Thyroid hormone affects embryonic mouse lung branching morphogenesis and cellular differentiation

2002 ◽  
Vol 282 (3) ◽  
pp. L359-L369 ◽  
Author(s):  
Kwanchai Archavachotikul ◽  
Teriggi J. Ciccone ◽  
Mala R. Chinoy ◽  
Heber C. Nielsen ◽  
Maryann V. Volpe
Keyword(s):  
Cell Differentiation ◽  
Thyroid Hormone ◽  
Lung Development ◽  
Mesenchymal Cell ◽  
Fetal Lung ◽  
Branching Morphogenesis ◽  
Mouse Lung ◽  
Embryonic Mouse ◽  
Fetal Lung Development ◽  
Terminal Bud

Although thyroid hormone (T3) influences epithelial cell differentiation during late fetal lung development, its effects on early lung morphogenesis are unknown. We hypothesized that T3 would alter embryonic lung airway branching and temporal-spatial differentiation of the lung epithelium and mesenchyme. Gestational day 11.5 embryonic mouse lungs were cultured for 72 h in BGJb serum-free medium without or with added T3 (0.2, 2.0, 10.0, or 100 nM). Evaluation of terminal bud counts showed a dose- and time-dependent decrease in branching morphogenesis. Cell proliferation was also significantly decreased with higher doses of T3. Morphometric analysis of lung histology showed that T3 caused a dose-dependent decrease in mesenchyme and increase in cuboidal epithelia and airway space. Immunocytochemistry showed that with T3 treatment, Nkx2.1 and surfactant protein SP-C proteins became progressively localized to cuboidal epithelial cells and mesenchymal expression of Hoxb5 was reduced, a pattern resembling late fetal lung development. We conclude that exogenous T3 treatment during early lung development accelerated epithelial and mesenchymal cell differentiation at the expense of premature reduction in new branch formation and lung growth.

Functional diversity ofnotchfamily genes in fetal lung development

2004 ◽  
Vol 286 (5) ◽  
pp. L1075-L1083 ◽  
Author(s):  
Yanping Kong ◽  
Jonathon Glickman ◽  
Meera Subramaniam ◽  
Aliakbar Shahsafaei ◽  
K. P. Allamneni ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Neural Tissue ◽  
Fetal Lung ◽  
Branching Morphogenesis ◽  
Notch Receptor ◽  
Neuroendocrine Cells ◽  
Mouse Lung ◽  
Notch 1 ◽  
Embryonic Mouse ◽  
Notch 3

In Drosophila, developmental signaling via the transmembrane Notch receptor modulates branching morphogenesis and neuronal differentiation. To determine whether the notch gene family can regulate mammalian organogenesis, including neuroendocrine cell differentiation, we evaluated developing murine lung. After demonstrating gene expression for notch-1, notch-2, notch-3, and the Notch ligands jagged-1 and jagged-2 in embryonic mouse lung, we tested whether altering expression of these genes can modulate branching morphogenesis. Branching of embryonic day (E) 11.5 lung buds increased when they were treated with notch-1 antisense oligodeoxynucleotides in culture compared with the corresponding sense controls, whereas notch-2, notch-3, jagged-1, or jagged-2 antisense oligos had no significant effect. To assess cell differentiation, we immunostained lung bud cultures for the neural/neuroendocrine marker PGP9.5. Antisense to notch-1 or jagged-1 markedly increased numbers of PGP9.5-positive neuroendocrine cells alone without affecting neural tissue, whereas only neural tissue was promoted by notch-3 antisense in culture. There was no significant effect on cell proliferation or apoptosis in these antisense experiments. Cumulatively, these observations suggest that interactions between distinct Notch family members can have diverse tissue-specific regulatory functions during development, arguing against simple functional redundancy.

scholarly journals MicroRNA-127 modulates fetal lung development

2009 ◽  
Vol 37 (3) ◽  
pp. 268-278 ◽  
Author(s):  
Manoj Bhaskaran ◽  
Yang Wang ◽  
Honghao Zhang ◽  
Tingting Weng ◽  
Pradyumna Baviskar ◽  
...  
Keyword(s):  
Expression Pattern ◽  
Lung Development ◽  
Fetal Lung ◽  
Mirna Microarray ◽  
Mirna Expression Pattern ◽  
Opposite Trend ◽  
Fetal Lung Development ◽  
Terminal Bud ◽  
Lung Organ Culture

