Origin and characterization of alpha smooth muscle actin-positive cells during murine lung development

© 2017 The Authors Stem Cells published by Wiley Periodicals, Inc. on behalf of AlphaMed PressACTA2 expression identifies pulmonary airway and vascular smooth muscle cells (SMCs) as well as alveolar myofibroblasts (MYF). Mesenchymal progenitors expressing fibroblast growth factor 10 (Fgf10), Wilms tumor 1 (Wt1), or glioma-associated oncogene 1 (Gli1) contribute to SMC formation from early stages of lung development. However, their respective contribution and specificity to the SMC and/or alveolar MYF lineages remain controversial. In addition, the contribution of mesenchymal cells undergoing active WNT signaling remains unknown. Using Fgf10CreERT2, Wt1CreERT2, Gli1CreERT2, and Axin2CreERT2 inducible driver lines in combination with a tdTomatoflox reporter line, the respective differentiation of each pool of labeled progenitor cells along the SMC and alveolar MYF lineages was quantified. The results revealed that while FGF10+ and WT1+ cells show a minor contribution to the SMC lineage, GLI1+ and AXIN2+ cells significantly contribute to both the SMC and alveolar MYF lineages, but with limited specificity. Lineage tracing using the Acta2-CreERT2 transgenic line showed that ACTA2+ cells labeled at embryonic day (E)11.5 do not expand significantly to give rise to new SMCs at E18.5. However, ACTA2+ cells labeled at E15.5 give rise to the majority (85%–97%) of the SMCs in the lung at E18.5 as well as alveolar MYF progenitors in the lung parenchyma. Fluorescence-activated cell sorting-based isolation of different subpopulations of ACTA2+ lineage-traced cells followed by gene arrays, identified transcriptomic signatures for alveolar MYF progenitors versus airway and vascular SMCs at E18.5. Our results establish a new transcriptional landscape for further experiments addressing the function of signaling pathways in the formation of different subpopulations of ACTA2+ cells. Stem Cells 2017;35:1566–1578

Translational research in acute lung injury and pulmonary fibrosis attenuating endogenous Fgfr2b ligands during bleomycin-induced lung fibrosis does not compromise murine lung repair

© 2015 the American Physiological Society Fibroblast growth factors (Fgfs) mediate organ repair. Lung epithelial cell overexpression of Fgf10 postbleomycin injury is both protective and therapeutic, characterized by increased survival and attenuated fibrosis. Exogenous administration of FGF7 (palifermin) also showed prophylactic survival benefits in mice. The role of endogenous Fgfr2b ligands on bleomycin-induced lung fibrosis is still elusive. This study reports the expression of endogenous Fgfr2b ligands, receptors, and signaling targets in wild-type mice following bleomycin lung injury. In addition, the impact of attenuating endogenous Fgfr2b-ligands following bleomycin-induced fibrosis was tested by using a doxycycline (dox)-based inducible, soluble, dominant-negative form of the Fgfr2b receptor. Double-transgenic (DTG) Rosa26rtTA/+;tet(O)solFgfr2b mice were validated for the expression and activity of soluble Fgfr2b (failure to regenerate maxillary incisors, attenuated recombinant FGF7 signal in the lung). As previously reported, no defects in lung morphometry were detected in DTG (+dox) mice exposed from postnatal days (PN) 1 through PN105. Female single-transgenic (STG) and DTG mice were subjected to various levels of bleomycin injury (1.0, 2.0, and 3.0 U/kg). Fgfr2b ligands were attenuated either throughout injury (days 0-11; days 0-28) or during later stages (days 6-28 and 14-28). No significant changes in survival, weight, lung function, confluent areas of fibrosis, or hydroxyproline deposition were detected in DTG mice. These results indicate that endogenous Fgfr2b ligands do not significantly protect against bleomycin injury, nor do they expedite the resolution of bleomycin-induced lung injury in mice

Solar magnetism eXplorer (SolmeX)

The magnetic field plays a pivotal role in many fields of Astrophysics. This is especially true for the physics of the solar atmosphere. Measuring the magnetic field in the upper solar atmosphere is crucial to understand the nature of the underlying physical processes that drive the violent dynamics of the solar corona—that can also affect life on Earth. SolmeX, a fully equipped solar space observatory for remote-sensing observations, will provide the first comprehensive measurements of the strength and direction of the magnetic field in the upper solar atmosphere. The mission consists of two spacecraft, one carrying the instruments, and another one in formation flight at a distance of about 200 m carrying the occulter to provide an artificial total solar eclipse. This will ensure high-quality coronagraphic observations above the solar limb. SolmeX integrates two spectro-polarimetric coronagraphs for off-limb observations, one in the EUV and one in the IR, and three instruments for observations on the disk. The latter comprises one imaging polarimeter in the EUV for coronal studies, a spectro-polarimeter in the EUV to investigate the low corona, and an imaging spectro-polarimeter in the UV for chromospheric studies. SOHO and other existing missions have investigated the emission of the upper atmosphere in detail (not considering polarization), and as this will be the case also for missions planned for the near future. Therefore it is timely that SolmeX provides the final piece of the observational quest by measuring the magnetic field in the upper atmosphere through polarimetric observations

