Preterm White Matter Injury Research Articles

Can or should we try to predict preterm white matter injury?

Can or should we try to predict preterm white matter injury?

Childhood Health and Educational outcomes afteR perinatal Brain injury (CHERuB): protocol for a population-matched cohort study

IntroductionOver 3000 infants suffer a brain injury around the time of birth every year in England. Although these injuries can have important implications for children and their families, our understanding...

Circ_19038 and lnc-AK016022 synergistically regulate Sirt1 to promote remyelination and alleviate white matter injury in preterm mice

Maternal inflammation can lead to premature birth and fetal brain damage. CircRNA_19038 and lncRNA-AK016022 have been shown to be significantly reduced in brain tissues of preterm mice, while whether they are involved in the regulation of preterm white matter injury remains to be explored. Pregnant mice were intraperitoneally injected with lipopolysaccharide (LPS) to establish a preterm brain injury model. Healthy mice born at term served as controls. Lentivirus-mediated circ_19038 overexpression vector (LV-circ_19038), LV-lnc-AK016022, LV-Sirt1 and LV-sh-Sirt1 were administered to preterm mice through the ventricles. The expression levels of circ_19038, lnc-AK016022 and Sirt1 in the brain tissues of preterm mice were significantly lower than those of full-term healthy mice, and circ_19038 and lnc-AK016022 were co-localized in the brain tissues. Upregulation of circ_19038 or/and lnc-AK016022 promoted remyelination and alleviated white matter structural damage, neuroinflammation, and long-term cognitive and motor deficits in preterm mice, and the combined effect of circ_19038 and lnc-AK016022 showed better results. Primary mouse neuronal cells were isolated to investigate the regulatory effects of circ_19038 and lnc-AK016022 on Sirt1. Circ_19038 and lnc-AK016022 jointly promoted the expression of Sirt1 by adsorbing miR-1b and miR-328, respectively. Moreover, silencing Sirt1 antagonized the beneficial effects of circ_19038 or/and lnc-AK016022 on brain white matter injury in preterm mice. In conclusion, circ_19038 and lnc-AK016022 synergistically regulated Sirt1 expression to promote remyelination and alleviate white matter injury in preterm mice.

Minimum effective dose of clemastine in a mouse model of preterm white matter injury

BackgroundPreterm white matter injury (PWMI) is the most common cause of brain injury in premature neonates. PWMI involves a differentiation arrest of oligodendrocytes, the myelinating cells of the central nervous system. Clemastine was previously shown to induce oligodendrocyte differentiation and myelination in mouse models of PWMI at a dose of 10 mg/kg/day. The minimum effective dose (MED) of clemastine is unknown. Identification of the MED is essential for maximizing safety and efficacy in neonatal clinical trials. We hypothesized that the MED in neonatal mice is lower than 10 mg/kg/day.MethodsMouse pups were exposed to normoxia or hypoxia (10% FiO2) from postnatal day 3 (P3) through P10. Vehicle or clemastine at one of four doses (0.5, 2, 7.5 or 10 mg/kg/day) was given to hypoxia-exposed pups. Myelination was assessed at age P14 and 10 weeks to determine the MED. Clemastine pharmacokinetics were evaluated at steady-state on day 8 of treatment.ResultsClemastine rescued hypoxia-induced hypomyelination with a MED of 7.5 mg/kg/day. Pharmacokinetic analysis of the MED revealed Cmax 44.0 ng/mL, t1/2 4.6 h, and AUC24 280.1 ng*hr/mL.ConclusionsBased on these results, myelination-promoting exposures should be achievable with oral doses of clemastine in neonates with PWMI.ImpactPreterm white matter injury (PWMI) is the most common cause of brain injury and cerebral palsy in premature neonates.Clemastine, an FDA-approved antihistamine, was recently identified to strongly promote myelination in a mouse model of PWMI and is a possible treatment.The minimum effective dose in neonatal rodents is unknown and is critical for guiding dose selection and balancing efficacy with toxicity in future clinical trials.We identified the minimum effective dose of clemastine and the associated pharmacokinetics in a murine chronic hypoxia model of PWMI, paving the way for a future clinical trial in human neonates.

Role of the Gut Microbiota-Brain Axis in Brain Damage in Preterm Infants.

