Intracortical transplantation of human induced pluripotent stem cell-derived progenitors ameliorates delayed thalamic degeneration following cortical stroke

Ischemic stroke, a leading cause of death and disability worldwide, frequently results in cortical damage. Due to disrupted neural connectivity, cortical lesions often trigger secondary neurodegeneration in remote brain regions, such as the thalamus. This secondary thalamic injury exacerbates neurological deficits, leading to long-term sensory, motor, and cognitive impairments. Although animal models have demonstrated that secondary thalamic damage is driven by retrograde degeneration, excitotoxicity, apoptosis, blood-brain barrier disruption, and neuroinflammation, the mechanisms linking cortical stroke to thalamic degeneration remain poorly understood. In this study, we investigated the dynamics of secondary thalamic injury in a rat model of cortical stroke. We evaluated the therapeutic potential of intracortical transplantation of human induced pluripotent stem cell (iPSC)-derived neuronal progenitors. Cortical ischemic stroke was induced via distal middle cerebral artery occlusion, and animals were assessed at multiple time points post-stroke. We observed stable cortical infarcts by 2 weeks, followed by progressive thalamic degeneration, particularly in the ventral posterior nucleus (VPN), which began at 3 months and persisted up to 6 months. Neuronal loss in the VPN correlated with the size of the cortical lesion, and microglial activation in the thalamus peaked at 2-4 months, suggesting a role for neuroinflammation in secondary degeneration. Intracortical transplantation of cortically primed iPSC-derived progenitors 48 hours post-stroke did not alter the cortical infarct volume but significantly reduced thalamic neuronal loss. Grafted cells integrated into the host tissue and presumably established functional connections, potentially mitigating secondary thalamic injury. These findings highlight the therapeutic potential of stem cell-based interventions to prevent secondary neurodegeneration and improve long-term outcomes after cortical stroke. This study provides critical insights into the mechanisms of secondary thalamic injury and demonstrates the feasibility of intracortical transplantation as a strategy to enhance post-stroke recovery.