scholarly journals A critical role for miR-142 in alveolar epithelial lineage formation in mouse lung development

2019 ◽  
Vol 76 (14) ◽  
pp. 2817-2832 ◽  
Author(s):  
Amit Shrestha ◽  
Gianni Carraro ◽  
Nicolas Nottet ◽  
Ana Ivonne Vazquez-Armendariz ◽  
Susanne Herold ◽  
...  
Keyword(s):  
Lung Development ◽  
Critical Role ◽  
Mouse Lung ◽  
Alveolar Epithelial

Abrogation of mesenchyme-specific TGF-β signaling results in lung malformation with prenatal pulmonary cysts in mice

2021 ◽  
Author(s):  
Qing Miao ◽  
Hui Chen ◽  
Yongfeng Luo ◽  
Joanne Chiu ◽  
Ling Chu ◽  
...  
Keyword(s):  
Lung Development ◽  
Muscle Growth ◽  
Branching Morphogenesis ◽  
Mouse Lung ◽  
Cystic Lesions ◽  
Alveolar Epithelial ◽  
Pulmonary Cysts ◽  
Β Receptor ◽  
Airway Branching

The TGF-β signaling pathway plays a pivotal role in controlling organogenesis during fetal development. Although the role of TGF-β signaling in promoting lung alveolar epithelial growth has been determined, mesenchymal TGF-β signaling in regulating lung development has not been studied in vivo due to a lack of genetic tools for specifically manipulating gene expression in lung mesenchymal cells. Therefore, the integral roles of TGF-β signaling in regulating lung development and congenital lung diseases are not completely understood. Using a Tbx4 lung enhancer-driven Tet-On inducible Cre transgenic mouse system, we have developed a mouse model in which lung mesenchyme-specific deletion of TGF-β receptor 2 gene (Tgfbr2) is achieved. Reduced airway branching accompanied by defective airway smooth muscle growth and later peripheral cystic lesions occurred when lung mesenchymal Tgfbr2 was deleted from embryonic day 13.5 to 15.5, resulting in postnatal death due to respiratory insufficiency. Although cell proliferation in both lung epithelium and mesenchyme was reduced, epithelial differentiation was not significantly affected. Tgfbr2 downstream Smad-independent ERK1/2 may mediate these mesenchymal effects of TGF-β signaling through the GSK3β--β-catenin--Wnt canonical pathway in fetal mouse lung. Our study suggests that Tgfbr2-mediated TGF-β signaling in prenatal lung mesenchyme is essential for lung development and maturation, and defective TGF-β signaling in lung mesenchyme may be related to abnormal airway branching morphogenesis and congenital airway cystic lesions.

scholarly journals Hypoxia Inducible Factor 3α Plays a Critical Role in Alveolarization and Distal Epithelial Cell Differentiation during Mouse Lung Development

PLoS ONE ◽  
2013 ◽  
Vol 8 (2) ◽  
pp. e57695 ◽  
Author(s):  
Yadi Huang ◽  
Joshua Kapere Ochieng ◽  
Marjon Buscop-van Kempen ◽  
Anne Boerema-de Munck ◽  
Sigrid Swagemakers ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Epithelial Cell ◽  
Lung Development ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Mouse Lung ◽  
Epithelial Cell Differentiation

scholarly journals miR-184 mediates hyperoxia-induced injury by targeting cell death and angiogenesis signalling pathways in the developing lung

2020 ◽  
pp. 1901789 ◽  
Author(s):  
Dilip Shah ◽  
Karmyodh Sandhu ◽  
Pragnya Das ◽  
Zubair H. Aghai ◽  
Sture Andersson ◽  
...  
Keyword(s):  
Lung Development ◽  
Zinc Finger Protein ◽  
Critical Role ◽  
Alveolar Epithelial Cells ◽  
Therapeutic Interventions ◽  
Normal Lung ◽  
Alveolar Epithelial ◽  
Fetal Mice ◽  
And Function ◽  
Neonatal Lungs

