Faculty Opinions recommendation of The branching programme of mouse lung development.

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.

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

Thrombosis and Haemostasis ◽

10.1160/th04-10-0656 ◽

2005 ◽

Vol 94 (07) ◽

pp. 175-183 ◽

Cited By ~ 29

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.

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

eLife ◽

10.7554/elife.26575 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 84

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.

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Mouse Lung Organoid Responses to Reduced, Increased, and Cyclic Stretch

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00310.2020 ◽

2021 ◽

Author(s):

Rashika Joshi ◽

Matthew R. Batie ◽

Qiang Fan ◽

Brian Michael Varisco

Keyword(s):

Lung Development ◽

Histone Deacetylases ◽

Cyclic Strain ◽

Cyclic Stretch ◽

Mouse Lung ◽

Proliferating Cells ◽

Double Positive ◽

Cross Sectional ◽

Static Stretch

Most lung development occurs in the context of cyclic stretch. Alteration of the mechanical microenvironment is a common feature of many pulmonary diseases with congenital diaphragmatic hernia (CDH) and fetal tracheal occlusion (FETO, a therapy for CDH) being extreme examples with changes in lung structure, cell differentiation and function. To address limitations in cell culture and in vivo mechanotransductive models we developed two mouse lung organoid (mLO) mechanotransductive models using postnatal day 5 (PND5) mouse lung CD326-positive cells and fibroblasts subjected to increased, decreased, and cyclic strain. In the first model, mLOs were exposed to forskolin (FSK) and/or disrupted (DIS) and evaluated at 20 hours. mLO cross-sectional area changed by +59%, +24% and -68% in FSK, control, and DIS mLOs respectively. FSK-treated organoids had twice as many proliferating cells as other organoids. In the second model, 20 hours of 10.25% biaxial cyclic strain increased the mRNAs of lung mesenchymal cell lineages compared to static stretch and no stretch. Cyclic stretch increased TGF-β and integrin-mediated signaling with upstream analysis indicating roles for histone deacetylases, microRNAs, and long non-coding RNAs. Cyclic stretch mLOs increased αSMA- and αSMA-PDGFRα-double positive cells compared to no stretch and static stretch mLOs. In this PND5 mLO mechanotransductive model, cell proliferation is increased by static stretch, and cyclic stretch induces mesenchymal gene expression changes important in postnatal lung development.

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

Development ◽

10.1242/dev.124.23.4867 ◽

1997 ◽

Vol 124 (23) ◽

pp. 4867-4878 ◽

Cited By ~ 74

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.

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

Cellular and Molecular Life Sciences ◽

10.1007/s00018-019-03067-8 ◽

2019 ◽

Vol 76 (14) ◽

pp. 2817-2832 ◽

Cited By ~ 2

Author(s):

Amit Shrestha ◽

Gianni Carraro ◽

Nicolas Nottet ◽

Ana Ivonne Vazquez-Armendariz ◽

Susanne Herold ◽

...

Keyword(s):

Lung Development ◽

Critical Role ◽

Mouse Lung ◽

Alveolar Epithelial

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Targeted Disruption of Mouse Dip2B Leads to Abnormal Lung Development and Prenatal Lethality

International Journal of Molecular Sciences ◽

10.3390/ijms21218223 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8223

Author(s):

Rajiv Kumar Sah ◽

Jun Ma ◽

Fatoumata Binta Bah ◽

Zhenkai Xing ◽

Salah Adlat ◽

...

Keyword(s):

Lung Development ◽

Cell Types ◽

Branching Morphogenesis ◽

Brdu Incorporation ◽

Mouse Lung ◽

Alveolar Type ◽

Type I ◽

Lung Maturation ◽

M Phase

Molecular and anatomical functions of mammalian Dip2 family members (Dip2A, Dip2B and Dip2C) during organogenesis are largely unknown. Here, we explored the indispensable role of Dip2B in mouse lung development. Using a LacZ reporter, we explored Dip2B expression during embryogenesis. This study shows that Dip2B expression is widely distributed in various neuronal, myocardial, endothelial, and epithelial cell types during embryogenesis. Target disruption of Dip2b leads to intrauterine growth restriction, defective lung formation and perinatal mortality. Dip2B is crucial for late lung maturation rather than early-branching morphogenesis. The morphological analysis shows that Dip2b loss leads to disrupted air sac formation, interstitium septation and increased cellularity. In BrdU incorporation assay, it is shown that Dip2b loss results in increased cell proliferation at the saccular stage of lung development. RNA-seq analysis reveals that 1431 genes are affected in Dip2b deficient lungs at E18.5 gestation age. Gene ontology analysis indicates cell cycle-related genes are upregulated and immune system related genes are downregulated. KEGG analysis identifies oxidative phosphorylation as the most overrepresented pathways along with the G2/M phase transition pathway. Loss of Dip2b de-represses the expression of alveolar type I and type II molecular markers. Altogether, the study demonstrates an important role of Dip2B in lung maturation and survival.

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