Differentiation of human fetal mesenchymal stem cells into cells with an oligodendrocyte phenotype.

The potential of mesenchymal stem cells (MSC) to differentiate into neural lineages has raised the possibility of autologous cell transplantation as a therapy for neurodegenerative diseases. We have identified a population of circulating human fetal mesenchymal stem cells (hfMSC) that are highly proliferative and can readily differentiate into mesodermal lineages such as bone, cartilage, fat and muscle. Here, we demonstrate for the first time that primary hfMSC can differentiate into cells with an oligodendrocyte phenotype both in vitro and in vivo. By exposing hfMSC to neuronal conditioned medium or by introducing the pro-oligodendrocyte gene, Olig-2, hfMSC adopted an oligodendrocyte-like morphology, expressed oligodendrocyte markers and appeared to mature appropriately in culture. Importantly we also demonstrate the differentiation of a clonal population of hfMSC into both mesodermal (bone) and ectodermal (oligodendrocyte) lineages. In the developing murine brain transplanted hfMSC integrated into the parenchyma but oligodendrocyte differentiation of these naïve hfMSC was very low. However, the proportion of cells expressing oligodendrocyte markers increased significantly (from 0.2% to 4%) by preexposing the cells to differentiation medium in vitro prior to transplantation. Importantly, the process of in vivo differentiation occurred without cell fusion. These findings suggest that hfMSC may provide a potential source of oligodendrocytes for study and potential therapy.

Antenatal infection/inflammation and fetal tissue injury.

There is a clear association between antenatal infection/inflammation and preterm labour, with intrauterine infection complicating up to one third of preterm deliveries. In addition to this, there is now accumulating evidence that intrauterine infection and inflammation can lead to the development of a systemic inflammatory response in the fetus and subsequent tissue injury. The fetal inflammatory response is characterized by funisitis, high levels of pro-inflammatory cytokines in the amniotic fluid and cord blood, and systemic immune activation. This review discusses the evidence for this process and focuses on the clinical and experimental data supporting the hypothesis that these inflammatory processes contribute to brain and lung injury in the newborn.

Detection of vascular expression of E-selectin in vivo with MR imaging.

PURPOSE: To develop a contrast agent for targeting E-selectin expressed on activated vascular endothelium and to evaluate detection of the agent with magnetic resonance (MR) imaging in an in vivo mouse model of inflammation. MATERIALS AND METHODS: All animal experiments were approved according to animal welfare and local ethics committee regulations. An anti-murine E-selectin F(ab')2 monoclonal antibody, MES-1, was conjugated with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles. Flow cytometry, Perl Prussian blue staining for iron, and MR imaging were performed by using Chinese hamster ovary (CHO) cells expressing mouse E-selectin to detect binding of the conjugate in vitro, and a mouse model of contact hypersensitivity to oxazolone in the ear was used to investigate the in vivo characteristics of the MES-1-USPIO. Serial imaging was performed by using a 9.4-T MR imaging system with a custom receive-only coil. Tissue slices were stained to define distribution of E-selectin expression and localization of the MES-1-USPIO conjugate. RESULTS: MES-1-USPIO was shown to bind to CHO cells expressing mouse E-selectin in vitro. After injection of MES-1-USPIO in vivo, distinct changes in R2 relaxation rate (1/T2) characteristics were detected in inflamed ears when they were compared with control ears. Histologic analysis confirmed the vascular endothelial distribution of MES-1-USPIO. CONCLUSION: E-selectin expression in vivo can be selectively and directly imaged noninvasively with MR. This has the potential to be useful in the study of inflammatory disease.

Perinatal applications of neural stem cells.

The brain, unlike many tissues, has a limited capacity for self-repair and so there has been great interest in the possibility of transplanting neural cells to replace those lost through injury or disease. Encouraging research in humans is already underway examining the possibility of neural cell replacement in adult neurodegenerative conditions such as Parkinson's disease and Huntington disease. In addition, experiments exploring neural stem cell replacement in rodent models of acute stroke, demyelination and spinal cord injury have demonstrated functional improvements in treated animals. When considering perinatal neural stem cell therapy, it should not be overlooked that the immature, developing brain might provide a more favourable environment for stem cell integration. However, considerable advances need to be made both in understanding the basic biology of neural stem cells, including the instructive signals that determine their proliferation and differentiation, and in characterising their responses when transplanted in a damaged or diseased area of the brain.

Increased lung water and tissue damage in bronchopulmonary dysplasia.

OBJECTIVES: To test the hypothesis that high and asymmetrical water content persists in infants with bronchopulmonary dysplasia (BPD) and that this is associated with nonuniform lung damage. STUDY DESIGN: Magnetic resonance imaging was used to assess lung water content in 20 infants and tissue injury in 35 infants of 23 to 33 weeks' gestational age (15 with severe BPD, 13 with mild BPD, and 7 without BPD). Relative proton density provided an index of water content and distribution. The location and extent of focal densities and cyst-like appearances indicating lung damage were defined. RESULTS: Proton density was significantly higher in dependent regions. Average proton density, proton density gradient, and severity of lung damage were greater in infants with severe BPD. Indicators of damage were greatest in dorsal lung regions. BPD was associated with a higher lung water burden and gravity-dependent atelectasis and/or alveolar flooding. Lesions were more common in dorsal lung regions in infants with severe lung damage. CONCLUSIONS: Infants with BPD have increased lung water and are susceptible to gravity-induced collapse and/or alveolar flooding in the dependent lung. Focal tissue damage appears to be distributed inhomogenously.

