EGF shifts human airway basal cell fate toward a smoking-associated airway epithelial phenotype

Shaykhiev, Renat; Zuo, Wu-Lin; Chao, IonWa; Fukui, Tomoya; Witover, Bradley; Brekman, Angelika; Crystal, Ronald G.

doi:10.1073/pnas.1303058110

Cited by 80 publications

(105 citation statements)

References 51 publications

(105 reference statements)

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“…Nitric oxide, which enhances viral clearance and limits RV-stimulated proinflammatory cytokines (39,40), is produced primarily by ciliated cells in the airway epithelium (41), and these cells are absent in injured/regenerating epithelium. Finally, undifferentiated polarized cells also showed higher expression of EGFR than did mucociliary-differentiated cells (37,42). Therefore, it is likely that RV, which is not cleared effectively in injured/regenerating airway epithelial cell cultures, may activate the EGFR that is already highly expressed in injured/regenerating cells, thereby prolonging barrier dysfunction and promoting abnormal differentiation.…”

Section: Original Researchmentioning

confidence: 98%

“…Chronic EGFR activation by Sendai virus induces goblet-cell metaplasia in welldifferentiated airway epithelial cells by promoting survival and transdifferentiation of ciliated cells to goblet cells (36). EGFR activation in basal airway epithelial cells reduces the expression of genes involved in ciliogenesis and the secretory phenotype, shifting cells toward squamous and EMTlike phenotypes (37). In this study, we found that RV, by activating EGFR, inhibits the expression of E-cadherin and CRB3, each of which regulates the polarization of cells, the event that dictates subsequent cell differentiation (3)(4)(5).…”

Section: Discussionmentioning

confidence: 99%

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Rhinovirus Delays Cell Repolarization in a Model of Injured/Regenerating Human Airway Epithelium

Faris¹,

Ganesan²,

Chattoraj³

et al. 2016

Am J Respir Cell Mol Biol

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Rhinovirus (RV), which causes exacerbation in patients with chronic airway diseases, readily infects injured airway epithelium and has been reported to delay wound closure. In this study, we examined the effects of RV on cell repolarization and differentiation in a model of injured/regenerating airway epithelium (polarized, undifferentiated cells). RV causes only a transient barrier disruption in a model of normal (mucociliary-differentiated) airway epithelium. However, in the injury/regeneration model, RV prolongs barrier dysfunction and alters the differentiation of cells. The prolonged barrier dysfunction caused by RV was not a result of excessive cell death but was instead associated with epithelial-to-mesenchymal transition (EMT)-like features, such as reduced expression of the apicolateral junction and polarity complex proteins, E-cadherin, occludin, ZO-1, claudins 1 and 4, and Crumbs3 and increased expression of vimentin, a mesenchymal cell marker. The expression of Snail, a transcriptional repressor of tight and adherence junctions, was also up-regulated in RV-infected injured/regenerating airway epithelium, and inhibition of Snail reversed RV-induced EMT-like features. In addition, compared with sham-infected cells, the RV-infected injured/regenerating airway epithelium showed more goblet cells and fewer ciliated cells. Inhibition of epithelial growth factor receptor promoted repolarization of cells by inhibiting Snail and enhancing expression of E-cadherin, occludin, and Crumbs3 proteins, reduced the number of goblet cells, and increased the number of ciliated cells. Together, these results suggest that RV not only disrupts barrier function, but also interferes with normal renewal of injured/regenerating airway epithelium by inducing EMT-like features and subsequent goblet cell hyperplasia.Keywords: barrier function; epithelial-to-mesenchymal transition; Crumbs polarity complex; epithelial growth factor receptor; goblet cell hyperplasia Clinical RelevanceTo the best of our knowledge, this is the first study to demonstrate that rhinovirus delays cell repolarization in a model of injured/regenerating, but not normal, airway epithelium by inducing epithelial-to-mesenchymal transition-like features. Furthermore, rhinovirus reduces ciliated cell differentiation and promotes goblet-cell differentiation and mucin gene expression. These changes depended partially on persistent EGFR activation induced by rhinovirus. Such changes during regeneration can lead to airway epithelium with impaired barrier and mucociliary clearance functions.Airway epithelium that lines the respiratory tract acts as a physical barrier between the external environment and the lung and plays an important role in maintaining tissue homeostasis. Paracellular permeability of airway epithelium is maintained through the co-operation of two functionally distinct structural components: tight and adherence junctions located in the apicolateral membranes. Tight junctions regulate the transport of solutes and ions across airway epithelium...

