CD133 cells from human umbilical cord blood reduce cortical damage and promote axonal growth in neonatal rat organ co-cultures exposed to hypoxia

To evaluate the effect of CD133⁺ cells (endothelial progenitor cells) on the hypoxia-induced suppression of axonal growth of cortical neurons and the destruction of blood vessels (endothelial cells), we used anterograde axonal tracing and immunofluorescence in organ co-cultures of the cortex and the spinal cord from 3-day-old neonatal rats. CD133⁺ cells prepared from human umbilical cord blood were added to the organ co-cultures after hypoxic insult, and axonal growth, vascular damage and apoptosis were evaluated. Anterograde axonal tracing with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate was used to analyze axonal projections from the cortex to the spinal cord. Immunolabeling co-cultured tissues of the cortex and the spinal cord were used to investigate the effect of CD133⁺ cells on the survival of blood vessels and apoptosis in the brain cortex. Hypoxia remarkably suppressed axonal growth in organ co-cultures of the cortex and the spinal cord, and this suppression was significantly restored by the addition of CD133⁺ cells. CD133⁺ cells also reduced the hypoxia-induced destruction of the cortical blood vessels and apoptosis. CD133⁺ cells had protective effects on hypoxia-induced injury of neurons and blood vessels of the brain cortex in vitro. These results suggest that CD133⁺ cell transplantation may be a possible therapeutic intervention for perinatal hypoxia-induced brain injury.     

Neutrophil dynamics,plasticity and function in acute neurodegeneration following neonatal hypoxia–ischemia

Neonatal encephalopathy following hypoxia–ischemia (HI) is a major cause of long-term morbidity and mortality in children. Even though HI-induced neuroinflammation, involving infiltration of peripheral immune cells into the CNS has been associated with disease pathogenesis, the specific role of neutrophils is highly debated. Due to immaturity of the neonatal immune system, it has been assumed that neutrophils are less clinically relevant in neonatal HI-induced brain injury. In the present study, we demonstrate that neutrophils are rapidly activated in the neonatal brain after exposure to experimental HI, revealed by an enhanced proportion of CD86⁺ cells and an increased expression of CD11b compared to splenic and blood neutrophils. Furthermore, production of reactive oxygen species and the proportion of hyperactivated/aged (CXCR4⁺CD62L⁻) cells was enhanced in brain compared to peripheral neutrophils. Delayed neutrophil depletion, initiated 12 h after HI resulted in reduced cellular neurodegeneration, associated with reduced micro- and astroglial activation. In the present study, we uncovered a new complex switch of the phenotype in brain neutrophils, which may offer new possibilities for the development of selective therapeutic approaches by modulation of neutrophils in the early post-hypoxic disease phase.     

Mesenchymal stem cell treatment after neonatal hypoxic-ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration

Birth asphyxia is a frequent cause of perinatal morbidity and mortality and treatment options are very limited. Our aim was to determine the effects of treatment with bone marrow-derived mesenchymal stem cells (MSC) after neonatal hypoxic-ischemic brain injury (HI).Nine-day old mice were exposed to cerebral HI and endogenous cell proliferation was determined by BrdU-incorporation. Maximal endogenous cell proliferation, indicative for a trophic milieu, was observed at 3 days after HI. MSC transplantation at this time point decreased neuronal and oligodendrocyte loss when determined 21 days after HI by 42% and 31%, respectively. MSC treatment enhanced BrdU-incorporation in the ischemic hemisphere mainly in cells of recipient origin. The percentage of recently divided neurons and oligodendrocytes in hippocampus and cortex was increased after MSC transplantation. MSC treatment reduced the percentage of cortical and increased the percentage of hippocampal BrdU⁺-astrocytes. The percentage of BrdU⁺-microglia decreased after MSC treatment. Motoric behavior in the cylinder rearing test at 10 and 21 days after HI was significantly improved by MSC treatment 3 days after the insult. Moreover, even when treatment was started at 10 days after HI, there was a significant reduction in lesion size and improvement of behavioral outcome.Our data show that MSC treatment after neonatal HI brain damage improved functional outcome, reduced lesion volume, increased differentiation of recently divided cells towards neurons and oligodendrocytes and decreased proliferating inflammatory cells. We propose that MSC transplantation is a powerful treatment to improve behavioral outcome and cerebral lesion volume after neonatal brain damage via stimulation of endogenous repair processes.     

