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

Abstract

Cortical ischemic stroke can trigger secondary neurodegeneration in remote brain regions connected to the primary lesion, particularly the thalamus. Although secondary thalamic degeneration is well established, the temporal relationship among early disruption of the thalamocortical pathway, neuronal degeneration, neuroinflammation, and delayed thalamic atrophy remains incompletely defined. Here, we investigated the longitudinal progression of secondary thalamic degeneration after cortical stroke, with particular emphasis on diffusion MRI tractography to monitor changes in anatomically defined thalamocortical pathways. We further determined whether early intracortical transplantation of human induced pluripotent stem cell (hiPSC)-derived neuronal progenitors could protect the remote thalamus and preserve thalamocortical connectivity.Cortical ischemic stroke was induced by distal middle cerebral artery occlusion in rats, and animals were assessed at multiple time points up to 6 months after stroke using longitudinal volumetric MRI and diffusion MRI tractography, combined with histological analyses of neuronal degeneration and microglial activation. The cortical infarct was established within 3-4 days, whereas alterations in diffusion metrics of thalamocortical pathways were detected within the first days after stroke. Neuronal degeneration in the ipsilateral ventral posterior nucleus (VPN) was evident at 2 weeks and preceded measurable VPN atrophy, which began at 3 months. Microglial activation also peaked at 2 weeks, coinciding with the onset of neuronal degeneration. Early intracortical transplantation of cortically primed hiPSC-derived neuronal progenitors 48 h after stroke did not alter cortical infarct volume but preserved VPN neurons, reduced subsequent thalamic atrophy, and maintained diffusion properties of affected thalamocortical pathways.These findings define secondary thalamic degeneration as a temporally ordered process in which early alterations in the thalamocortical pathway precede neuronal loss and delayed structural atrophy. Importantly, longitudinal tractography monitored both cortical stroke-induced thalamocortical degeneration and its modification by hiPSC-derived neuronal transplantation, establishing an in vivo approach to assess remote circuit degeneration and transplantation-dependent neuroprotection after cortical stroke.