MicroRNAs (miRs) have been shown to disrupt normal lung development and function by interrupting alveolarization and vascularisation leading to development of bronchopulmonary dysplasia (BPD). Here we report that miR-184 has a critical role in the induction of BPD phenotype characterised by abnormal alveolarization and pulmonary angiogenesis in the developing lung. We observed an increased expression of miR-184 in BPD clinical specimens: tracheal aspirates (TA), human neonatal lungs with BPD and in fetal human lung Type II alveolar epithelial cells (TIIAECs) exposed to hyperoxia. Consistent with this, we also detected an upregulated miR-184-3p expression in whole lungs, in freshly isolated TIIAECs from lungs of hyperoxia-induced experimental BPD mice and in fetal mice lung TIIAECs exposed to hyperoxia. We demonstrate that overexpression of miR-184-3p exacerbates the BPD pulmonary phenotype, while downregulation of miR-184-3p expression ameliorated the BPD phenotype and also improved respiratory function. We identified miR-184 specific targets: platelet-derived growth factor-beta (Pdgf-β) and friend of Gata 2 (Fog2), also known as zinc finger protein family member (Zfpm2), and show that they are critically involved in pulmonary alveolarization and angiogenesis. Using cell-based luciferase analysis, downregulation of miR-184-3p expression and gene knockdown of miR-184-3p targets Pdgf-β and Fog2 in lung TIIAECs and endothelial cells, we mechanistically show that inhibition of miR-184-3p expression improves pulmonary alveolarization by regulating PDGF-β/AKT/Foxo3/Bax, Bcl2 signalling and enhances angiogenesis by Fog2/VEGF-A/Angiopoietin-1/2 pathway. Collectively, these data suggest that the use of miR-184-3p specific inhibitors may act as novel therapeutic interventions to control the adverse effects of hyperoxia on lung development and function.

Dexamethasone Effect on Embryonic Chick Respiratory Epithelium

1982 ◽  
Vol 40 ◽  
pp. 248-249
Author(s):  
M.R. Richter ◽  
R.V. Blystone
Keyword(s):  
Lung Development ◽  
Critical Role ◽  
Respiratory Epithelium ◽  
Chick Embryos ◽  
Embryonic Chick ◽  
White Leghorn ◽  
Lung Maturation ◽  
Synthetic Analogs ◽  
Lung Physiology ◽  
Avian Lung

Dexamethasone and other synthetic analogs of corticosteroids have been employed clinically as enhancers of lung development. The mechanism(s) by which this steroid induction of later lung maturation operates is not clear. This study reports the effect on lung epithelia of dexamethasone administered at different intervals during development. White Leghorn chick embryos were used so as to remove possible maternal and placental influences on the exogenously applied steroid. Avian lung architecture does vary from mammals; however, respiratory surfactant produced by the lung epithelia serves an equally critical role in avian lung physiology.

Differential expression of matrix metalloproteinases and their inhibitors in human and mouse lung development

2005 ◽  
Vol 94 (07) ◽  
pp. 175-183 ◽  
Author(s):  
Julie Ryu ◽  
Alfin G. Vicencio ◽  
Michael E. Yeager ◽  
Michael Kashgarian ◽  
Gabriel G. Haddad ◽  
...  
Keyword(s):  
Growth Factor ◽  
Lung Development ◽  
Epithelial To Mesenchymal Transition ◽  
Developmental Stages ◽  
Human Lung ◽  
Matrix Metalloproteases ◽  
Mouse Lung ◽  
Mesenchymal Transition ◽  
Expression Arrays ◽  
Human And Mouse

