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Emerging evidence is fueling a new appreciation of oligodendrocyte diversity that is overturning the traditional view that oligodendrocytes are a homogenous cell population.Oligodendrocytes of distinct origins,maturational stages,and regional locations may differ in their functional capacity or susceptibility to injury.One of the most unique qualities of the oligodendrocyte is its ability to produce myelin.Myelin abnormalities have been ascribed to a remarkable array of perinatal brain injuries,with concomitant oligodendrocyte dysregulation.Within this review,we discuss new insights into the diversity of the oligodendrocyte lineage and highlight their relevance in paradigms of perinatal brain injury.Future therapeutic development will be informed by comprehensive knowledge of oligodendrocyte pathophysiology that considers the particular facets of heterogeneity that this lineage exhibits.

Background Extremely preterm infants (EPIs) are at high-risk of white matter injury (WMI), leading to long-term neurodevelopmental impairments. We aimed to develop nomograms for WMI. Methods The study included patients from 31 provinces, spanning ten years. 6074 patients before 2018 were randomly divided into a training and internal validation group (7:3). The external validation group comprised 1492 patients from 2019. Predictors were identified using the least absolute shrinkage and selection operator (LASSO) and multivariable logistic regression and nomograms were constructed. Models’ performance was evaluated using receiver operating characteristic (ROC), decision curve analysis (DCA) and calibration curves. Results The prenatal nomogram included multiple gestation, premature rupture of membranes (PROM), chorioamnionitis, prenatal glucocorticoids, hypertensive disorder complicating pregnancy (HDCP) and Apgar 1 min, with area under the curve (AUC) of 0.805, 0.816 and 0.799 in the training, internal validation and external validation group, respectively. Days of mechanical ventilation (MV), shock, patent ductus arteriosus (PDA) ligation, intraventricular hemorrhage (IVH) grade III–IV, septicemia, hypothermia and necrotizing enterocolitis (NEC) stage II–III were identified as postpartum predictors. The AUCs were 0.791, 0.813 and 0.823 in the three groups, respectively. DCA and calibration curves showed good clinical utility and consistency. Conclusion The two nomograms provide clinicians with precise and efficient tools for prediction of WMI. Impact This study is a large-sample multicenter study, spanning 10 years. The two nomograms are convenient for identifying high-risk infants early, allowing for reducing poor prognosis.

Although the extra cellular matrix (ECM) comprises a major proportion of the CNS parenchyma, new roles for the ECM in regeneration and repair responses to CNS injury have only recently been appreciated. The ECM undergoes extensive remodeling following injury to the developing or mature CNS in disorders that –include perinatal hypoxic-ischemic cerebral injury, multiple sclerosis and age-related vascular dementia. Here we focus on recently described mechanisms involving hyaluronan (HA), which negatively impact myelin repair after cerebral white matter injury. Injury induced depolymerization of hyaluronan (HA)—a component of the neural ECM—can inhibit myelin repair through the actions of specific sizes of HA fragments. These bioactive fragments selectively block the maturation of late oligodendrocyte progenitors via an immune tolerance-like pathway that suppresses pro-myelination signaling. We highlight emerging new pathophysiological roles of the neural ECM, particularly of those played by HA fragments (HAf) after injury and discuss strategies to promoter repair and regeneration of chronic myelination failure.