Mobilization of CD133+CD34− cells in healthy individuals following whole‐body acupuncture for spinal cord injuries

Acupuncture can alleviate symptoms of spinal cord injuries (SCI). The underlying mechanism, however, is unknown. We hypothesized that stem cells could be mobilized by acupuncture. Therefore, we enrolled 14 healthy study participants using acupuncture points for the treatment of SCI. The frequency of CD133 and CD34 cells in peripheral blood and the serum concentrations of matrix metalloproteinase (MMP)‐9, brain‐derived neurotrophic factor (BDNF), nerve growth factor (NGF), and interleukin‐6 were determined before and after acupuncture (<1 hr, 24 hr, and 48 hr). CD133⁺34^? cells were doubled 48 hr after acupuncture, with concomitant decreases in BDNF and MMP‐9 levels. Interleukin‐6 remained below detectable levels, eliminating a stress‐induced cell release. Individuals acupunctured on control counterpoints showed no changes in CD133⁺ cells. Our results indicate that acupuncture for SCI can mobilize human CD133⁺34^? cells. © 2009 Wiley‐Liss, Inc.     

Human Umbilical Cord Blood CD45<Superscript>+</Superscript> Pan-Hematopoietic Cells Induced a Neurotherapeutic Effect in Mice with Traumatic Brain Injury: Immunophenotyping,Comparison of Maternal and Neonatal Parameters,and Immunomodulation

Human umbilical cord blood (HUCB) transplantation has become an alternative cell therapy for hematological and oncological malignancies in the clinic and is considered for neurological disorders. The heterogeneity in the content of the different stem and progenitor cells composing HUCB mononuclear cells (MNC) may influence their engraftment and neurotherapeutic effect. We hypothesized that CD45 pan-hematopoietic marker expression is heterogeneous in MNC, and therefore, CD45⁺ subpopulation enrichment for neurotherapy may provide a tool to overcome cellular variance in different HUCB units. We employed an immunomagnetic separation method to isolate and characterize HUCB CD45⁺ pan-hematopoietic subpopulation and to investigate whether the vaginal or cesarean deliveries influence their neurotherapeutic effect in a traumatic brain injury (TBI) mouse model. Adult C57BL/6J male mice were subjected to moderate TBI and intravenously xenotransplanted with 1?×?10⁶ CD45⁺ cells derived from either vaginal or cesarean HUCB units. A large heterogeneity in the expression of CD45 marker in MNC, both in vaginal and cesarean HUCB units, was found, regardless of the number of live births. A higher expression of hematopoietic markers was found in the CD45⁺ subpopulation while low expressional levels of typical mesenchymal markers were detected. Neurotherapeutic effects, evaluated with an established neurological severity score and novel object recognition test, indicated improved functional motor and memory recovery and found independent of delivery type. Cytokine analysis in extracts of TBI brain cortices indicated an acute immunomodulatory effect by HUCB CD45⁺ subpopulation upon xenotransplantation. These results may provide insights to CD45 marker as a predictor of HUCB units’ quality for neurotherapy in TBI.     

Erythropoietin reduces white matter damage in two-day-old rats exposed to hypoxic/ischemia injury

Objective: The aim of the study was to investigate whether erythropoietin (EPO) could protect against white matter damage (WMD) in a preterm equivalent neonatal rat hypoxic-ischemia (HI) model.

Methods: 113 two-day-old male rat pups were divided randomly into three groups: sham-treated, bilateral carotid artery occlusion (BCAO)-treated, BCAO + EPO-treated group. EPO (50 U/10 g body weight) or saline alone was administered intraperitoneally immediately after BCAO surgery. Body weight, brain weight, brain water content, and expression of myelin basic protein (MBP) were assessed at day 1, 3, 7, and 14 after HI insult. Morris water-maze (MWM) test was used to assess neurological behavior from day 31 to 35 after HI insult.

