 in the stroke-injured brain is sufficient to enhance neural repair.

Keywords: Neurod1; adeno-associated virus; astrocyte-to-neuron conversion; brain repair; direct lineage conversion; ectopic transcription factor expression; functional recovery; gait analysis; neuroregeneration; stroke.

Grants and funding

This work was supported by grants to C.M.M. from the Heart and Stroke Foundation, Ontario Institute of Regenerative Medicine, Canada First Research Excellence Fund (Medicine by Design, MbD), CIHR, and the National Sciences and Engineering Research Council (C.M.P. studentship; C.M.M). J.M.L. held a postdoctoral fellowship (Medicine by Design, C.M.M.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.