Background Breastmilk stem cells (BSCs) have been reported to have potential benefits for infants. However, whether the BSCs could improve brain injury is unknown. A culture system for BSCs was established, and the roles of BSCs in treating white matter injury (WMI) were investigated in our study. Methods Breastmilk samples were collected from healthy lactating women between days 1 and 5 after delivery. The BSCs were cultured in a specialized culture medium and then characterized through flow cytometry and immunofluorescence methods. A rat model with WMI was established by ligating the right carotid artery of Sprague–Dawley rats at postnatal day 3 (P3) and exposing the rats to 6% hypoxia for 2 h. Rats were categorized into sham, WMI with breastmilk cell (WMI + BC), and WMI with (WMI + NS) groups. In the WMI + BC group, 5 µL BCs (1 × 10 6 ) was injected into the lateral ventricle 24 h post-modeling. Four different stages of oligodendrocyte (OL) markers were observed. Long-term neurobehavioral evaluations were conducted using the Morris water maze test. The inflammatory cytokines and proportion of proinflammatory microglial cells were detected to study the mechanisms of BSC treatment. Results The isolated BSCs expressed mesenchymal stem cell-positive markers, including CD105 , CD73 , CD29 , CD166 , CD44 , and CD90 . Meanwhile, the mesenchymal stem cell-negative markers, including HLA-DR , CD45 , and CD79a , were also found in BSCs. The BSCs did not express pluripotent stem cell markers, including SOX2 , Nanog , OCT4 , SSEA4 , and TRA-1-60 . Immunofluorescence detection showed that BSCs expressed neural stem/progenitor cell markers, including Vimentin , Nestin , and A2B5 . Following BSC treatment, pathological improvements were observed in WMI. The expressions of mature OLs markers myelin basic protein and myelin-associated glycoprotein were increased in the corpus callosum and periventricular areas. Meanwhile, the numbers of myelin sheath increased, and learning and memory abilities improved. Furthermore, a decrease in B7-2+/Iba1 +  proinflammatory microglia and an increase in CD206+/Iba1 + anti-inflammatory microglia were observed. The mRNA expressions of proinflammatory factors ( Il1b , Il6 , Ifng , and Tnfa ) and anti-inflammatory factors ( Arg1 and Tgfb ) decreased and increased, respectively. Conclusion Our findings suggest that BSCs can improve the maturation of OLs following WMI in newborn rats. The mechanisms may be attributed to the reduced proinflammatory microglia cells and factors as well as the increased anti-inflammatory microglia cells and factors.

Background Thrombin has been implicated in playing a role in hydrocephalus development following intraventricular hemorrhage (IVH). However, the mechanisms underlying the sex differences to the detrimental effects of thrombin post-IVH remain elusive. Method Three-month old male and female Sprague-Dawley rats underwent unilateral intracerebroventricular (ICV) injections of 3U or 5U thrombin, or saline, to examine differences in thrombin-induced hydrocephalus and white matter injury. Mortality, and lateral ventricle volume and white matter injury were measured on magnetic resonance imaging evaluation at 24 h post-injection. In addition, male rats were pretreated with 17-β estradiol (E2, 5 mg/kg) or vehicle at 24 and 2 h prior to ICV injection of 3U thrombin. All rats were euthanized at 24 h post-injection for histology and immunohistochemistry. Results ICV injection of 5U thrombin caused 100 and 0% mortality in female and male rats, respectively. 3U of thrombin resulted in significant ventricular dilation and white matter damage at 24 h in both male and female rats, but both were worse in females (p < 0.05). Furthermore, neutrophil infiltration into choroid plexus and periventricular white matter was enhanced in female rats and may play a critical role in the sex difference in brain injury. Pre-treating male rats with E2, increased thrombin (3U)-induced hydrocephalus, periventricular white matter injury and neutrophil infiltration into the choroid plexus and white matter. Conclusions ICV thrombin injection induced more severe ventricular dilation and white matter damage in female rats compared to males. Estrogen appears to contribute to this difference which may involve greater neutrophil infiltration in females. Understanding sex differences in thrombin-induced brain injury may shed light on future interventions for hemorrhagic stroke.

Preterm infants are especially vulnerable to infection-induced white matter injury, associated with cerebral palsy, cognitive and psychomotor impairment, and other adverse neurological outcomes. The etiology of such lesions is complex and multifactorial. Furthermore, timing and length of exposure to infection also influence neurodevelopmental outcomes. Different mechanisms have been posited to mediate the observed brain injury including microglial activation followed by subsequent release of pro-inflammatory species, glutamate-induced excitotoxicity, and vulnerability of developing oligodendrocytes to cerebral insults. The prevalence of such neurological impairments requires an urgent need for early detection and effective neuroprotective strategies. Accordingly, noninvasive methods of monitoring disease progression and therapy effectiveness are essential. While diagnostic tools using biomarkers from bodily fluids may provide useful information regarding potential risks of developing neurological diseases, the use of magnetic resonance imaging/spectroscopy has emerged as a promising candidate for such purpose. Various pharmacological agents have demonstrated protective effects in the immature brain in animal models; however, few studies have progressed to clinical trials with promising results.

