scholarly journals SENP1 has an important role in lung development and influences the differentiation of alveolar type 2 cells

2018 ◽  
Author(s):  
Xue‑Qing Wan ◽  
Jia‑Yu Cai ◽  
Yue Zhu ◽  
Qiu‑Xia Wang ◽  
Hai‑Tao Zhu ◽  
...  
Keyword(s):  
Lung Development ◽  
Alveolar Type

scholarly journals Failure to Down-Regulate miR-154 Expression in Early Postnatal Mouse Lung Epithelium Suppresses Alveologenesis, with Changes in Tgf-β Signaling Similar to those Induced by Exposure to Hyperoxia

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 859 ◽  
Author(s):  
Cho-Ming Chao ◽  
Gianni Carraro ◽  
Zvonimir A. Rako ◽  
Johannes Kolck ◽  
Jamschid Sedighi ◽  
...  
Keyword(s):  
Lung Development ◽  
Mouse Lung ◽  
Alveolar Type ◽  
Lung Epithelium ◽  
Downstream Target ◽  
Developmental Program ◽  
The Common ◽  
Distal Lung ◽  
Preterm Born

Background: Bronchopulmonary dysplasia (BPD) is a lung disease of preterm born infants, characterized by alveolar simplification. MicroRNA (miR) are known to be involved in many biological and pathological processes in the lung. Although a changed expression has been described for several miR in BPD, a causal role remains to be established. Results: Our results showed that the expression level of miR-154 increases during lung development and decreases postnatally. Further, hyperoxia treatment maintains high levels of miR-154 in alveolar type 2 cells (AT2). We hypothesized that the decrease in miR-154 expression in AT2 cells is required for normal alveologenesis. To test this hypothesis, we generated a novel transgenic mouse allowing doxycycline-based miR-154 overexpression. Maintenance of miR-154 expression in the postnatal distal lung epithelium under normoxia conditions is sufficient to reproduce the hypoalveologenesis phenotype triggered by hyperoxia. Using a pull-down assay, we identified Caveolin1 as a key downstream target of miR-154. Caveolin1 protein is downregulated in response to overexpression of miR-154. This is associated with increased phosphorylation of Smad3 and Tgf-ß signaling. We found that AT2 cells overexpressing miR-154 display decreased expression of AT2 markers and increased expression of AT1 markers. Conclusion: Our results suggest that down-regulation of miR-154 in postnatal lung may function as an important physiological switch that permits the induction of the correct alveolar developmental program, while conversely, failure to down-regulate miR-154 suppresses alveolarization, leading to the common clinically observed phenotype of alveolar simplification.

scholarly journals G9a methyltransferase governs cell identity in the lung and is required for KRAS G12D tumor development and propagation

2020 ◽  
Author(s):  
Ariel Pribluda ◽  
Anneleen Daemen ◽  
Anthony Lima ◽  
Xi Wang ◽  
Marc Hafner ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Wnt Signaling ◽  
Lung Development ◽  
Transcriptional Activity ◽  
Substrate Inhibition ◽  
Tumor Development ◽  
Tumor Formation ◽  
Alveolar Type ◽  
Cell Of Origin

AbstractLung development, integrity and repair rely on precise Wnt signaling, which is corrupted in diverse diseases, including cancer. Here, we discover that G9a methyltransferase regulates Wnt signaling in the lung by controlling the transcriptional activity of chromatin-bound β-catenin, through a non-histone substrate. Inhibition of G9a induces transcriptional, morphologic, and molecular changes consistent with alveolar type 2 (AT2) lineage commitment. Mechanistically, G9a activity functions to support regenerative properties of KrasG12D tumors and normal AT2 cells – the predominant cell of origin of this cancer. Consequently, G9a inhibition prevents KrasG12D lung adenocarcinoma tumor formation and propagation,and disrupts normal AT2 cell trans-differentiation. Consistent with these findings, low G9a expression in human lung adenocarcinoma correlates with enhanced AT2 gene expression and improved prognosis. These data reveal G9a as a critical regulator of Wnt signaling, implicating G9a as a potential target in lung cancer and other AT2-mediated lung pathologies.