MicroRNAs (miRNAs) are small endogenous RNAs and are widely regarded as one of the most important regulators of gene expression in both plants and animals. To define the roles of miRNAs in fetal lung development, we profiled the miRNA expression pattern during lung development with a miRNA microarray. We identified 21 miRNAs that showed significant changes in expression during lung development. These miRNAs were grouped into four distinct clusters based on their expression pattern. Cluster 1 contained miRNAs whose expression increased as development progressed, while clusters 2 and 3 showed the opposite trend of expression. miRNAs in cluster 4 including miRNA-127 (miR-127) had the highest expression at the late stage of fetal lung development. Quantitative real-time PCR validated the microarray results of six selected miRNAs. In situ hybridization demonstrated that miR-127 expression gradually shifted from mesenchymal cells to epithelial cells as development progressed. Overexpression of miR-127 in fetal lung organ culture significantly decreased the terminal bud count, increased terminal and internal bud sizes, and caused unevenness in bud sizes, indicating improper development. These findings suggest that miR-127 may have an important role in fetal lung development.

Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung

Development ◽  
1997 ◽  
Vol 124 (23) ◽  
pp. 4867-4878 ◽  
Author(s):  
S. Bellusci ◽  
J. Grindley ◽  
H. Emoto ◽  
N. Itoh ◽  
B.L. Hogan
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Lung Development ◽  
Expression Patterns ◽  
Branching Morphogenesis ◽  
Mouse Lung ◽  
Fibroblast Growth ◽  
Embryonic Mouse ◽  
Fibroblast Growth Factor 10

During mouse lung morphogenesis, the distal mesenchyme regulates the growth and branching of adjacent endoderm. We report here that fibroblast growth factor 10 (Fgf10) is expressed dynamically in the mesenchyme adjacent to the distal buds from the earliest stages of lung development. The temporal and spatial pattern of gene expression suggests that Fgf10 plays a role in directional outgrowth and possibly induction of epithelial buds, and that positive and negative regulators of Fgf10 are produced by the endoderm. In transgenic lungs overexpressing Shh in the endoderm, Fgf10 transcription is reduced, suggesting that high levels of SHH downregulate Fgf10. Addition of FGF10 to embryonic day 11.5 lung tissue (endoderm plus mesenchyme) in Matrigel or collagen gel culture elicits a cyst-like expansion of the endoderm after 24 hours. In Matrigel, but not collagen, this is followed by extensive budding after 48–60 hours. This response involves an increase in the rate of endodermal cell proliferation. The activity of FGF1, FGF7 and FGF10 was also tested directly on isolated endoderm in Matrigel culture. Under these conditions, FGF1 elicits immediate endodermal budding, while FGF7 and FGF10 initially induce expansion of the endoderm. However, within 24 hours, samples treated with FGF10 give rise to multiple buds, while FGF7-treated endoderm never progresses to bud formation, at all concentrations of factor tested. Although exogenous FGF1, FGF7 and FGF10 have overlapping activities in vitro, their in vivo expression patterns are quite distinct in relation to early branching events. We conclude that, during early lung development, localized sources of FGF10 in the mesoderm regulate endoderm proliferation and bud outgrowth.

MEK-1/2 inhibition reduces branching morphogenesis and causes mesenchymal cell apoptosis in fetal rat lungs

2002 ◽  
Vol 282 (3) ◽  
pp. L370-L378 ◽  
Author(s):  
David E. Kling ◽  
Hans K. Lorenzo ◽  
Alexander M. Trbovich ◽  
T. Bernard Kinane ◽  
Patricia K. Donahoe ◽  
...  
Keyword(s):  
Map Kinases ◽  
Mesenchymal Cell ◽  
Fetal Lung ◽  
Branching Morphogenesis ◽  
Nuclear Antigen ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Fetal Lung Development ◽  
Mitogen Activated Protein ◽  
Upstream Kinase

The roles of the mitogen-activated protein (MAP) kinases extracellular signal-regulated kinases-1 and -2 (ERK-1/2) in fetal lung development have not been extensively characterized. To determine if ERK-1/2 signaling plays a role in fetal lung branching morphogenesis, U-0126, an inhibitor of the upstream kinase MAP ERK kinase (MEK), was added to fetal lung explants in vitro. Morphometry as measured by branching, area, perimeter, and complexity were significantly reduced in U-0126-treated lungs. At the same time, U-0126 treatment reduced ERK-1/2, slightly increased p38 kinase, but did not change c-Jun NH2-terminal kinase activities, indicating that U-0126 specifically inhibited the ERK-1/2 enzymes. These changes were associated with increased apoptosis as measured by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and immunofluorescent labeling of anti-active caspase-3 in the mesenchyme of explants after U-0126 treatment compared with the control. Mitosis characterized by immunolocalization of proliferating cell nuclear antigen was found predominantly in the epithelium and was reduced in U-0126-treated explants. Thus U-0126 causes specific inhibition of ERK-1/2 signaling, diminished branching morphogenesis, characterized by increased mesenchymal apoptosis, and decreased epithelial proliferation in fetal lung explants.