The greatest repository of microbes in the human body, the intestinal microbiome, is involved in neurological development, aging, and brain illnesses such as white matter injury (WMI) in preterm newborns. Intestinal microorganisms constitute a microbial gut-brain axis that serves as a crucial conduit for communication between the gut and the nervous system. This axis controls inflammatory cytokines, which in turn influence the differentiation of premyelinating oligodendrocytes (pre-OLs) and influence the incidence of WMI in premature newborns through the metabolites generated by gut microbes. Here, we describe the effects of white matter injury (WMI) on intestinal dysbiosis and gut dysfunction and explain the most recent research findings on the gut-brain axis in both humans and animals. We also emphasize the delicate relationship that exists between the microbiota and the brain following acute brain injury. The role that the intestinal microflora plays in influencing host metabolism, the immune system, brain health, and the course of disease is becoming increasingly clear, but there are still gaps in the field of WMI treatment. Thus, this review demonstrates the function of the gut microflora-brain axis in WMI and elucidates the possible mechanisms underlying the communication between gut bacteria and the developing brain via the gut-brain axis, potentially opening up new avenues for microbial-based intervention and treatment for preterm WMI.

Potential Role of Endoplasmic Reticulum Stress in Modulating Protein Homeostasis in Oligodendrocytes to Improve White Matter Injury in Preterm Infants.

Preterm white matter injury (WMI) is a demyelinating disease with high incidence and mortality in premature infants. Oligodendrocyte cells (OLs) are a specialized glial cell that produces myelin proteins and adheres to the axons providing energy and metabolic support which susceptible to endoplasmic reticulum protein quality control. Disruption of cellular protein homeostasis led to OLs dysfunction and cell death, immediately, the unfolded protein response (UPR) activated to attempt to restore the protein homeostasis via IRE1/XBP1s, PERK/eIF2α and ATF6 pathway that reduced protein translation, strengthen protein-folding capacity, and degraded unfolding/misfolded protein. Moreover, recent works have revealed the conspicuousness function of ER signaling pathways in regulating influenced factors such as calcium homeostasis, mitochondrial reactive oxygen generation, and autophagy activation to regulate protein hemostasis and improve the myelination function of OLs. Each of the regulation modes and their corresponding molecular mechanisms provides unique opportunities and distinct perspectives to obtain a deep understanding of different actions of ER stress in maintaining OLs' health and function. Therefore, our review focuses on summarizing the current understanding of ER stress on OLs' protein homeostasis micro-environment in myelination during white matter development, as well as the pathophysiology of WMI, and discussing the further potential experimental therapeutics targeting these factors that restore the function of the UPR in OLs myelination function.

Inhibition of the proteoglycan receptor PTPσ promotes functional recovery on a rodent model of preterm hypoxic-ischemic brain injury

BackgroundPreterm white matter injury (WMI) is the most common brain injury in preterm infants and is associated with long-term adverse neurodevelopmental outcomes. Protein tyrosine phosphatase sigma (PTPσ) was discovered as chondroitin sulfate proteoglycan (CSPG) receptor that played roles in inhibiting myelin regeneration in spinal injury, experimental autoimmune encephalomyelitis, and stroke models. However, the role of PTPσ in perinatal WMI is not well understood. AimsThis study examines the effect of PTPσ inhibition on neurodevelopmental outcomes, myelination, and neuroinflammation in a mouse model of preterm WMI. Materials and methodsModified Rice-Vannucci model was performed on postnatal day 3 (P3) C57BL/6 mice. Intracellular Sigma Peptide (ISP) or vehicle was administrated subcutaneously one hour after injury for an additional 14 consecutive days. A battery of behavioral tests was performed to evaluate the short- and long-term effects of ISP on neurobehavioral deficit. Real time qPCR, western blot, immunofluorescence, and transmission electron microscopy were performed to assess white matter development. qPCR and flow cytometry were performed to evaluate neuroinflammation and microglia/macrophage phenotype. ResultsThe expression of PTPσ was increased after preterm WMI. ISP improved short-term neurological outcomes and ameliorated long-term motor and cognitive function of mice after preterm WMI. ISP promoted oligodendrocyte differentiation, maturation, myelination, and improved microstructure of myelin after preterm WMI. Furthermore, ISP administration fostered a beneficial inflammatory response in the acute phase after preterm WMI, inhibited the infiltration of peripheral macrophages, and promoted anti-inflammatory phenotype of microglia/macrophages. ConclusionPTPσ inhibition can ameliorate neurofunctional deficit, promote white matter development, modulate neuroinflammation and microglia/macrophage phenotype after preterm WMI. Thus, ISP administration may be a potential therapeutic strategy to improve neurodevelopmental outcomes of perinatal WMI.