T2 relaxation values in the developing preterm brain.

BACKGROUND AND PURPOSE: MR imaging is increasingly used to assess maturation and disease in the preterm brain. Knowledge of the changes in T2 values with increasing postmenstrual age (PMA) will aid image interpretation and help in the objective assessment of maturation and disease of the brain in infants. The aim of this study was to obtain T2 values in the preterm brain from 25 weeks' gestational age (GA) until term-equivalent age in infants who had normal neurodevelopmental findings at a minimum corrected age of 1 year. METHODS: The study group consisted of 18 preterm infants, born at 33 weeks' GA or sooner. The median GA of the infants at birth was 27 weeks (range, 23-33 weeks), and the median PMA at imaging was 31 weeks (range, 25-41 weeks). T2 measurements were obtained using a 1.0-T MR system and a four-echo pulse sequence (TR/TE, 2500/ 30, 60, 110, and 600). T2 values were measured in the thalami, lentiform nuclei, frontal white matter, occipital white matter, and central white matter at the level of the centrum semiovale. RESULTS: A significant negative linear correlation between T2 values and PMA was demonstrated in the lentiform nuclei (P =.003), frontal white matter (P <.0001), occipital white matter (P <.0001), and central white matter at the level of the centrum semiovale (P <.0001). T2 values were not significantly reduced with increasing PMA in the thalami (P =.06). CONCLUSION: T2 values decrease with increasing PMA in the preterm brain.

Diffusion-weighted imaging of the brain in preterm infants with focal and diffuse white matter abnormality.

OBJECTIVE: The most common finding on magnetic resonance imaging (MRI) of the brain in preterm infants at term-equivalent age is diffuse excessive high signal intensity (DEHSI) in the white matter. It is unclear whether DEHSI represents a biological abnormality. This study used diffusion-weighted imaging (DWI) to compare apparent diffusion coefficient (ADC) values in DEHSI with infants with normal imaging and those with overt brain damage to determine whether DEHSI shows the diffusion characteristics of normal or abnormal tissue. METHODS: MRI, using conventional and diffusion-weighted imaging (DWI), was performed in 50 preterm infants at term-equivalent age using a 1.5 Tesla MR scanner. The infants were divided into 3 groups on the basis of their MRI results: 1) normal white matter, 2) DEHSI, or 3) overt white matter pathology. ADC values were measured in the frontal, central, and posterior white matter at the level of the centrum semiovale. ADC values in the 3 groups of preterm infants were compared using a 1-way analysis of variance with a Bonferroni test for multiple comparisons. RESULTS: ADC values were significantly higher in infants with DEHSI and infants with overt white matter pathology than in infants with normal white matter. There was no significant difference between ADC values in infants with DEHSI and those with overt white matter pathology. CONCLUSIONS: This study provides objective evidence that DEHSI represents diffuse white matter abnormality.

Magnetic resonance imaging of lung water content and distribution in term and preterm infants.

An increase in lung liquid may contribute to respiratory disease in preterm infants. Uneven distribution of lung liquid may cause heterogeneity in the lung disease seen in these infants. We used magnetic resonance imaging to investigate lung water content and distribution in 16 preterm (24-31 weeks) and 9 term infants in the first week of life. Images of lung parenchyma were examined and relative proton density quantified to give an index of lung water. Lung water content and distribution were compared between preterm and term infants, and in preterm infants regional signal distribution between dependent and nondependent lung on T1 weighted images was also compared after turning between prone and supine positions. Relative proton density was higher in preterm than in term lung (p < 0.008) and greater in dependent than in nondependent regions, particularly in the preterm (p < 0.001). Repositioning preterm infants rapidly redistributed signal intensities, with more even distribution lying prone than supine (p < 0.001). Small, low-signal regions were seen in the lung parenchyma in preterm but not in term infants, which may indicate peribronchial fluid or overdistension of compliant lung units. We conclude that lung water content is higher in preterm than in term infants and is associated with gravity-related changes consistent with dependent atelectasis.

Neural stem cells.

Neural stem cells (NSCs) have the ability to self-renew, and are capable of differentiating into neurones, astrocytes and oligodendrocytes. Such cells have been isolated from the developing brain and more recently from the adult central nervous system. This review aims to provide an overview of the current research in this evolving area. There is now increasing knowledge of the factors controlling the division and differentiation of NSCs during normal brain development. In addition, the cues for differentiation in vitro, and the possibility of transdifferentiation are reviewed. The discovery of these cells in the adult brain has encouraged research into their role during neurogenesis in the normal mature brain and after injury. Lastly other sources of neural precursors are discussed, and the potential for stem cells to be used in cell replacement therapy for brain injury or degenerative brain diseases with a particular emphasis on cerebral ischaemia and Parkinson's disease.