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Section: Original Researchmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Rhinovirus Delays Cell Repolarization in a Model of Injured/Regenerating Human Airway Epithelium

Faris¹,

Ganesan²,

Chattoraj³

et al. 2016

Am J Respir Cell Mol Biol

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“…Among these questions are whether the chronic inflammatory conditions prevalent in disorders such as asthma, smoking-associated COPD, and CF result in epigenetic changes in basal cells. Such changes might make them inherently more likely to differentiate into secretory rather than multiciliated cells, or into squamous versus mucociliary epithelium, even when pathological conditions revert to normal (Shaykhiev et al, 2013).…”

Section: Organoids From Human Basal Cellsmentioning

confidence: 99%

Lung organoids: current uses and future promise

Barkauskas¹,

Chung²,

Fioret³

et al. 2017

Development

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305

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Lungs are composed of a system of highly branched tubes that bring air into the alveoli, where gas exchange takes place. The proximal and distal regions of the lung contain epithelial cells specialized for different functions: basal, secretory and ciliated cells in the conducting airways and type II and type I cells lining the alveoli. Basal, secretory and type II cells can be grown in three-dimensional culture, with or without supporting stromal cells, and under these conditions they give rise to self-organizing structures known as organoids. This Review summarizes the different methods for generating organoids from cells isolated from human and mouse lungs, and compares their final structure and cellular composition with that of the airways or alveoli of the adult lung. We also discuss the potential and limitations of organoids for addressing outstanding questions in lung biology and for developing new drugs for disorders such as cystic fibrosis and asthma.

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“…Immunohistochemical evidence suggests that epidermal growth factor receptor (EGFR) signaling plays a role in airway diseases including asthma (3,15), chronic obstructive pulmonary disease (53), chronic bronchitis (28,44), and cystic fibrosis (51). Furthermore, increased EGFR expression was detected in basal cells located in regions of repairing epithelium in asthmatic patients (33,45) and in basal cells of chronic smokers (25,40). A specific role for EGFR in basal cell proliferation is supported by the finding that successful culture of basal cells from normal adult human bronchial and nasal tissue (26,55) and from hamster (54), rat (46), and mouse trachea require epidermal growth factor (EGF).…”

mentioning

confidence: 99%

Epidermal growth factor receptor activity is necessary for mouse basal cell proliferation

Brechbuhl

Smith

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Brechbuhl HM, Li B, Smith RW, Reynolds SD. Epidermal growth factor receptor activity is necessary for mouse basal cell proliferation. Am J Physiol Lung Cell Mol Physiol 307: L800-L810, 2014. First published September 12, 2014 doi:10.1152/ajplung.00201.2014.-ERB family receptors (EGFR, ERB-B2, ERB-B3, and ERB-B4) regulate epithelial cell function in many tissue types. In the human airway epithelium, changes in ERB receptor expression are associated with epithelial repair defects. However, the specific role(s) played by ERB receptors in repair have not been determined. We aimed to determine whether ERB receptors regulate proliferation of the tracheobronchial progenitor, the basal cell. Receptor tyrosine kinase arrays were used to evaluate ERB activity in normal and naphthalene (NA)-injured mouse trachea and in air-liquid interface cultures. Roles for epidermal growth factor (EGF), EGFR, and ERB-B2 in basal cell proliferation were evaluated in vitro. NA injury and transgenic expression of an EGFRdominant negative (DN) receptor were used to evaluate roles for EGFR signaling in vivo. EGFR and ERB-B2 were active in normal and NA-injured trachea and were the only active ERB receptors detected in proliferating basal cells in vitro. EGF was necessary for basal cell proliferation in vitro. The EGFR inhibitor, AG1478, decreased proliferation by 99, and the Erb-B2 inhibitor, AG825, decreased proliferation by ϳ66%. In vivo, EGFR-DN expression in basal cells significantly decreased basal cell proliferation after NA injury. EGF and EGFR are necessary for basal cell proliferation. The EGFR/EGFR homo-and the EGFR/ERB-B2 heterodimer account for ϳ34 and 66%, respectively, of basal cell proliferation in vitro. Active EGFR is necessary for basal cell proliferation after NA injury. We conclude that EGFR activation is necessary for mouse basal cell proliferation and normal epithelial repair.

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EGF shifts human airway basal cell fate toward a smoking-associated airway epithelial phenotype

Cited by 80 publications

References 51 publications

Rhinovirus Delays Cell Repolarization in a Model of Injured/Regenerating Human Airway Epithelium

Rhinovirus Delays Cell Repolarization in a Model of Injured/Regenerating Human Airway Epithelium

Lung organoids: current uses and future promise

Epidermal growth factor receptor activity is necessary for mouse basal cell proliferation

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