Oligodendrocyte Progenitor Cell Transplantation Ameliorates Preterm Infant Cerebral White Matter Injury in Rats Model.

Cerebral white matter injury (WMI) is the most common brain injury in preterm infants, leading to motor and developmental deficits often accompanied by cognitive impairment. However, there is no effective treatment. One promising approach for treating preterm WMI is cell replacement therapy, in which lost cells can be replaced by exogenous oligodendrocyte progenitor cells (OPCs). This study developed a method to differentiate human neural stem cells (hNSCs) into human OPCs (hOPCs). The preterm WMI animal model was established in rats on postnatal day 3, and OLIG2+/NG2+/PDGFRα+/O4+ hOPCs were enriched and transplanted into the corpus callosum on postnatal day 10. Then, histological analysis and electron microscopy were used to detect lesion structure; behavioral assays were performed to detect cognitive function. Transplanted hOPCs survived and migrated throughout the major white matter tracts. Morphological differentiation of transplanted hOPCs was observed. Histological analysis revealed structural repair of lesioned areas. Re-myelination of the axons in the corpus callosum was confirmed by electron microscopy. The Morris water maze test revealed cognitive function recovery. Our study showed that exogenous hOPCs could differentiate into CC1+ OLS in the brain of WMI rats, improving their cognitive functions.

Two different isoforms of osteopontin modulate myelination and axonal integrity.

Abnormal myelination underlies the pathology of white matter diseases such as preterm white matter injury and multiple sclerosis. Osteopontin (OPN) has been suggested to play a role in myelination. Murine OPN mRNA is translated into a secreted isoform (sOPN) or an intracellular isoform (iOPN). Whether there is an isoform-specific involvement of OPN in myelination is unknown. Here we generated mouse models that either lacked both OPN isoforms in all cells (OPN-KO) or lacked sOPN systemically but expressed iOPN specifically in oligodendrocytes (OLs-iOPN-KI). Transcriptome analysis of isolated oligodendrocytes from the neonatal brain showed that genes and pathways related to increase of myelination and altered cell cycle control were enriched in the absence of the two OPN isoforms in OPN-KO mice compared to control mice. Accordingly, adult OPN-KO mice showed an increased axonal myelination, as revealed by transmission electron microscopy imaging, and increased expression of myelin-related proteins. In contrast, neonatal oligodendrocytes from OLs-iOPN-KI mice compared to control mice showed differential regulation of genes and pathways related to the increase of cell adhesion, motility, and vasculature development, and the decrease of axonal/neuronal development. OLs-iOPN-KI mice showed abnormal myelin formation in the early phase of myelination in young mice and signs of axonal degeneration in adulthood. These results suggest an OPN isoform-specific involvement, and a possible interplay between the isoforms, in myelination, and axonal integrity. Thus, the two isoforms of OPN need to be separately considered in therapeutic strategies targeting OPN in white matter injury and diseases.

Alpha-asaronol promoted oligodendrocyte precursor cell differentiation and improved myelination as an activator PPARγ

Preterm white matter injury (PWMI), characterized by oligodendrocyte precursor cell (OPC) differentiation disorder and dysmyelination, is a prevalent demyelinating disease of the central nervous system in premature infants, necessitating the development of mitigating strategies. Convincing evidence suggests that peroxisome proliferator-activated receptor γ (PPARγ) activation is a stimulative factor against the hindered process of oligodendrocyte (OL) differentiation. However, much remains unknown about its promotive mechanism. Our previous study indicated that alpha-asaronol (α-asaronol) could alleviate myelination disorder in a neonatal PWMI rat model, but the mechanism remained unclear. In this study, we demonstrated that α-asaronol attenuated cognitive deficits, repaired myelin damage, and stimulated OL differentiation in the corpus callosum of PWMI rats. Co-immunoprecipitation analysis confirmed that α-asaronol induced the binding of PPARγ with its coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), which in turn activated oligodendroglial PPARγ. This activation subsequently upregulated the expression of phosphatase and tensin homolog (PTEN) and pro-differentiation-associated genes of Cnp1 and Klk6 and downregulated the expression of Clk1. However, the benefits of α-asaronol were blocked by GW9662, an antagonist of PPARγ. Moreover, α-asaronol also promoted OPC differentiation under oxygen-glucose deprivation conditions. In conclusion, α-asaronol can promote OL differentiation and myelination and alleviate cognitive deficits in neonatal PWMI rats by activating PPARγ and modulating OL differentiation-associated gene expression. This study suggests that α-asaronol may be a potential therapeutic drug for myelination failure in PWMI.