Results: Body weights of BCAO + EPO group were greater than those of BCAO group rats (P < 0.05). Specifically, at day 3 and 7 after HI, brain weights of BCAO + EPO-treated rats were higher than BCAO-treated animals (P < 0.05); at day 7 and 14 after HI, MBP of BCAO + EPO-treated rats were higher than BCAO-treated animals (P < 0.05). Similarly, the brain water content at day 3 after HI in BCAO + EPO-treated rats was lower than BCAO-treated animals (P < 0.05). The body weight, brain weight, brain water content, and MBP expression in BCAO + EPO-treated group were comparable to those in the sham-treated group. Spatial learning and memory of BCAO + EPO-treated rats was significantly improved over the BCAO-treated group and was comparable to the sham-operated animals.

Conclusion: EPO treatment could be a potential intervention in treating WMD for preterm infants.     

Therapeutic effects of human mesenchymal and hematopoietic stem cells on rotenone‐treated parkinsonian mice

To appreciate the potential applications of stem cell technology in neurodegenerative diseases, including Parkinson's disease (PD), it is important to understand the characteristics of the various types of stem cells. In this study, we designed a set of experiments to compare the ability of three types of human stem cells—mesenchymal stem cells (MSCs), bone marrow CD34⁺ cells (BM), and cord blood CD34⁺ cells (CB)—using rotenone‐treated NOD/SCID mice. Rotenone was orally administered once daily at a dose of 30 mg/kg for 56 days to induce a parkinsonian phenotype. Intravenous delivery of CB into rotenone‐treated mice was slightly more beneficial than that of MSCs or BM according to both histological and behavioral analyses. Human nucleus (hNu)⁺ cells, which are a specific marker of human cells, were observed in the striatum of rotenone‐treated mice transplanted with stem cells. These hNu⁺ cells expressed tyrosine hydroxylase (TH). Additionally, α‐synuclein⁺/TH⁺ cells in the substantia nigra pars compacta decreased significantly following stem cell transplantation. Immunohistochemical analysis also revealed that chronic exposure to rotenone decreased glial cell line‐derived neurotrophic factor immunoreactivity and that the reduction was improved by each stem cell transplantation. Gene expression analyses revealed that MSCs, BM, and CB expressed several neurotrophic factors. These results suggest that the beneficial effects of intravenous delivery of stem cells into rotenone‐treated mice may result not only from a neurotrophic effect but also from endogenous brain repair mechanisms and the potential of intravenous delivery of stem cells derived from an autologous source for clinical applications in PD. © 2012 Wiley Periodicals, Inc.     

Blood vessels expressing CD90 in human and rat brain tumors

Blood vessels in brain tumors, particularly glioblastomas, have been shown to express CD90. CD90⁺ cells in and around blood vessels in cancers including brain tumors have been identified as endothelial cells, cancer stem cells, fibroblasts or pericytes. In this study, we aimed to determine the nature or type(s) of cells that express CD90 in human brain tumors as well as an experimental rat glioma model by double immunofluorescence staining. The majority of CD90⁺ cells in human glioblastoma tissue expressed CD31, CD34 and von Willebrand factor, suggesting that they were endothelial cells. Vasculatures in a metastatic brain tumor and meningioma also expressed CD90. CD90⁺ cells often formed glomeruloid structures, typical of angiogenesis in malignant tumors, not only in glioblastoma but also in metastatic tumors. Some cells in the middle and outer layers of the vasculatures expressed CD90. Similar results were obtained in the rat glioma model. There were cells expressing both α‐smooth muscle actin and CD90 in the middle layer of blood vessels, indicating that smooth muscle cells and/or pericytes may express CD90. CD90⁺ vasculatures were surrounded by tumor‐associated macrophages (TAMs). Thus, in addition to endothelial cells, some other types of cells, such as smooth muscle cells, pericytes and fibroblasts constituting the vasculature walls in brain tumors expressed CD90. Because CD90 has been shown to interact with integrins expressed by circulating monocytes, CD90 might be involved in angiogenesis through recruitment and functional regulation of TAMs in tumors. CD90⁺ vasculatures may also interact with tumor cells through interactions with integrins. Because CD90 was not expressed by vasculatures in normal brain tissue, it might be a possible therapeutic target to suppress angiogenesis and tumor growth.     