Despite substantial progress in neonatal care over the past two decades leading to improved survival of extremely premature infants, extreme prematurity continues to be associated with long term neurodevelopmental impairments. Cerebral white matter injury is the predominant form of insult in preterm brain leading to adverse neurological consequences. Such brain injury pattern and unfavorable neurologic sequelae is commonly encountered in premature infants exposed to systemic inflammatory states such as clinical or culture proven sepsis with or without evidence of meningitis, prolonged mechanical ventilation, bronchopulmonary dysplasia, necrotizing enterocolitis and chorioamnionitis. Underlying mechanisms may include cytokine mediated processes without direct entry of pathogens into the brain, developmental differences in immune response and complex neurovascular barrier system that play a critical role in regulating the cerebral response to various systemic inflammatory insults in premature infants. Understanding of these pathologic mechanisms and clinical correlates of such injury based on serum biomarkers or brain imaging findings on magnetic resonance imaging will pave way for future research and translational therapeutic opportunities for the developing brain.

Purpose Poststroke cognitive impairment (PSCI) is a common functional disorder that occurs following stroke, but there are few effective therapies. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulatory technique that has been used to improve cognitive function in stroke patients. Despite its widespread use in clinical research, the underlying mechanisms of rTMS are largely unknown. This study hypothesized that rTMS ameliorates PSCI by regulating white matter injury, which is of vital importance in cerebral ischemia. Method An ischemic stroke rat model was created using transient middle cerebral artery occlusion. The extents of brain damage and white matter injury, including diffusion tensor imaging and diffusion tensor tractography, were evaluated using MRI. Behavioral tests, including the modified neurological severity score test and Morris water maze test, were also used. In addition, we preliminarily explored the potential role of SDF‐1α/CXCR4 by Western blot analysis and real‐time reverse transcription PCR. Finding The results showed that 10 Hz rTMS promoted neurological recovery and cognitive deficits in ischemic rats. Additionally, 10 Hz rTMS alleviated cerebral infarct severity and attenuated white matter lesions. Furthermore, the expression levels of components of the SDF‐1α/CXCR4 axis influenced the effect of rTMS on ischemic stroke. Conclusion This research provides further evidence that 10 Hz rTMS can alleviate white matter injury in affected brain regions and improve PSCI after ischemic stroke, potentially through the activation of the SDF‐1α/CXCR4 axis. 10 Hz rTMS can alleviate white matter injury and improve functional impairments after ischemic stroke, which is potentially associated with the activation of the SDF‐1α/CXCR4 axis.

One of the central, unanswered questions in perinatology is why preterm infants continue to have such poor long-term neurodevelopmental, cognitive and learning outcomes, even though severe brain injury is now rare. There is now strong clinical evidence that one factor underlying disability may be infection, as well as nonspecific inflammation, during fetal and early postnatal life. In this review, we examine the experimental evidence linking both acute and chronic infection/inflammation with perinatal brain injury and consider key experimental determinants, including the microglia response, relative brain and immune maturity and the pattern of exposure to infection. We highlight the importance of the origin and derivation of the bacterial cell wall component lipopolysaccharide. Such experimental paradigms are essential to determine the precise time course of the inflammatory reaction and to design targeted neuroprotective strategies to protect the perinatal brain from infection and inflammation.

Dexamethasone, a synthetic glucocorticoid, has been widely used to prevent or ameliorate morbidity of chronic lung disease in preterm infants with respiratory distress syndrome. Despite its beneficial effect on neonatal lung function, growing concern has arisen about adverse effects of this clinical practice on fetal brain development. We demonstrated previously that neonatal dexamethasone (DEX) treatment may render the newborn brain to be more vulnerable to hypoxia/ischemia (HI)-induced gray matter injury. Here, we examined whether neonatal DEX treatment may also affect the extent of HI-induced subcortical white matter (WM) injury in the developing rat brain. Using a HI model of premature brain injury, we demonstrated that a 3-day tapering course (0.5, 0.3, and 0.1 mg/kg) of DEX treatment in rat pups on postnatal days 1–3 (P1–3) significantly reduced the number of all stages of the oligodendroglial lineage cells on P7 and exacerbated HI-induced WM injury. Neonatal DEX treatment also enhanced HI-induced oligodendroglial apoptosis and astrocyte activation in the developing WM on P14. Likewise, HI-induced reductions in myelin thickness, axon caliber, and function during WM development were exacerbated by neonatal DEX treatment. Furthermore, neonatal DEX treatment further aggravated HI-induced motor deficits as assessed in the rotarod test. We also found that the administration of β-lactam antibiotic ceftriaxone increased glutamate transporter-1 protein expression and significantly reduced HI-induced WM injury in neonatal DEX-treated rats. These results suggest that neonatal DEX treatment may lead the developing brain to be more vulnerable to subsequent HI-induced WM injury, which can be ameliorated by ceftriaxone administration.