Endothelin-1-Endothelin receptor B complex contributes to oligodendrocyte differentiation and myelin deficits during preterm white matter injury.

Preterm cerebral white matter injury (WMI), a major form of prenatal brain injury, may potentially be treated by oligodendrocyte (OL) precursor cell (OPC) transplantation. However, the defective differentiation of OPCs during WMI seriously hampers the clinical application of OPC transplantation. Thus, improving the ability of transplanted OPCs to differentiate is critical to OPC transplantation therapy for WMI. We established a hypoxia-ischemia-induced preterm WMI model in mice and screened the molecules affected by WMI using single-cell RNA sequencing. We revealed that endothelin (ET)-1 and endothelin receptor B (ETB) are a pair of signaling molecules responsible for the interaction between neurons and OPCs and that preterm WMI led to an increase in the number of ETB-positive OPCs and premyelinating OLs. Furthermore, the maturation of OLs was reduced by knocking out ETB but promoted by stimulating ET-1/ETB signaling. Our research reveals a new signaling module for neuron-OPC interaction and provides new insight for therapy targeting preterm WMI.

MicroRNA-21-5p agomir inhibits apoptosis of oligodendrocyte precursor cell and attenuates white matter injury in neonatal rats

Background and research question/hypothesisExcessive oligodendrocyte precursor cell (OPC) apoptosis occurs during intrauterine infection-induced white matter injury (WMI) in premature infants, preventing excessive apoptosis of OPCs is one of the mechanisms protecting WMI. Micro-RNA-21-5p (miR-21-5p) mediating anti-apoptotic activity was observed in other diseases. Therefore, the aim of this study was to determine whether miR-21-5p protects against WMI by modulating phosphatase and tensin homologue deleted on chromosome 10/phosphatidylinositol-3-kinase/protein kinase B (PTEN/PI3K/Akt) signalling pathway. MethodsA lipopolysaccharide (LPS)-induced neonatal Sprague–Dawley (SD) rat model of preterm WMI was established. To explore the effect of miR-21-5p on WMI, we intraventricularly injected miR-21-5p agomir and miR-21-5p antagomir to activate or inhibit endogenous miR-21-5p. Immunofluorescent labelling of myelin basic protein, immunohistochemical labelling of 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase), and terminal deoxynucleotidyl transferase dUTP nick end labelling assays were conducted to observe pathological white matter changes. The antibody of anti-oligodendrocyte marker 4 (O4) was used to specifically recognise OPCs. The expressions of miR-21-5p and PTEN mRNA in the brain were detected with quantitative real-time polymerase chain reaction (qRT-PCR). PTEN, Akt, and phosphorylated Akt (p-Akt) protein levels were assayed with western blotting, and apoptotic proteins associated with PI3K/Akt signalling were quantified. ResultsIntense white matter dysplasia and excessive OPC apoptosis were observed in the brains of rats with WMI. When the miR-21-5p agonist miR-21-5p agomir was used in the WMI group, apoptosis of OPCs was significantly reduced, and myelin maturation increased. MiR-21-5p agomir relieved WMI. MiR-21-5p agomir inhibited the mRNA and protein expression of PTEN, increased p-Akt phosphorylation, and decreased the expression and activation of related apoptotic proteins.On the other hand, the administration of miR-21-5p specific blocker, miR-21-5p antagomir, reduced the level of p-AKT, increased OPC apoptosis, and worsened WMI. InterpretationOur findings revealed that miR-21-5p agomir had anti-OPC over-apoptotic effects and enhanced myelin development in WMI by modulating the PTEN/Akt signalling pathway.

Alpha-Asaronol Alleviates Dysmyelination by Enhancing Glutamate Transport Through the Activation of PPARγ-GLT-1 Signaling in Hypoxia-Ischemia Neonatal Rats.