Bombesin-like peptide receptor gene expression, regulation, and function in fetal murine lung

2004 ◽  
Vol 286 (1) ◽  
pp. L165-L173 ◽  
Author(s):  
Lin Shan ◽  
Rodica L. Emanuel ◽  
Denise Dewald ◽  
John S. Torday ◽  
Nithiananthan Asokanathan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Development ◽  
Gene Expression Regulation ◽  
Receptor Gene ◽  
Fetal Lung ◽  
Mouse Lung ◽  
Receptor Subtype ◽  
Fetal Lung Development ◽  
And Function ◽  
Receptor Gene Expression

Bombesin-peptide (BLP) immunoreactivity occurs at high levels in fetal lung. Previous studies showed that bombesin promotes fetal lung development. To test the hypothesis that such effects are mediated by known mammalian bombesin receptors [gastrin-releasing peptide (GRP)/bombesin-preferring receptor (GRPR), neuromedin B (NMB) receptor (NMBR), and the orphan bombesin receptor subtype-3 (BRS-3)], we analyzed the ontogeny of GRPR, NMBR, and BRS-3 gene expression in mouse lung. We examined the regulation of these three genes by dexamethasone and bombesin, which modulate lung development. Using incorporation of [3H]thymidine and [3H]choline, we then assessed whether GRP, NMB, and Leu8-phyllolitorin modulate lung growth and maturation in fetal lung explants. GRPR gene expression was detected predominantly in utero, whereas NMBR and BRS-3 genes were expressed from embryonic days 13–16 and on multiple postnatal days. All three mRNAs are present in airway epithelium and mesenchymal cells but occur in different relative patterns. These genes were regulated differently. Dexamethasone and bombesin increased GRPR mRNA, bombesin downregulated NMBR, and neither agent affected BRS-3. GRP increased incorporation of [3H]thymidine and [3H]choline in explants, whereas NMB induced cell proliferation and Leu8-phyllolitorin yielded variable results. Cumulative data suggest the involvement of multiple BLP receptors, including novel molecules, and argue against simple functional redundancy within this gene family during lung development.

Distribution of laminin 5, integrin receptors, and branching morphogenesis during human fetal lung development

2002 ◽  
Vol 225 (2) ◽  
pp. 176-185 ◽  
Author(s):  
Christelle Coraux ◽  
Guerrino Meneguzzi ◽  
Patricia Rousselle ◽  
Edith Puchelle ◽  
Dominique Gaillard
Keyword(s):  
Lung Development ◽  
Fetal Lung ◽  
Branching Morphogenesis ◽  
Integrin Receptors ◽  
Laminin 5 ◽  
Fetal Lung Development ◽  
Human Fetal Lung

scholarly journals Impaired Fetal Lung Development can be Rescued by Administration of Extracellular Vesicles Derived from Amniotic Fluid Stem Cells

2020 ◽  
Author(s):  
Lina Antounians ◽  
Vincenzo D. Catania ◽  
Louise Montalva ◽  
Benjamin D. Liu ◽  
Huayun Hou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Amniotic Fluid ◽  
Extracellular Vesicles ◽  
Lung Development ◽  
Pulmonary Hypoplasia ◽  
Fetal Lung ◽  
Branching Morphogenesis ◽  
Amniotic Fluid Stem Cells ◽  
Fetal Lung Development ◽  
Regenerative Ability

AbstractIncomplete lung development, also known as pulmonary hypoplasia, is a recognized cause of neonatal death and poor outcome for survivors. To date, there is no effective treatment that promotes fetal lung growth and maturation. Herein, we describe a novel stem cell-based approach that enhances fetal lung development via the administration of extracellular vesicles (EVs) derived from amniotic fluid stem cells (AFSCs). In experimental models of pulmonary hypoplasia, administration of AFSC-EVs promoted lung branching morphogenesis and alveolarization, and stimulated pulmonary epithelial cell and fibroblast differentiation. This regenerative ability was confirmed in two models of injured human lung cells, where human AFSC-EVs obtained following good manufacturing practices restored pulmonary epithelial homeostasis. AFSC-EV beneficial effects were exerted via the release of RNA cargo, primarily miRNAs, that regulate the expression of genes involved in fetal lung development. Our findings suggest that AFSC-EVs hold regenerative ability for underdeveloped fetal lungs, demonstrating potential for therapeutic application.One Sentence SummaryFetal lung regeneration via administration of extracellular vesicles derived from amniotic fluid stem cells

