Sox10 glial-neuron nuclear communication mediates anti-apoptosis neuroprotection after ischaemic stroke.

BACKGROUND

Neuronal apoptosis is a hallmark of ischaemic stroke, yet effective neuroprotective therapies remain scarce. Recent studies suggest that Sox10-lineage cells (SOL) can transfer nuclear material to neurons. However, whether this process contributes to neuronal survival after stroke remains unknown.

METHODS

Sox10-iCreERT2:Ai9 mice subjected to distal middle cerebral artery occlusion (dMCAO) were used to investigate SOL to neuron material transfer after ischaemic injury. High-resolution confocal imaging, AAV-based lineage tracing and single-nucleus RNA sequencing were employed to identify tdTomato-positive neurons and characterise their transcriptional profiles. Behavioural tests and histological analyses were performed to evaluate the neuroprotective effects of tamoxifen treatment.

RESULTS

A subset of neurons from cortical layer 6 expressed tdTomato protein derived from SOL, suggesting intercellular material transfer. Notably, tdTomato+ neurons exhibited enhanced Bcl2 expression. High-dose tamoxifen (160 mg/kg) increased the number of tdTomato+ neurons by approximately fourfold compared with low-dose treatment. Correspondingly, the proportion of apoptotic neurons (TUNEL+/NeuN+) in the high-dose tamoxifen group was reduced from 33.4% to 19.3%, and infarct volume decreased from 11.68% to 7.26% of the ipsilateral hemisphere after ischaemic stroke. Functionally, high-dose tamoxifen significantly improved sensorimotor recovery, as evidenced by faster adhesive removal (6.9 s vs 22.2 s) and reduced forelimb error rates in the grid-walk test.

CONCLUSIONS

We identify Sox10 lineage-associated tdTomato+ neurons in the ischaemic cortex, with their prevalence higher under high-dose tamoxifen and associated with reduced neuronal loss and improved neurological outcomes. These findings suggest a potential link between Sox10 lineage-related cellular plasticity and neuroprotection.