Preterm white matter injury (PWMI) is the most common form of brain damage in premature infants caused by hypoxia-ischemia (HI), inflammation, or excitotoxicity. It is characterized by oligodendrocyte precursor cell (OPC) differentiation disorder and dysmyelination. Our previous study confirmed that alpha-asarone (α-asaronol), a major compound isolated from the Chinese medicinal herb Acorus gramineus by our lab, could alleviate neuronal overexcitation and improve the cognitive function of aged rats. In the present study, we investigated the effect and mechanism of α-asaronol on myelination in a rat model of PWMI induced by HI. Notably, α-asaronol promoted OPC differentiation and myelination in the corpus callosum of PWMI rats. Meanwhile, the concentration of glutamate was significantly decreased, and the levels of PPARγ and glutamate transporter 1 (GLT-1) were increased by α-asaronol treatment. In vitro, it was also confirmed that α-asaronol increased GLT-1 expression and recruitment of the PPARγ coactivator PCG-1a in astrocytes under oxygen and glucose deprivation (OGD) conditions. The PPARγ inhibitor GW9662 significantly reversed the effect of α-asaronol on GLT-1 expression and PCG-1a recruitment. Interestingly, the conditioned medium from α-asaronol-treated astrocytes decreased the number of OPCs and increased the number of mature oligodendrocytes. These results suggest that α-asaronol can promote OPC differentiation and relieve dysmyelination by regulating glutamate levels via astrocyte PPARγ-GLT-1 signaling. Although whether α-asaronol binds to PPARγ directly or indirectly is not investigated here, this study still indicates that α-asaronol may be a promising small molecular drug for the treatment of myelin-related diseases.

Cognitive performance during adulthood in a rat model of neonatal diffuse white matter injury

RationaleInfants born prematurely risk developing diffuse white matter injury (WMI), which is associated with impaired cognitive functioning and an increased risk of autism spectrum disorder. Recently, our rat model of preterm diffuse WMI induced by combined fetal inflammation and postnatal hypoxia showed impaired motor performance, anxiety-like behaviour and autism-like behaviour in juvenile rats, especially males. Immunohistochemistry showed delayed myelination in the sensory cortex and impaired oligodendrocyte differentiation.ObjectiveTo assess long-term cognitive deficits in this double-hit rat model of diffuse WMI, animals were screened on impulsivity, attention and cognitive flexibility in adulthood using the 5-choice serial reaction time task (5CSRTT) and a probabilistic reversal learning task, tests that require a proper functioning prefrontal cortex. Thereafter, myelination deficits were evaluated by immunofluorescent staining in adulthood.ResultsOverall, little effect of WMI or sex was found in the cognitive tasks. WMI animals showed subtle differences in performance in the 5CSRTT. Manipulating 5CSRTT parameters resulted in performance patterns previously seen in the literature. Sex differences were found in perseverative responses and omitted trials: female WMI rats seem to be less flexible in the 5CSRTT but not in the reversal learning task. Males collected rewards faster in the probabilistic reversal learning task. These findings are explained by temporally rather than permanently affected myelination and by the absence of extensive injury to prefrontal cortical subregions, confirmed by immunofluorescent staining in both adolescence and adulthood.ConclusionThis rat model of preterm WMI does not lead to long-term cognitive deficits as observed in prematurely born human infants.

Transplanted Human Oligodendrocyte Progenitor Cells Restore Neurobehavioral Deficits in a Rat Model of Preterm White Matter Injury.

Background: Preterm white matter injury (PWMI) is a common brain injury and a leading cause of life-long neurological deficits in premature infants; however, no effective treatment is available yet. This study aimed to investigate the fate and effectiveness of transplanted human oligodendrocyte progenitor cells (hOPCs) in a rat model of PWMI.Methods: Hypoxia-ischemia was induced in rats at postnatal day 3, and hOPCs (6 × 105 cells/5 μL) were intracerebroventricularly transplanted at postnatal day 7. Neurobehavior was assessed 12 weeks post-transplant using the CatWalk test and Morris water maze test. Histological analyses, as well as immunohistochemical and transmission electron microscopy, were performed after transcardial perfusion.Results: Transplanted hOPCs survived for 13 weeks in PWMI brains. They were widely distributed in the injured white matter, and migrated along the corpus callosum to the contralateral hemisphere. Notably, 82.77 ± 3.27% of transplanted cells differentiated into mature oligodendrocytes, which produced myelin around the axons. Transplantation of hOPCs increased the fluorescence intensity of myelin basic protein and the thickness of myelin sheaths as observed in immunostaining and transmission electron microscopy, while it reduced white matter atrophy at the level of gross morphology. With regard to neurobehavior, the CatWalk test revealed improved locomotor function and inter-paw coordination after transplantation, and the cognitive functions of hOPC-transplanted rats were restored as revealed by the Morris water maze test.Conclusions: Myelin restoration through the transplantation of hOPCs led to neurobehavioral improvements in PWMI rats, suggesting that transplanting hOPCs may provide an effective and promising therapeutic strategy in children with PWMI.