Gremlin negatively modulates BMP-4 induction of embryonic mouse lung branching morphogenesis

2001 ◽  
Vol 280 (5) ◽  
pp. L1030-L1039 ◽  
Author(s):  
Wei Shi ◽  
Jingsong Zhao ◽  
Kathryn D. Anderson ◽  
David Warburton
Keyword(s):  
Fetal Lung ◽  
Surfactant Protein ◽  
Branching Morphogenesis ◽  
Negative Regulator ◽  
Mouse Lung ◽  
Lung Maturation ◽  
Embryonic Mouse ◽  
Peripheral Lung ◽  
Large Airways ◽  
Lung Branching

Bone morphogenetic protein-4 (BMP-4) is a key morphogen for embryonic lung development that is expressed at high levels in the peripheral epithelium, but the mechanisms that modulate BMP-4 function in early mouse lung branching morphogenesis are unclear. Here, we studied the BMP-4 antagonist Gremlin, which is a member of the DAN family of BMP antagonists that can bind and block BMP-2/4 activity. The expression level of gremlin in embryonic mouse lungs is highest in the early embryonic pseudoglandular stage [embryonic days (E) 11.5–14.5] and is reduced during fetal lung maturation (E18.5 to postnatal day 1). In situ hybridization indicates that gremlin is diffusely expressed in peripheral lung mesenchyme and epithelium, but relatively high epithelial expression occurs in branching buds at E11.5 and in large airways after E16.5. In E11.5 lung organ culture, we found that exogenous BMP-4 dramatically enhanced peripheral lung epithelial branching morphogenesis, whereas reduction of endogenous gremlin expression with antisense oligonucleotides achieved the same gain-of-function phenotype as exogenous BMP-4, including increased epithelial cell proliferation and surfactant protein C expression. On the other hand, adenoviral overexpression of gremlin blocked the stimulatory effects of exogenous BMP-4. Therefore, our data support the hypothesis that Gremlin is a physiologically negative regulator of BMP-4 in lung branching morphogenesis.

scholarly journals In vitro models of fetal lung development to enhance research into congenital lung diseases

2021 ◽  
Author(s):  
Soichi Shibuya ◽  
Jessica Allen-Hyttinen ◽  
Paolo De Coppi ◽  
Federica Michielin
Keyword(s):  
Lung Development ◽  
Lung Diseases ◽  
Ex Vivo ◽  
Fetal Lung ◽  
Branching Morphogenesis ◽  
In Vitro Models ◽  
Normal Lung ◽  
Novel Therapeutic Strategies ◽  
Pseudoglandular Stage

Abstract Purpose This paper aims to build upon previous work to definitively establish in vitro models of murine pseudoglandular stage lung development. These can be easily translated to human fetal lung samples to allow the investigation of lung development in physiologic and pathologic conditions. Methods Lungs were harvested from mouse embryos at E12.5 and cultured in three different settings, i.e., whole lung culture, mesenchyme-free epithelium culture, and organoid culture. For the whole lung culture, extracted lungs were embedded in Matrigel and incubated on permeable filters. Separately, distal epithelial tips were isolated by firstly removing mesothelial and mesenchymal cells, and then severing the tips from the airway tubes. These were then cultured either in branch-promoting or self-renewing conditions. Results Cultured whole lungs underwent branching morphogenesis similarly to native lungs. Real-time qPCR analysis demonstrated expression of key genes essential for lung bud formation. The culture condition for epithelial tips was optimized by testing different concentrations of FGF10 and CHIR99021 and evaluating branching formation. The epithelial rudiments in self-renewing conditions formed spherical 3D structures with homogeneous Sox9 expression. Conclusion We report efficient protocols for ex vivo culture systems of pseudoglandular stage mouse embryonic lungs. These models can be applied to human samples and could be useful to paediatric surgeons to investigate normal lung development, understand the pathogenesis of congenital lung diseases, and explore novel therapeutic strategies.

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