人脐带间充质干细胞移植治疗大鼠创伤性脑损伤

背景：脐带间充质干细胞体内移植治疗脑损伤的效果目前尚较少见报道。 目的：观察人脐带间充质干细胞移植对大鼠液压冲击脑损伤的治疗作用。 方法：从新生儿脐带中分离、培养间充质干细胞。制作中度打击大鼠脑损伤模型。实验分为4组：①脐带间充质干细胞移植组：损伤后原位移植脐带间充质干细胞。②对照组：损伤后原位注射等量DMEN/F12培养基。③单纯损伤组：仅施行损伤。④假损伤组：仅切开头皮及颅骨,不实施机械性损伤。 结果与结论：脐带间充质干细胞移植后1~3周,动物神经功能评分较对照组明显改善;4周后,各组动物神经功能评分均恢复正常。免疫组织化学检测表明少部分移植细胞表达神经元特异性烯醇化酶,胶质纤维酸性蛋白。与对照组相比,移植组损伤区血管内皮生长因子表达明显增加,凋亡细胞减少。提示脐带充间质干细胞脑内移植有助于促进创伤性脑损伤后的早期功能恢复,这种治疗效果是通过刺激宿主细胞分泌血管内皮生长因子,增加损伤区微血管密度,抑制宿主细胞凋亡等实现的。     

Temporal kinetics of macrophage polarization in the injured rat spinal cord

Local activated macrophages derived from infiltrating monocytes play an important role in the damage and repair process of spinal cord injury (SCI). The present study investigates the dynamic change of classically activated proinflammatory (M1) and alternatively activated anti‐inflammatory (M2) cells in a rat model with contusive SCI by flow cytometry (FCM) and immunohistochemistry. The macrophage subsets were immunophenotyped by using antibodies against cluster of differentiation (CD)?68, C‐C chemokine receptor type 7 (CCR7), CD163, and arginase 1 (Arg1). The CD68⁺CD163^– and CD68⁺CCR7⁺ cells were determined to be M1 subsets, whereas the CD68⁺CD163⁺ and CD68⁺Arg1⁺ cell subpopulations represented M2 cells. The subsets of macrophages in the injured spinal cord at 1, 3, 5, 7, 14, and 28 days postinjury (dpi) were examined. In the sham‐opened spinal cord, few M1 or M2 cells were found. After SCI, the phenotypes of both M1 and M2 cells were rapidly induced. However, M1 cells were detected and maintained at a high level for up to 28 dpi (the longest time evaluated in this study). In contrast, M2 cells were transiently detected at high levels before 7 dpi and returned to preinjury levels at 14 dpi. These results indicate that M1 cell response is rapidly induced and sustained, whereas M2 induction is transient after SCI in rat. Increasing the fraction of M2 cells and prolonging their residence time in the injured local microenvironment is a promising strategy for the repair of SCI. © 2015 Wiley Periodicals, Inc.     

Transplantation of human umbilical cord blood mesenchymal stem cells to treat a rat model of traumatic brain injury

In the present study, human umbilical cord blood mesenchymal stem cells were injected into a rat model of traumatic brain injury via the tail vein. Results showed that 5-bromodeoxyuridine-labeled cells aggregated around the injury site, surviving up to 4 weeks post-transplantation. In addition, transplantation-related death did not occur, and neurological functions significantly improved. Histological detection revealed attenuated pathological injury in rat brain tissues following human umbilical cord blood mesenchymal stem cell transplantation. In addition, the number of apoptotic cells decreased. Immunohistochemistry and in situ hybridization showed increased expression of brain-derived neurotrophic factor, nerve growth factor, basic fibroblast growth factor, and vascular endothelial growth factor, along with increased microvessel density in surrounding areas of brain injury. Results demonstrated migration of transplanted human umbilical cord blood mesenchymal stem cells into the lesioned boundary zone of rats, as well as increased angiogenesis and expression of related neurotrophic factors in the lesioned boundary zone.     