Interaction between Preterm White Matter Injury and Childhood Thalamic Growth.

The purpose of this study was to determine how preterm white matter injury (WMI) and long-term thalamic growth interact to predict 8-year neurodevelopmental outcomes. A prospective cohort of 114 children born at 24 to 32 weeks' gestational age (GA) underwent structural and diffusion tensor magnetic resonance imaging early in life (median 32 weeks), at term-equivalent age and at 8 years. Manual segmentation of neonatal WMI was performed on T1-weighted images and thalamic volumes were obtained using the MAGeT brain segmentation pipeline. Cognitive, motor, and visual-motor outcomes were evaluated at 8 years of age. Multivariable regression was used to examine the relationship among neonatal WMI volume, school-age thalamic volume, and neurodevelopmental outcomes. School-age thalamic volumes were predicted by neonatal thalamic growth rate, GA, sex, and neonatal WMI volume (p < 0.0001). After accounting for total cerebral volume, WMI volume remained associated with school-age thalamic volume (β=-0.31, p=0.005). In thalamocortical tracts, fractional anisotropy (FA) at term-equivalent age interacted with early WMI volume to predict school-age thalamic volumes (all p < 0.02). School-age thalamic volumes and neonatal WMI interacted to predict full-scale IQ (p=0.002) and adverse motor scores among those with significant WMI (p=0.01). Visual-motor scores were predicted by thalamic volumes (p=0.04). In very preterm-born children, neonatal thalamic growth and WMI volume predict school-age thalamic volumes. The emergence at term of an interaction between FA and WMI to impact school-age thalamic volume indicates dysmaturation as a mechanism of thalamic growth failure. Cognition is predicted by the interaction of WMI and thalamic growth, highlighting the need to consider multiple dimensions of brain injury in these children. ANN NEUROL 2021;90:584-594.

Preterm White Matter Injury: A Prospective Cohort Study

To determine the incidence and risk factors of preterm white matter injury [WMI; periventricular-intraventricular hemorrhage (PIVH) and/or periventricular leukomalacia (PVL)]. Prospective cohort study. Level-3 neonatal intensive care unit. Inborn preterm neonates (n=140) delivered at <32 weeks gestation or birthweight <1500 g. Serial cranial ultrasounds were performed at postnatal ages of 3 days (±12 hour), 7 (±1) days, 21 (±3) days and 40 (±1) weeks postmenstrual age (PMA). PIVH and PVL were graded as per Volpe and De-Vries criteria, respectively. Univariate followed by multivariate analysis was done to evaluate risk factors for PIVH and PVL. The primary outcome was the incidence of preterm WMI. The secondary outcomes were evaluation of risk factors and natural course of WMI. The mean (range) gestation and birth weight of enrolled neonates were 29.7 (24-36) weeks and 1143 (440-1887) g, respectively. PIVH occurred in 25 (17.8%) neonates. PVL occurred in 34 (24.3%) neonates. None of them were grade III or IV PVL. Preterm WMI (any grade PIVH and/or PVL) occurred in 52 (37.1%) neonates. Severe PIVH (grade III) and cystic PVL occurred in 7 (5%) and 5 (3.6%) neonates, respectively. On multivariate analysis, none of the presumed risk factors were associated with PIVH. However, hemodynamically significant patent ductus arteriosus, and apnea of prematurity were significantly associated with increased risk of PVL. Significant WMI occurred only in one-third of the cohort, which is comparable to that described in literature from the developed countries.

