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Traumatic brain injury (TBI) is a leading cause of death and disability in pediatric patients and often results in delayed neural development and altered connectivity, leading to lifelong learning, memory, behavior, and motor function deficits. Induced pluripotent stem cell-derived neural stem cells (iNSCs) may serve as a novel multimodal therapeutic as iNSCs possess neuroprotective, regenerative, and cell-replacement capabilities post-TBI. In this study, we evaluated the effects of iNSC treatment on cellular, tissue, and functional recovery in a translational controlled cortical impact TBI piglet model. Five days post-craniectomy (n = 6) or TBI (n = 18), iNSCs (n = 7) or PBS (n = 11) were injected into perilesional brain tissue. Modified Rankin Scale (mRS) neurological evaluation, magnetic resonance imaging, and immunohistochemistry were performed over the 12-week study period. At 12-weeks post-transplantation, iNSCs showed long-term engraftment and differentiation into neurons, astrocytes, and oligodendrocytes. iNSC treatment enhanced endogenous neuroprotective and regenerative activities indicated by decreasing intracerebral immune responses, preserving endogenous neurons, and increasing neuroblast formation. These cellular changes corresponded with decreased hemispheric atrophy, midline shift, and lesion volume as well as the preservation of cerebral blood flow. iNSC treatment increased piglet survival and decreased mRS scores. The results of this study in a predictive pediatric large-animal pig model demonstrate that iNSC treatment is a robust multimodal therapeutic that has significant promise in potentially treating human pediatric TBI patients. [ABSTRACT FROM AUTHOR]

The Stroke Therapy Academic Industry Roundtable (STAIR) has recommended that novel therapeutics be tested in a large animal model with similar anatomy and physiology to humans. The pig is an attractive model due to similarities in brain size, organization, and composition relative to humans. However, multiple pig breeds have been used to study ischemic stroke with potentially differing cerebral anatomy, architecture and, consequently, ischemic stroke pathologies. The objective of this study was to characterize brain anatomy and assess spatiotemporal gait parameters in Yucatan (YC) and Landrace (LR) pigs pre- and post-stroke using magnetic resonance imaging (MRI) and gait analysis, respectively. Ischemic stroke was induced via permanent middle cerebral artery occlusion (MCAO). MRI was performed pre-stroke and 1-day post-stroke. Structural and diffusion-tensor sequences were performed at both timepoints and analyzed for cerebral characteristics, lesion diffusivity, and white matter changes. Spatiotemporal and relative pressure gait measurements were collected pre- and 2-days post-stroke to characterize and compare acute functional deficits. The results from this study demonstrated that YC and LR pigs exhibit differences in gross brain anatomy and gait patterns pre-stroke with MRI and gait analysis showing statistical differences in the majority of parameters. However, stroke pathologies in YC and LR pigs were highly comparable post-stroke for most evaluated MRI parameters, including lesion volume and diffusivity, hemisphere swelling, ventricle compression, caudal transtentorial and foramen magnum herniation, showing no statistical difference between the breeds. In addition, post-stroke changes in velocity, cycle time, swing percent, cadence, and mean hoof pressure showed no statistical difference between the breeds. These results indicate significant differences between pig breeds in brain size, anatomy, and motor function pre-stroke, yet both demonstrate comparable brain pathophysiology and motor outcomes post-stroke. The conclusions of this study suggest pigs of these different breeds generally show a similar ischemic stroke response and findings can be compared across porcine stroke studies that use different breeds. [ABSTRACT FROM AUTHOR]