大鼠脐带源间充质干细胞的分离及生物学性状**☆

背景：关于大鼠骨髓来源的间充质干细胞用于移植免疫耐受及进行组织修复的研究很多,但尚无脐带来源间充质干细胞的相关研究。 目的：建立从大鼠脐带分离间充质干细胞的方法,并观察其生物学性状。 方法：大鼠脐带经酶消化和组织块培养两种方法进行分离培养,于DMEM-LG培养基中培养,倒置显微镜观察细胞形态,细胞计数绘制生长曲线,流式细胞仪测定细胞周期及细胞表型,免疫组织化学染色检测其体外诱导成脂肪和成骨分化的能力。 结果与结论：两种方法均能成功地从大鼠脐带中获得大量的间充质干细胞：原代培养显示,胶原酶消化法比组织块培养法的效率更高,大约10 d就可以进行传代,而组织块培养法要14 d才能传代;传代扩增两者之间没有差别。免疫表型分析显示,大鼠脐带源细胞表达黏附分子和基质细胞标记CD90、CD106,不表达造血细胞标记CD34、CD45。体外诱导实验证实,大鼠脐带间充质干细胞具有成脂肪和成骨分化的能力。     

Early-life fluoxetine exposure reduced functional deficits after hypoxic-ischemia brain injury in rat pups

Neuroplasticity after perinatal programming may allow for neuroprotection against hypoxic-ischemia (HI) at birth. The cAMP response element-binding protein (CREB) is a key mediator of stimulus-induced nuclear responses that underlie survival, memory and plasticity of nervous system. Chronic treatment of fluoxetine, a selective serotonin reuptake inhibitor, can upregulate CREB activation in the hippocampus. We examined whether fluoxetine administration before HI may protect against neonatal HI brain injury through CREB-mediated mechanisms. We found that low-dose fluoxetine pretreatment in a neonatal HI brain injury model significantly reduced functional deficits at adulthood. The neuroprotective mechanisms were associated with increased CREB phosphorylation and increased brain-derived neurotrophic factor and synapsin I mRNA expression in the hippocampus. Neurogenesis also increased because of greater precursor cell survival in the hippocampal dentate gyrus. These findings suggest that functional deficits after HI in the developing brain can be reduced by agents that enhance neural plasticity and neurogenesis through CREB activation.     

Resident microglia,rather than blood‐derived macrophages,contribute to the earlier and more pronounced inflammatory reaction in the immature compared with the adult hippocampus after hypoxia‐ischemia

The mechanisms of neuronal injury after hypoxia–ischemia (HI) are different in the immature and the adult brain, but microglia activation has not been compared. The purpose of this study was to phenotype resident microglia and blood‐derived macrophages in the hippocampus after HI in neonatal (postnatal day 9, P9) or adult (3 months of age, 3mo) mice. Unilateral brain injury after HI was induced in Cx3cr1^GFP/+Ccr2^RFP/+ male mice on P9 (n = 34) or at 3mo (n = 53) using the Vannucci model. Resident microglia (Cx3cr1‐GFP+) proliferated and were activated earlier after HI in the P9 (1–3 days) than that in the 3mo hippocampus, but remained longer in the adult brain (3–7 days). Blood‐derived macrophages (Ccr2‐RFP+) peaked 3 days after HI in both immature (P9) and adult (3mo) hippocampi but were twice as frequent in adult brains, 41% vs. 21% of all microglia/macrophages. CCL2 expression was three times higher in the P9 hippocampi, indicating that the proinflammatory response was more pronounced in the immature brain after HI. This corresponded well with the higher numbers of galectin‐3‐positive resident microglia in the P9 hippocampi, but did not correlate with CD16/32‐ or CD206‐positive resident microglia or blood‐derived macrophages. In conclusion, resident microglia, rather than infiltrating blood‐derived macrophages, proliferate and are activated earlier in the immature than in the adult brain, but remain increased longer in the adult brain. The inflammatory response is more pronounced in the immature brain, and this correlate well with galectin‐3 expression in resident microglia. GLIA 2015;63:2220–2230     

