INTRACORTICAL TRANSPLANTATION OF HUMAN INDUCED PLURIPOTENT STEM CELL-DERIVED PROGENITORS AMELIORATES DELAYED THALAMIC DEGENERATION FOLLOWING CORTICAL STROKE

Ischemic stroke frequently causes cortical damage leading to disrupted neural connectivity and subsequent secondary neurodegeneration in remote regions such as the thalamus, which can exacerbate neurological deficits. Although this injury involves 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 cortical stroke model, and evaluated the therapeutic potential of stem cell-based transplantation. The animals that underwent distal middle cerebral artery occlusion or sham surgery were assessed at multiple time points post-stroke. We observed stable cortical infarcts by 3-4 days, followed by progressive thalamic degeneration, particularly in the ventral posterior nucleus (VPN), which began at 3 months and persisted to 6 months. Neuronal loss in the VPN started at 2 weeks and correlated with thalamic lesion size. MRI-based tractography detected damage in the tracts connecting the thalamus and stroke-injured cortex much earlier than the thalamic neuronal death. Microglial activation in the thalamus peaked at 2 weeks, suggesting neuroinflammation. 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 were shown to integrate into the host tissue. These findings highlight the therapeutic potential of stem cell-based interventions to mitigate secondary neurodegeneration and improve long-term outcomes after cortical stroke. This study provides critical insights into secondary thalamic injury mechanisms and demonstrates the feasibility of intracortical transplantation as a strategy to enhance post-stroke recovery.