Targeting miR-34a/Pdgfra interactions partially corrects alveologenesis in experimental bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth characterized by arrested lung alveolarization, which generates lungs that are incompetent for effective gas exchange. We report here deregulated expression of miR-34a in a hyperoxia-based mouse model of BPD, where miR-34a expression was markedly increased in platelet-derived growth factor receptor (PDGFR)α-expressing myofibroblasts, a cell type critical for proper lung alveolarization. Global deletion of miR-34a; and inducible, conditional deletion of miR-34a in PDGFRα+ cells afforded partial protection to the developing lung against hyperoxia-induced perturbations to lung architecture. Pdgfra mRNA was identified as the relevant miR-34a target, and using a target site blocker in vivo, the miR-34a/Pdgfra interaction was validated as a causal actor in arrested lung development. An antimiR directed against miR-34a partially restored PDGFRα+ myofibroblast abundance and improved lung alveolarization in newborn mice in an experimental BPD model. We present here the first identification of a pathology-relevant microRNA/mRNA target interaction in aberrant lung alveolarization and highlight the translational potential of targeting the miR-34a/Pdgfra interaction to manage arrested lung development associated with preterm birth

卒後13年目の研修医

© 2015. Published by The Company of Biologists Ltd. Lipid-containing alveolar interstitial fibroblasts (lipofibroblasts) are increasingly recognized as an important component of the epithelial stem cell niche in the rodent lung. Although lipofibroblasts were initially believed merely to assist type 2 alveolar epithelial cells in surfactant production during neonatal life, recent evidence suggests that these cells are indispensable for survival and growth of epithelial stem cells during adulthood. Despite increasing interest in lipofibroblast biology, little is known about their cellular origin or the molecular pathways controlling their formation during embryonic development. Here, we showthat a population of lipid-droplet-containing stromal cells emerges in the developing mouse lung between E15.5 and E16.5. This is accompanied by significant upregulation, in the lung mesenchyme, of peroxisome proliferator-activated receptor gamma (master switch of lipogenesis), adipose differentiation-related protein (marker of mature lipofibroblasts) and fibroblast growth factor 10 (previously shown to identify a subpopulation of lipofibroblast progenitors). We also demonstrate that although only a subpopulation of total embryonic lipofibroblasts derives from Fgf10+ progenitor cells, in vivo knockdown of Fgfr2b ligand activityand reduction in Fgf10 expression lead to global reduction in the expression levels of lipofibroblast markers at E18.5. Constitutive Fgfr1b knockouts and mutants with conditional partial inactivation of Fgfr2b in the lung mesenchyme reveal the involvement of both receptors in lipofibroblast formation and suggest a possible compensation between the two receptors. We also provide data from human fetal lungs to demonstrate the relevance of our discoveries to humans. Our results reveal an essential role for Fgf10 signaling in the formation of lipofibroblasts during late lung development

Die Aufhebung des Erbverzichts

Die nur fragmentarische Regelung des Erbverzichts im fünften Buch des BGB hat zahlreiche Rechtsfragen aufgeworfen, die auch heute, ein Jahrhundert nach Inkrafttreten der Kodifikation, noch immer nicht abschließend geklärt sind. Ein Teilkomplex der Problematik betrifft die Aufhebung des Erbverzichts. Wie, von wem, unter welchen Voraussetzungen und mit welchen Wirkungen, insbesondere aber auch innerhalb welcher zeitlichen Grenzen kann ein einmal vereinbarter Erbverzicht wieder aufgehoben werden? Was gilt nach dem Tod des Erblassers, was nach dem des Verzichtenden? Ist die Aufhebung Verfügung von Todes wegen?Nach einer kurzen Einführung in das Erbverzichtsrecht erörtert der Verfasser zunächst die Rechtsnatur der Erbverzichtsaufhebung sowie den Regelungsbereich des § 2351 BGB, bevor er sich der postmortalen Aufhebung zuwendet, die im Mittelpunkt der Untersuchung steht. Markus Quantius legt dar, daß eine Aufhebung des Erbverzichts nach dem Tod des Erblassers zwar ausgeschlossen ist, jedoch nicht nach dem des Verzichtenden, da es in diesem Fall zu einer Rechtsnachfolge in die Aufhebungsbefugnis des Verzichtenden kommt. Diese Rechtsnachfolge vollzieht sich im Wege der Gesamterbfolge nach § 1922 Abs. 1 BGB. Abweichend von allgemeinen Grundsätzen ist der Rechtsübergang jedoch auf allein diejenigen Erben beschränkt, die zugleich auch Abkömmlinge des Verzichtenden sind.Am Ende behandelt Markus Quantius die Frage der Aufhebungsmöglichkeit auch für diejenigen Rechtsinstitute, die als Sonderformen des Erbverzichts oder aber als zu diesem in einer rechtsverwandtschaftlichen Beziehung stehend anzusehen sind, namentlich für den Pflichtteilsverzicht, den Zuwendungsverzicht und den Verzicht auf den Anteil an einer fortgesetzten Gütergemeinschaft