Human umbilical cord blood stem cells and brain-derived neurotrophic factor for optic nerve injury:a biomechanical evaluation

Treatment for optic nerve injury by brain-derived neurotrophic factor or the transplantation of human umbilical cord blood stem cells has gained progress, but analysis by biomechanical indicators is rare. Rabbit models of optic nerve injury were established by a clamp. At 7 days after injury, the vitreous body received a one-time injection of 50 μg brain-derived neurotrophic factor or 1 × 106 human umbilical cord blood stem cells. After 30 days, the maximum load, maximum stress, maximum strain, elastic limit load, elastic limit stress, and elastic limit strain had clearly improved in rabbit models of optical nerve injury after treatment with brain-derived neurotrophic factor or human umbilical cord blood stem cells. The damage to the ultrastructure of the optic nerve had also been reduced. These findings suggest that human umbilical cord blood stem cells and brain-derived neurotrophic factor effectively repair the injured optical nerve, improve biomechanical properties, and contribute to the recovery after injury.     

Temporal kinetics of CD8+CD28+ and CD8+CD28− T lymphocytes in the injured rat spinal cord

This study aims to explore the temporal changes of cytotoxic CD8⁺CD28⁺ and regulatory CD8⁺ CD28⁻ T‐cell subsets in the lesion microenvironment after spinal cord injury (SCI) in rats, by combination of immunohistochemistry (IHC) and flow cytometry (FCM). In the sham‐opened spinal cord, few CD8⁺ T cells were found. After SCI, the CD8⁺ T cells were detected at one day post‐injury (dpi), then markedly increased and were significantly higher at 3, 7, and 14 dpi compared with one dpi (p < 0.01), the highest being seven dpi. In CD8⁺ T cells, more than 90% were CD28⁺, and there were only small part of CD28⁻ ( < 10%). After 14 days, the infiltrated CD8⁺ T cells were significantly decreased, and few could be found in good condition at 21 and 28 dpi. Annexin V and propidium iodide (PI) staining showed that the percentages of apoptotic/necrotic CD8⁺ cells at 14 dpi and 21 dpi were significantly higher than those of the other early time‐points (p < 0.01). These results indicate that CD8⁺ T cells could rapidly infiltrate into the injured spinal cords and survive two weeks, however, cytotoxic CD8⁺ T cells were dominant. Therefore, two weeks after injury might be the “time window” for treating SCI by prolonging survival times and increasing the fraction of CD8⁺ regulatory T‐cells. © 2016 Wiley Periodicals, Inc.     

Monocytes are essential for the neuroprotective effect of human cord blood cells following middle cerebral artery occlusion in rat

Systemic administration of human umbilical cord blood (HUCB) mononuclear cells (MNC) following middle cerebral artery occlusion (MCAO) in the rat reduces infarct size and, more importantly, restores motor function. The HUCB cell preparation is composed of immature T-cells, B-cells, monocytes and stem cells. In this study we examined whether the beneficial effects of HUCB injection were attributable to one of these cell types. Male Sprague Dawley rats underwent permanent MCAO followed 48 h later by intravenous administration of HUCB MNC preparations depleted of either CD14 ⁺ monocytes, CD133 ⁺ stem cells, CD2 ⁺ T-cells or CD19 ⁺ B cells. Motor function was measured prior to MCAO and 30 days post-stroke. When CD14 ⁺ monocytes were depleted from the HUCB MNC, activity and motor asymmetry were similar to the MCAO only treated animals. Monocyte depletion prevented HUCB cell treatment from reducing infarct size while monocyte enrichment was sufficient to reduce infarct size. Administration of monocyte-depleted HUCB cells did not suppress Iba1 labeling of microglia in the infarcted area relative to treatment with the whole HUCB preparation. These data demonstrate that the HUCB monocytes provide the majority of the efficacy in reducing infarct volume and promoting functional recovery.     