scholarly journals Loss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung

2017 ◽  
Vol 112 ◽  
pp. 578-586 ◽  
Author(s):  
Geri Traver ◽  
Stacey Mont ◽  
David Gius ◽  
William E. Lawson ◽  
George X. Ding ◽  
...  
Keyword(s):  
Cell Loss ◽  
Alveolar Type

scholarly journals Hypercapnia limits β-catenin mediated alveolar type 2 cell progenitor function by altering Wnt production from adjacent fibroblasts

2022 ◽  
Author(s):  
Laura A Dada ◽  
Lynn C Welch ◽  
Natalia D Magnani ◽  
Ziyou Ren ◽  
Patricia L Brazee ◽  
...  
Keyword(s):  
Alveolar Type ◽  
Mechanically Ventilated ◽  
Persistent Symptoms ◽  
Low Tidal Volume ◽  
Lung Repair ◽  
Ventilator Induced Lung Injury ◽  
Lung Flooding ◽  
Volume Ventilation

Persistent symptoms and radiographic abnormalities suggestive of failed lung repair are among the most common symptoms in patients with COVID-19 after hospital discharge. In mechanically ventilated patients with ARDS secondary to SARS-CoV-2 pneumonia, low tidal volume ventilation to reduce ventilator-induced lung injury necessarily elevate blood CO2 levels, often leading to hypercapnia. The role of hypercapnia on lung repair after injury is not completely understood. Here, we show that hypercapnia limits β-catenin signaling in alveolar type 2 (AT2) cells, leading to reduced proliferative capacity. Hypercapnia alters expression of major Wnts in PDGFRα-fibroblasts from those maintaining AT2 progenitor activity and towards those that antagonize β-catenin signaling and limit progenitor function. Activation of β-catenin signaling in AT2 cells, rescues the effects of hypercapnia on proliferation. Inhibition of AT2 proliferation in hypercapnic patients may contribute to impaired lung repair after injury, preventing sealing of the epithelial barrier, increasing lung flooding, ventilator dependency and mortality.

scholarly journals Evidence for Overlapping and Distinct Biological Activities and Transcriptional Targets Triggered by Fibroblast Growth Factor Receptor 2b Signaling between Mid- and Early Pseudoglandular Stages of Mouse Lung Development

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1274
Author(s):  
Matthew R. Jones ◽  
Arun Lingampally ◽  
Jin Wu ◽  
Jamschid Sedighi ◽  
Negah Ahmadvand ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Lung Development ◽  
Fibroblast Growth Factor Receptor ◽  
Biological Activities ◽  
Growth Factor Receptor ◽  
Branching Morphogenesis ◽  
Soluble Form ◽  
Alveolar Type ◽  
Fibroblast Growth

Branching morphogenesis is the basic developmental mode common to organs such as the lungs that undergo a process of ramification from a rudimentary tree. However, the precise molecular and cellular bases underlying the formation of branching organs are still unclear. As inactivation of fibroblast growth factor receptor 2b (Fgfr2b) signaling during early development leads to lung agenesis, thereby preventing the analysis of this pathway at later developmental stages, we used transgenic mice to induce expression of a soluble form of Fgfr2b to inactivate Fgfr2b ligands at embryonic day (E) 14.5, corresponding to the mid-pseudoglandular stage of lung development. We identified an Fgfr2b signaling signature comprised of 46 genes enriched in the epithelium, some of which were common to, but most of them distinct from, the previously identified Fgfr2b signaling signature at E12.5. Our results indicate that Fgfr2b signaling at E14.5 controls mostly proliferation and alveolar type 2 cell (AT2) differentiation. In addition, inhibition of Fgfr2b signaling at E14.5 leads to morphological and cellular impairment at E18.5, with defective alveolar lineage formation. Further studies will have to be conducted to elucidate the role of Fgfr2b signaling at successive stages (canalicular/saccular/alveolar) of lung development as well as during homeostasis and regeneration and repair after injury.

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

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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