SummaryLung development is a highly orchestrated process characterized by timed expression and activation of growth factor and protease/antiprotease systems. This interplay is essential in regulating vasculogenesis, alveolarization, and epithelial to mesenchymal transition during lung development. Alterations in the proteolytic/antiproteolytic balance of the lung have been associated with several respiratory diseases characterized by changes in the lung extracellular matrix (ECM). Here, we characterized the expression pattern of matrix metalloproteases (MMP) and their inhibitors, the tissue inhibitors of metalloproteases (TIMP), in human and mouse lung development. Using MMP/TIMP expression arrays, RT-PCR, Western Blotting, and ELISA analyses, we demonstrate that fetal human lung is characterized by a dominant proteolytic profile with high MMP-2 and little TIMP-3 expression. Adult human lung, in contrast, exhibits a more anti-proteolytic profile with decreased MMP-2 and increasedTIMP-3 expression. MMP-14, MMP-20,TIMP-1, and TIMP-2 were constitutively expressed, irrespective of the developmental stage. Similar results were obtained using mouse lungs of different developmental stages, with the addition that in mouse lung, TIMP-2 and TIMP-3 were upregulated as lung development progressed. Exposure of neonatal mice to chronic hypoxia (10% O2), a stimulus that leads to an arrest of lung development, resulted in upregulation of MMP-2 with a concomitant downregulation of TIMP-2.These results provide a comprehensive analysis of MMP and TIMP expression during human and mouse lung development. MMP-2, TIMP-2, and TIMP-3 may be key regulatory enzymes during lung development, possibly through their complex action on ECM components, membrane receptor ectodomain shedding, and growth factor bioactivity.

scholarly journals Human embryonic lung epithelial tips are multipotent progenitors that can be expanded in vitro as long-term self-renewing organoids

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Marko Z Nikolić ◽  
Oriol Caritg ◽  
Quitz Jeng ◽  
Jo-Anne Johnson ◽  
Dawei Sun ◽  
...  
Keyword(s):  
Lung Development ◽  
Mouse Lung ◽  
Lung Epithelium ◽  
Human Embryonic Lung ◽  
Self Renewal ◽  
Embryonic Mouse ◽  
Multipotent Progenitors ◽  
Lung Epithelial

The embryonic mouse lung is a widely used substitute for human lung development. For example, attempts to differentiate human pluripotent stem cells to lung epithelium rely on passing through progenitor states that have only been described in mouse. The tip epithelium of the branching mouse lung is a multipotent progenitor pool that self-renews and produces differentiating descendants. We hypothesized that the human distal tip epithelium is an analogous progenitor population and tested this by examining morphology, gene expression and in vitro self-renewal and differentiation capacity of human tips. These experiments confirm that human and mouse tips are analogous and identify signalling pathways that are sufficient for long-term self-renewal of human tips as differentiation-competent organoids. Moreover, we identify mouse-human differences, including markers that define progenitor states and signalling requirements for long-term self-renewal. Our organoid system provides a genetically-tractable tool that will allow these human-specific features of lung development to be investigated.

scholarly journals P-Rex1 Cooperates With TGFβR2 to Drive Lung Fibroblast Migration in Pulmonary Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Qing Liang ◽  
Yanhua Chang ◽  
Jing Liu ◽  
Yan Yu ◽  
Wancheng Qiu ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Fibroblast ◽  
Alveolar Epithelial Cells ◽  
Lung Fibroblasts ◽  
Mouse Lung ◽  
Nucleotide Exchange ◽  
Alveolar Epithelial ◽  
Fibroblast Migration ◽  
Overexpression System ◽  
Tgf Β1

Pulmonary fibrosis is a kind of interstitial lung disease with progressive pulmonary scar formation, leading to irreversible loss of lung functions. The TGF-β1/Smad signaling pathway plays a key role in fibrogenic processes. It is associated with the increased synthesis of extracellular matrix, enhanced proliferation of fibroblasts, and transformation of alveolar epithelial cells into interstitial cells. We investigated P-Rex1, a PIP3-Gβγ–dependent guanine nucleotide exchange factor (GEF) for Rac, for its potential role in TGF-β1–induced pulmonary fibrosis. A high expression level of P-Rex1 was identified in the lung tissue of patients with pulmonary fibrosis than that from healthy donors. Using the P-Rex1 knockdown and overexpression system, we established a novel player of P-Rex1 in mouse lung fibroblast migration. P-Rex1 contributed to fibrogenic processes in lung fibroblasts by targeting the TGF-β type Ⅱ receptor (TGFβR2). The RNA-seq analysis for expression profiling confirmed the modulation of P-Rex1 in cell migration and the involvement of P-Rex1 in TGF-β1 signaling. These results identified P-Rex1 as a signaling molecule involved in TGF-β1–induced pulmonary fibrosis, suggesting that P-Rex1 may be a potential target for pulmonary fibrosis treatment.

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