Contribution of Histologic Chorioamnionitis and Fetal Inflammatory Response Syndrome to Increased Risk of Brain Injury in Infants With Preterm Premature Rupture of Membranes

BackgroundTo determine the association of histologic chorioamnionitis (HCA) and fetal inflammatory response syndrome (FIRS) with brain injuries in infants born to mothers with preterm premature rupture of membranes.MethodsA total of 103 singleton infants born to mothers with preterm premature rupture of membranes were enrolled. The placental inflammation was confirmed by HCA, and FIRS was defined in fetuses with preterm labor and an elevation of the fetal plasma interleukin-6 concentration. Examination of brain images was conducted to confirm the existence of brain injuries. Based on placental HCA and umbilical cord blood interleukin-6 level, all patients were divided into three groups: HCA⁻FIRS⁺, HCA⁺FIRS⁻, and HCA⁺FIRS⁺.ResultsAmong all infants with preterm premature rupture of membranes, 53.40% were exposed to HCA, 20.38% experienced FIRS, and the overall incidence of brain injuries was 38.83%. The incidence of brain injury in HCA⁻FIRS⁺, HCA⁺FIRS⁻, and HCA⁺FIRS⁺ groups were 20.83%, 41.18%, and 76.19%, respectively. HCA at the advanced grades and stages was associated with increased risk of brain injury. Umbilical cord blood levels of interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-α), and granulocyte-colony stimulating factor (G-CSF) in premature infants with brain injuries were significantly higher than in those without brain injuries. Infants diagnosed with both HCA and FIRS showed significantly higher levels of IL-8, TNF-α, and G-CSF than those with HCA alone.ConclusionsPreterm infants exposed to severe chorioamnionitis had an increased risk of brain injury. IL-6, IL-8, TNF-α, and G-CSF in cord blood were associated with brain injuries in preterm infants and may be used as extradiagnostic criteria.     

Differential myelinogenic capacity of specific developmental stages of the oligodendrocyte lineage upon transplantation into hypomyelinating hosts

The capacity of oligodendrocytes (OLs) and their progenitors to migrate, proliferate, and differentiate in vivo was evaluated by transplanting highly enriched populations of sequential stage of the OL lineage (A2B5⁺ O4^?, O4⁺ GalC^?, and GalC⁺) into the telencephalon of the hypomyelinating mouse, shiverer. The shiverer mouse neither expresses the major myelin basic protein (MBP) nor makes normal myelin due to a large deletion in the gene for MBP. Thirty days after transplantation, serial 225 μm sections of the host brain were immunostained with antiserum to MBP and analyzed by confocal microscopy. The presence of MBP⁺ patches of myelin in the otherwise MBP^? host brain allowed a retrospective analysis of the myelinogenic activity of the transplanted progenitors cells. Both the extent of MBP⁺ myelin and the location of MBP⁺ structures relative to the initial site of cell deposition were highly dependent on the developmental stage of the transplanted cells. Specifically, A2B5⁺ O4^? OL progenitors migrated distances of ≥ 600 μm and produced MBP⁺ patches in nearly every slice of the host brain. An average of over 250 separate patches were found per host brain, some of which had cross-sectional areas of > 250,000 μm² containing as many as 60 MBP⁺ OL cell bodies, and with densities of myelination rivaling that of normal brain. In marked contrast, transplantation of O4⁺ GalC^? cells produced only small (1,000–25,000 μm²), scattered (25–40 per brain) patches of MBP⁺ myelin containing one to five cell bodies, all of which were within 50 μm of the needle track or the nearest ventricular surface. GalC⁺ cells produced MBP⁺ myelin at a level similar to that of O4⁺ CalC^? cells. These data suggest that the developmental transition of OL progenitors from the O4^? to the O4⁺ pheno-type is accompanied by a dramatic reduction in the innate capacity of the cells to migrate and survive in vivo. The use of developmentally identified, enriched populations of OL progenitor cells offers the opportunity for more precise analyses of transplantation and remyelination behavior, and relates to clinically relevant studies indicating that contaminant cell types can seriously interfere with the stable integration of donor tissue into the host. © 1993 Wiley-Liss, Inc.