ArticleAmerican journal of physiology. Lung cellular and molecular physiology2023
Notch signaling inactivation by small molecule γ-secretase inhibitors restores the multiciliated cell population in the airway epithelium.
Article in American journal of physiology. Lung cellular and molecular physiology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 26 citations in OpenAlex.
- Breaking the bottleneck of asthma treatment: the future of omni-targeted therapy.Journal of advanced research · 2026Review
- Therapeutic potential of synergistic mucociliary clearance for cystic fibrosis airways by β-adrenergic plus cholinergic agonists.The Journal of clinical investigation · 2026Article
- Epithelial cells in chronic obstructive pulmonary disease exacerbations: Targets for lung repair.Pharmacological reviews · 2026Review
- Transcriptomic and functional responses of the cystic fibrosis airway epithelium to CFTR modulator therapy.JCI insight · 2025Article
- STAT3-Dependent Regulation of CFTR and Ciliogenesis Is Essential for Mucociliary Clearance and Innate Airway Defense in Hyper-IgE Syndrome.American journal of respiratory and critical care medicine · 2025Article
- NOTCH pathway was involved in Kaempferol 3-O-gentiobioside attenuated airway inflammation and mucus hypersecretion.Scientific reports · 2025Article
- Notch Is Required for Neural Progenitor Proliferation During Embryonic Eye Regrowth.International journal of molecular sciences · 2025Article
- Undocking of an extensive ciliary network induces proteostasis and cell fate switching resulting in severe primary ciliary dyskinesia.Science translational medicine · 2025Article
- Durable reconstitution of sinonasal epithelium by transplant of CFTR gene corrected airway stem cells.bioRxiv : the preprint server for biology · 2025Article
- The next frontier in lung development and regeneration research: harnessing iPSC models to illuminate notch signaling pathways.Frontiers in cell and developmental biology · 2025Review
- Notch Signaling Pathway Interfering as a Possible Asthma Treatment: A Narrative Review.Journal of asthma and allergy · 2025Review
- Pulmonary-delivered Anticalin Jagged-1 antagonists reduce experimental airway mucus hyperproduction and obstruction.American journal of physiology. Lung cellular and molecular physiology · 2025Article
- Enhanced radiation sensitivity, decreased DNA damage repair, and differentiation defects in airway stem cells derived from patients with chronic obstructive pulmonary disease.Stem cells translational medicine · 2024Article
- Examining the contribution of Notch signaling to lung disease development.Naunyn-Schmiedeberg's archives of pharmacology · 2024Review
- The lysogenic filamentousPNAS nexus · 2024Article
- Surface Modification of Mesoporous Silica Nanoparticles as a Means to Introduce Inherent Cancer-Targeting Ability in a 3D Tumor Microenvironment.Small science · 2024Article
- Emerging cell and molecular targets for treating mucus hypersecretion in asthma.Allergology international : official journal of the Japanese Society of Allergology · 2024Review
- NOTCH3 and Pulmonary Arterial Hypertension.International journal of molecular sciences · 2024Review
- Loss of an extensive ciliary connectome induces proteostasis and cell fate switching in a severe motile ciliopathy.bioRxiv : the preprint server for biology · 2024Article
- The Inovirus Pf4 Triggers Antiviral Responses and Disrupts the Proliferation of Airway Basal Epithelial Cells.Viruses · 2024Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Multiciliated cell loss is a hallmark of airway epithelial remodeling in chronic inflammatory airway diseases including cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease. It disrupts mucociliary clearance, which fuels disease progression. Effective clearance requires an optimal proportion of multiciliated and secretory cells. This is controlled by Notch signaling such that between two adjacent cells the one that activates Notch becomes a secretory cell and the one that avoids Notch activation becomes a multiciliated cell. Consequently, blocking Notch by a small molecule inhibitor of the γ-secretase enzyme that cleaves the Notch receptor for signal activation directs differentiation toward the multiciliated lineage. Thus, γ-secretase inhibitor (GSI) treatment may alleviate multiciliated cell loss in lung disease. Here, we demonstrate the therapeutic restoration of multiciliated cells by the GSI LY450139 (semagacestat). LY450139 increased multiciliated cell numbers in a dose-dependent manner in healthy primary human nasal epithelial cells (HNECs) during differentiation and in mature cultures, but not when applied during early epithelialization of progenitors. LY450139 did not impact stem cell proliferation. Basal and apical administration were equally effective. In healthy adult mice, LY450139 increased multiciliated cell numbers without detectible toxicity. LY450139 also increased multiciliated cells and decreased excess mucus secretory cells in CF HNECs and IL-13 remodeled healthy HNECs. LY450139 normalized multiciliated cell numbers in CF HNECs without interfering with the activity of CFTR modulator compounds. In summary, we demonstrate that GSI administration is a promising therapeutic to restore multiciliated cells and potentially improve epithelial function in a wide range of chronic lung diseases.
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