Na&lt;sup&gt;+&lt;/sup&gt;/H&lt;sup&gt;+&lt;/sup&gt; Exchangers Are Required for the Development and Function of Vertebrate Mucociliary Epithelia

Sun, Dingyuan I; Tasca, Alexia; Haas, Maximilian; Baltazar, Grober; Harland, Richard M.; Finkbeiner, Walter E.; Walentek, Peter

doi:10.1159/000492973

Cited by 12 publications

(14 citation statements)

References 46 publications

(62 reference statements)

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“…In MCCs, Wnt/β-catenin signaling during differentiation stages is required for normal ciliation. These results are in line with previous work demonstrating that Wnt/β-catenin signaling is necessary for normal ciliogenesis in various vertebrate systems by co-regulating foxj1 , a master transcription factor for motile cilia (Caron et al, 2012; Sun et al, 2018; Walentek et al, 2015). The positive effect of Wnt/β-catenin on MCC specification suggested by some studies could be explained by the extensive positive cross-regulation between transcription factors expressed in MCCs.…”

Section: Discussionsupporting

confidence: 93%

ΔN-Tp63 Mediates Wnt/β-Catenin-Induced Inhibition of Differentiation in Basal Stem Cells of Mucociliary Epithelia

et al. 2019

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SUMMARY Mucociliary epithelia provide a first line of defense against pathogens. Impaired regeneration and remodeling of mucociliary epithelia are associated with dysregulated Wnt/β-catenin signaling in chronic airway diseases, but underlying mechanisms remain elusive, and studies yield seemingly contradicting results. Employing the Xenopus mucociliary epidermis, the mouse airway, and human airway Basal cells, we characterize the evolutionarily conserved roles of Wnt/β-catenin signaling in vertebrates. In multiciliated cells, Wnt is required for cilia formation during differentiation. In Basal cells, Wnt prevents specification of epithelial cell types by activating ΔN-TP63, a master transcription factor, which is necessary and sufficient to mediate the Wnt-induced inhibition of specification and is required to retain Basal cells during development. Chronic Wnt activation leads to remodeling and Basal cell hyperplasia, which are reversible in vivo and in vitro, suggesting Wnt inhibition as a treatment option in chronic lung diseases. Our work provides important insights into mucociliary signaling, development, and disease.

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Section: Discussionsupporting

confidence: 93%

ΔN-Tp63 Mediates Wnt/β-Catenin-Induced Inhibition of Differentiation in Basal Stem Cells of Mucociliary Epithelia

et al. 2019

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“…In MCCs, Wnt/β-catenin signaling during differentiation stages is required for normal ciliation. These results are in line with previous work demonstrating that Wnt/β-catenin signaling is necessary for normal ciliogenesis in various vertebrate systems by co-regulating foxj1 , a master transcription factor for motile cilia (Caron et al, 2012; Sun et al, 2019; Walentek et al, 2015). The positive effect of Wnt/β-catenin on MCC specification suggested by some studies could be explained by the extensive positive cross-regulation between transcription factors expressed in MCCs.…”

Section: Discussionsupporting

confidence: 93%

ΔN-Tp63 mediates Wnt/β-catenin-induced inhibition of differentiation in basal stem cells of mucociliary epithelia

Haas

Vázquez

Sun

et al. 2019

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SummaryMucociliary epithelia provide a first line of defense against pathogens in the airways and the epidermis of vertebrate larvae. Impaired regeneration and remodeling of mucociliary epithelia are associated with dysregulated Wnt/β-catenin signaling in chronic airway diseases, but underlying mechanisms remain elusive and studies of Wnt signaling in mucociliary cells yield seemingly contradicting results. Employing the Xenopus mucociliary epidermis, the mouse airway, and human airway basal stem cell cultures, we characterize the evolutionarily conserved roles of Wnt/β-catenin signaling in mucociliary cells in vertebrates. Wnt signaling is required in multiciliated cells for cilia formation during differentiation stages, but in Basal cells, Wnt signaling prevents specification and differentiation of epithelial cell types by activating ΔN-TP63 expression. We demonstrate that ΔN-TP63 is a master transcription factor in Basal cells, which is necessary and sufficient to mediate the Wnt-induced inhibition of differentiation and is required to retain basal stem cells during development. Chronic stimulation of Wnt signaling leads to mucociliary remodeling and Basal cell hyperplasia, but this is reversible in vivo and in vitro, suggesting Wnt inhibition as an option in the treatment of chronic lung diseases. Our work sheds light into the evolutionarily conserved regulation of stem cells and differentiation, resolves Wnt functions in mucociliary epithelia, and provides crucial insights into mucociliary development, regeneration and disease mechanisms.

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“…40 The same function has been ascribed to Na+/H+ exchangers (NHEs), a similar class of proton transporter with roles in maintenance of cellular pH. 41 Impaired ciliogenesis and changes in cellular composition of the mucosa can lead to a breakdown of mucociliary clearance in the airways, resulting in prolonged exposure to foreign particles and increased susceptibility to infection and damage. Accordingly, the ATP4A paralog, ATP12A, is dysregulated in cystic fibrosis 42 and dysregulation of NHEs has been implicated in tumorigenesis and airway infections in cystic fibrosis patients.…”

Section: Discussionmentioning

confidence: 99%

H+/K+ATPase Expression in the Larynx of Laryngopharyngeal Reflux and Laryngeal Cancer Patients

et al. 2020

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Objectives The gastric H+/K+ ATPase proton pump has previously been shown to be expressed in the human larynx, however its contribution to laryngopharyngeal reflux (LPR) signs, symptoms and associated diseases such as laryngeal cancer is unknown. Proton pump expression in the larynx of patients with LPR and laryngeal cancer was investigated herein. A human hypopharyngeal cell line expressing the proton pump was generated to investigate its effects. Study Design In‐vitro translational. Methods Laryngeal biopsies were obtained from three LPR and eight LSCC patients. ATP4A, ATP4B and HRPT1 were assayed via qPCR. Human hypopharyngeal FaDu cell lines stably expressing proton pump were created using lentiviral transduction and examined via transmission electron microscopy and qPCR for genes associated with inflammation or laryngeal cancer. Results Expression of ATP4A and ATP4B was detected in 3/3 LPR, 4/8 LSCC‐tumor and 3/8 LSCC‐adjacent specimens. Expression of ATP4A and ATP4B in FaDu elicited mitochondrial damage and expression of IL1B, PTGS2, and TNFA (P < .0001); expression of ATP4B alone did not. Conclusions Gastric proton pump subunits are expressed in the larynx of LPR and LSCC patients. Mitochondrial damage and changes in gene expression observed in cells expressing the full proton pump, absent in those expressing a single subunit, suggest that acid secretion by functional proton pumps expressed in upper airway mucosa may elicit local cell and molecular changes associated with inflammation and cancer. Level of Evidence NA Laryngoscope, 131:130–135, 2021

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Na<sup>+</sup>/H<sup>+</sup> Exchangers Are Required for the Development and Function of Vertebrate Mucociliary Epithelia

Cited by 12 publications

References 46 publications

ΔN-Tp63 Mediates Wnt/β-Catenin-Induced Inhibition of Differentiation in Basal Stem Cells of Mucociliary Epithelia

ΔN-Tp63 Mediates Wnt/β-Catenin-Induced Inhibition of Differentiation in Basal Stem Cells of Mucociliary Epithelia

ΔN-Tp63 mediates Wnt/β-catenin-induced inhibition of differentiation in basal stem cells of mucociliary epithelia

H+/K+ATPase Expression in the Larynx of Laryngopharyngeal Reflux and Laryngeal Cancer Patients

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