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In humans, fetal cerebellar development peaks during the final stages of pregnancy. Preterm infants experience hyperoxia (excessive oxygen) outside the uterus. Hyperoxia exposure causes neurological deficits in preterm infants. However, detailed mechanisms underlying hyperoxia-induced neurological deficits remain unclear. Previous studies on neurological deficits have focused on cerebral lesions. However, recently, cerebellar lesions have been observed on brain magnetic resonance imaging in preterm infants. We herein aimed to investigate behavioral and cerebellar tissue–level changes in Sprague–Dawley rat neonates exposed to 83% hyperoxia from within 24 h of birth to 14 days of age. In rats, cerebellar development peaks in the first postnatal week. We elucidated the mechanism by which hyperoxia exposure causes neurological deficits in these rats. We found that prolonged hyperoxia exposure, starting within 24 h of birth, induces behavioral impairments (such as motor, cognitive and memory, and social interaction deficits) in rats. At the tissue level, delayed granule cell migration and abnormal Purkinje cell dendritic development combined with impaired myelination were observed in the acute and chronic hyperoxia exposure phases, respectively. Thus, hyperoxia exposure may cause abnormalities in cerebellar morphology and function, resulting in neurological deficits in preterm infants.

Background Effective treatments for cerebral palsy caused by Hypoxic-ischemic encephalopathy are urgently needed. Current therapies primarily include prevention or acute intervention, leaving a major gap in the options for reversing established neurologic damage. Because of their ease of collection and unique trophic factor profile, stem cells from human exfoliated deciduous teeth (SHED) are promising candidates for cell-based therapy targeting neurological disorders. In this study, we examined the therapeutic potential of SHED in a rat model of cerebral palsy, focusing on neurogenic and functional recovery. Methods Hypoxic–ischemic encephalopathy was induced in neonatal rats using the Rice–Vannucci method. Rats with motor impairments received intravenous SHED injections, whereas the control group received a vehicle solution. Behavioral tests assessed motor coordination and cognitive performance. Proteomic analyses and immunohistochemistry were performed to examine the underlying mechanisms. The migration and biodistribution of SHED were tracked using quantum dot-labeled SHED with in vivo imaging. Neural stem cells were cocultured with SHED to evaluate neurogenesis, followed by RNA sequencing and the analysis of trophic factors in the conditioned media. Results SHED treatment significantly ameliorated motor coordination, memory, and learning. Proteomic analysis revealed increased expression of proteins associated with neurogenesis in the SHED group. Histopathologic evaluations revealed enhanced neurogenesis in the hippocampal dentate gyrus and subventricular zone 2 weeks posttreatment, with increased NeuN-positive cells in the hippocampus and cortex at ten weeks. In vivo imaging revealed the migration of quantum dot-labeled SHED to the brain. Neural stem cells co-cultured with SHED in vitro exhibited higher proliferation rates. The SHED-conditioned medium contained increased levels of hepatocyte growth factor (HGF), and HGF-neutralizing antibodies suppressed the enhanced cell proliferation. RNA sequencing revealed significant alterations in genes associated with the PI3K–Akt signaling pathway. Conclusions SHED treatment ameliorated motor, memory, and learning impairment in a rat model of cerebral palsy. These improvements were accompanied by enhanced neurogenesis, likely mediated by HGF secretion and activation of the PI3K–Akt signaling pathway. SHED is a promising candidate for postsymptom-onset treatment of cerebral palsy. Further studies to confirm these findings and examine the clinical utility of SHED are warranted.