The immune-inflammatory response of oligodendrocytes in a murine model of preterm white matter injury: the role of TLR3 activation

A leading cause of preterm birth is the exposure to systemic inflammation (maternal/fetal infection), which leads to neuroinflammation and white matter injury (WMI). A wide range of cytokines and chemokines are expressed and upregulated in oligodendrocytes (OLs) in response to inflammation and numerous reports show that OLs express several receptors for immune related molecules, which enable them to sense inflammation and to react. However, the role of OL immune response in WMI is unclear. Here, we focus our study on toll-like receptor-3 (TLR3) that is activated by double-strand RNA (dsRNA) and promotes neuroinflammation. Despite its importance, its expression and role in OLs remain unclear. We used an in vivo mouse model, which mimics inflammation-mediated WMI of preterm born infants consisting of intraperitoneal injection of IL-1β from P1 to P5. In the IL-1β-treated animals, we observed the upregulation of Tlr3, IL-1β, IFN-β, Ccl2, and Cxcl10 in both PDGFRα+ and O4+ sorted cells. This upregulation was higher in O4+ immature OLs (immOLs) as compared to PDGFRα+ OL precursor cells (OPCs), suggesting a different sensitivity to neuroinflammation. These observations were confirmed in OL primary cultures: cells treated with TLR3 agonist Poly(I:C) during differentiation showed a stronger upregulation of Ccl2 and Cxcl10 compared to cells treated during proliferation and led to decreased expression of myelin genes. Finally, OLs were able to modulate microglia phenotype and function depending on their maturation state as assessed by qPCR using validated markers for immunomodulatory, proinflammatory, and anti-inflammatory phenotypes and by phagocytosis and morphological analysis. These results show that during inflammation the response of OLs can play an autonomous role in blocking their own differentiation: in addition, the immune activation of OLs may play an important role in shaping the response of microglia during inflammation.

Umbilical cord blood cells for the treatment of preterm white matter injury: Potential effects and treatment options.

Preterm birth is a global public health problem. A large number of preterm infants survive with preterm white matter injury (PWMI), which leads to neurological deficits, and has multifaceted etiology, clinical course, monitoring, and outcomes. The principal upstream insults leading to PWMI initiation are hypoxia-ischemia and infection and/or inflammation and the key target cells are late oligodendrocyte precursor cells. Current PWMI treatments are mainly supportive, and thus have little effect in terms of protecting the immature brain or repairing injury to improve long-term outcomes. Umbilical cord blood (UCB) cells comprise abundant immunomodulatory and stem cells, which have the potential to reduce brain injury, mainly due to anti-inflammatory and immunomodulatory mechanisms, and also through their release of neurotrophic or growth factors to promote endogenous neurogenesis. In this review, we briefly summarize PWMI pathogenesis and pathophysiology, and the specific properties of different cell types in UCB. We further explore the potential mechanism by which UCB can be used to treat PWMI, and discuss the advantages of and potential issues related to UCB cell therapy. Finally, we suggest potential future studies of UCB cell therapy in preterm infants.

Clobetasol Attenuates White Matter Injury by Promoting Oligodendrocyte Precursor Cell Differentiation

Introduction: White matter injury (WMI) is the most common brain injury in preterm infants and can result in life-long neurological deficits. The main cause of WMI is damage to the oligodendrocyte precursor cells (OPC) in the brain that results in delayed myelin sheath formation, or the destruction of existing myelin sheaths. OPC undergo highly regulated and strictly timed developmental changes that result in their transformation to mature oligodendrocytes capable of myelin production. Objective: Studies have shown that clobetasol strongly promotes differentiation of OPC into myelin sheaths. Therefore, we hypothesized that clobetasol may be a therapeutic option for the treatment of preterm WMI. Methods: We induced a WMI rat model and observed white matter damage under an optical microscope. Rats subjected to WMI were injected intraperitoneally with clobetasol (2 or 5 mg/kg daily) from day 1 to day 5 in the early treatment groups, or from day 6 to day 10 in the late treatment groups. After 17 days, the rats were sacrificed and the expression of myelin basic protein (MBP) was visualized using immunofluorescence. In addition, we evaluated myelin sheath formation using electron microscopy. The rats were also subjected to the suspension test, ramp test, and open field test to evaluate neurobehavioral functions. Results: A rat model of WMI was successfully induced. It was found that clobetasol significantly induced MBP expression and myelin sheath formation and improved neurobehavioral function in the rats subjected to WMI. Conclusions: Our results indicate that clobetasol attenuates WMI by promoting OPC differentiation, and it may be an effective therapeutic agent for the treatment of preterm WMI.