Similar Characteristics of Endometrial and Endometriotic Epithelial Cells.

Epithelial-mesenchymal transition (EMT) is characterized by the loss of epithelial and acquisition of mesenchymal cell characteristics. Our aim was to assess the epithelial phenotype in the pathogenesis of endometriosis with epithelial and mesenchymal markers. We used 2 structural (keratin-18, -19 [K18, K19]), 1 membrane-associated (mucin-1 [MUC1]), and 2 mesenchymal proteins (vimentin; zinc finger E-box-binding homeobox 1, [ZEB1]) to compare epithelial and mesenchymal characteristics in eutopic endometrium with the 3 endometriotic entities, peritoneal, ovarian, and deep infiltrating endometriosis (DIE). Quantitation showed no differences for K18, K19, and MUC1 between endometrium with and without endometriosis. Also, K18 was not different between endometrium and endometriotic lesions. In contrast, K19 and MUC1 were modestly but significantly decreased in the endometriotic lesions compared to endometrium. However, the maintained expression of epithelial markers in all investigated tissues, regardless of the pathological condition, clearly indicates no loss of the epithelial phenotype. This is further supported by the reduced presence of epithelial vimentin in endometriotic lesions which is in contrast to an increase in stromal vimentin in ectopic endometrium, especially in ovarian endometriosis. The ZEB1 increase in endometriotic lesions, especially in DIE, on the other hand suggests a role of partial EMT in the development of endometriotic lesions, possibly connected with the gain of invasive capabilities or stemness. Taken together, although we found some hints for at least a partial EMT, we did not observe a severe loss of the epithelial cell phenotype. Thus, we propose that EMT is not a main factor in the pathogenesis of endometriosis.

The Potentials and Caveats of Mesenchymal Stromal Cell-Based Therapies in the Preterm Infant.

Preponderance of proinflammatory signals is a characteristic feature of all acute and resulting long-term morbidities of the preterm infant. The proinflammatory actions are best characterized for bronchopulmonary dysplasia (BPD) which is the chronic lung disease of the preterm infant with lifelong restrictions of pulmonary function and severe consequences for psychomotor development and quality of life. Besides BPD, the immature brain, eye, and gut are also exposed to inflammatory injuries provoked by infection, mechanical ventilation, and oxygen toxicity. Despite the tremendous progress in the understanding of disease pathologies, therapeutic interventions with proven efficiency remain restricted to a few drug therapies with restricted therapeutic benefit, partially considerable side effects, and missing option of applicability to the inflamed brain. The therapeutic potential of mesenchymal stromal cells (MSCs)-also known as mesenchymal stem cells-has attracted much attention during the recent years due to their anti-inflammatory activities and their secretion of growth and development-promoting factors. Based on a molecular understanding, this review summarizes the positive actions of exogenous umbilical cord-derived MSCs on the immature lung and brain and the therapeutic potential of reprogramming resident MSCs. The pathomechanistic understanding of MSC actions from the animal model is complemented by the promising results from the first phase I clinical trials testing allogenic MSC transplantation from umbilical cord blood. Despite all the enthusiasm towards this new therapeutic option, the caveats and outstanding issues have to be critically evaluated before a broad introduction of MSC-based therapies.

Early Pulmonary Interstitial Emphysema in Preterm Neonates-Respiratory Management and Case Report in Nonventilated Very Low Birth Weight Twins.

Early pulmonary interstitial emphysema in extreme preterm neonates is closely linked with respiratory distress syndrome and exposure to mechanical ventilation. In severe cases, maintaining adequate gas exchange aiming to avoid further lung damage and other neonatal morbidities associated with systemic/pulmonary hypoperfusion, prolonged hypoxia, and respiratory acidosis can be challenging and requires in-depth knowledge into the pathophysiology of the disease. Herein, we report on very low birth weight twins who developed early pulmonary interstitial emphysema during noninvasive respiratory support. We further review the current evidence from the literature, specifically addressing on possible preventive measures and the respiratory management options of this acute pulmonary disease in high-risk neonates.

Activation of the NF-κB pathway alters the phenotype of MSCs in the tracheal aspirates of preterm infants with severe BPD.

Mesenchymal stromal cells (MSCs) are released into the airways of preterm infants following lung injury. These cells display a proinflammatory phenotype and are associated with development of severe bronchopulmonary dysplasia (BPD). We aimed to characterize the functional properties of MSCs obtained from tracheal aspirates of 50 preterm infants who required invasive ventilation. Samples were separated by disease severity. The increased proliferative capacity of MSCs was associated with longer duration of mechanical ventilation and higher severity of BPD. Augmented growth depended on nuclear accumulation of NFκBp65 and was accompanied by reduced expression of cytosolic α-smooth muscle actin (α-SMA). The central role of NF-κB signaling was confirmed by inhibition of IκBα phosphorylation. The combined score of proliferative capacity, accumulation of NFκBp65, and expression of α-SMA was used to predict the development of severe BPD with an area under the curve (AUC) of 0.847. We mimicked the clinical situation in vitro, and stimulated MSCs with IL-1ß and TNF-α. Both cytokines induced similar and persistent changes as was observed in MSCs obtained from preterm infants with severe BPD. RNA interference was employed to investigate the mechanistic link between NFκBp65 accumulation and alterations in phenotype. Our data indicate that determining the phenotype of resident pulmonary MSCs represents a promising biomarker-based approach. The persistent alterations in phenotype, observed in MSCs from preterm infants with severe BPD, were induced by the pulmonary inflammatory response. NFκBp65 accumulation was identified as a central regulatory mechanism. Future preclinical and clinical studies, aimed to prevent BPD, should focus on phenotype changes in pulmonary MSCs.

Composition of the Stroma in the Human Endometrium and Endometriosis.

To analyze whether the endometrial and endometriotic microenvironment is involved in the pathogenesis of endometriosis, we characterized the stromal composition. We used CD90 for fibroblasts, α-smooth muscle actin for myofibroblasts as well as CD10 and CD140b for mesenchymal stromal cells. Quantification of eutopic endometrial stroma of cases without endometriosis showed a high percentage of stromal cells positive for CD140b (80.7%) and CD10 (67.4%), a moderate number of CD90-positive cells (57.9%), and very few α-smooth muscle actin-positive cells (8.5%). These values are highly similar to cases with endometriosis showing only minor changes: CD140b (76.7%), CD10 (63%), CD90 (53.9%), and α-smooth muscle actin (6.9%). There are no significant differences in the composition of CD140b- and CD10-positive stromal cells between the eutopic endometrial stroma and the 3 different endometriotic entities (ovarian, peritoneal, and deep infiltrating endometriosis), except for a significant difference between CD10-positive stromal cells in peritoneal lesions compared to ovarian lesions. However, the percentage of CD90-positive stromal cells was reduced in the 3 different endometriotic entities compared to the endometrium, especially significant in the ovarian lesions. In contrast, the percentage of α-smooth muscle actin-positive cells in the ovary was moderately increased. Taken together, the marker signature of eutopic endometrial and endometriotic stromal cells resembles mostly mesenchymal stromal cells. Our results show clearly that the proportion of the different stromal cell types in the endometrium with or without endometriosis does not differ significantly, thus suggesting that the stromal eutopic endometrial microenvironment does not contribute to the pathogenesis of endometriosis.