Notch signaling in the mammalian respiratory system, specifically the trachea and lungs, in development, homeostasis, regeneration, and disease

Kiyokawa, Hirofumi; Morimoto, Mitsuru

doi:10.1111/dgd.12628

Cited by 90 publications

(74 citation statements)

References 66 publications

(87 reference statements)

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“…Suppression of Notch signaling promotes ciliated cell fate, whereas high levels of Notch promote the differentiation toward mucus-secreting goblet cells. 12,13 Type 2 cytokines such as IL-4 and IL-13 stimulate Notch signaling, 14,15 which results in increased number of mucus-secreting goblet cells as found in asthma, CRS, and other diseases. 16 Ciliated epithelial cells contain a large number of cilia, which are necessary for the mucociliary clearance.…”

Section: Cellular Diversity In the Airway Epitheliummentioning

confidence: 99%

Epithelial barriers in allergy and asthma

Hellings

Steelant

2020

Journal of Allergy and Clinical Immunology

218

180

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The respiratory epithelium provides a physical, functional, and immunologic barrier to protect the host from the potential harming effects of inhaled environmental particles and to guarantee maintenance of a healthy state of the host. When compromised, activation of immune/inflammatory responses against exogenous allergens, microbial substances, and pollutants might occur, rendering individuals prone to develop chronic inflammation as seen in allergic rhinitis, chronic rhinosinusitis, and asthma. The airway epithelium in asthma and upper airway diseases is dysfunctional due to disturbed tight junction formation. By putting the epithelial barrier to the forefront of the pathophysiology of airway inflammation, different approaches to diagnose and target epithelial barrier defects are currently being developed. Using single-cell transcriptomics, novel epithelial cell types are being unraveled that might play a role in chronicity of respiratory diseases. We here review and discuss the current understandings of epithelial barrier defects in type 2-driven chronic inflammation of the upper and lower airways, the estimated contribution of these novel identified epithelial cells to disease, and the current clinical challenges in relation to diagnosis and treatment of allergic rhinitis, chronic rhinosinusitis, and asthma.

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Section: Cellular Diversity In the Airway Epitheliummentioning

confidence: 99%

Epithelial barriers in allergy and asthma

Hellings

Steelant

2020

Journal of Allergy and Clinical Immunology

218

180

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“…The NOTCH signaling pathway plays a crucial role in regulating cell fate decisions of multiple cell types in the human and murine airway epithelium including basal, ciliated, club and goblet cells(11). Here we demonstrate that CSE exposure of airway epithelium generated from nonsmoker and COPD-smoker derived HBECs on ALI culture promotes GCMH in a NOTCHdependent manner.…”

mentioning

confidence: 57%

Cigarette Smoke Activates NOTCH3 to Promote Goblet Cell Differentiation in Human Airway Epithelial Cells

Bodas

Moore

Bharathiraja

et al. 2020

Preprint

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Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death in the United States and is primarily caused by cigarette smoking. Increased numbers of mucus-producing secretory (goblet) cells defined as goblet cell metaplasia or hyperplasia (GCMH), contributes significantly to COPD pathophysiology. The objective of this study was to determine whether NOTCH signaling regulates goblet cell differentiation in response to cigarette smoke. Primary human bronchial epithelial cells (HBECs) from nonsmokers and COPD smokers were differentiated in vitro on air-liquid interface and exposed to cigarette smoke extract (CSE) for 7 days. NOTCH signaling activity was modulated using (1) the NOTCH/γ-secretase inhibitor Dibenzazepine (DBZ), (2) lentiviral over-expression of the NOTCH3-intracellular domain (NICD3) or (3) NOTCH3-specific siRNA. Cell differentiation and response to CSE were evaluated by qPCR, Western blotting, immunostaining and RNA-Seq. We found that CSE exposure of nonsmoker airway epithelium induced goblet cell differentiation characteristic of GCMH. Treatment with DBZ suppressed CSE-dependent induction of goblet cell differentiation. Furthermore, CSE induced NOTCH3 activation, as revealed by increased NOTCH3 nuclear localization and elevated NICD3 protein levels. Over-expression of NICD3 increased the expression of goblet cell associated genes SPDEF and MUC5AC, whereas NOTCH3 knockdown suppressed CSE-mediated induction of SPDEF and MUC5AC. Finally, CSE exposure of COPD airway epithelium induced goblet cell differentiation in a NOTCH3-dependent manner. These results identify NOTCH3 activation as one of the important mechanisms by which cigarette smoke induces goblet cell differentiation, thus providing a novel potential strategy to control GCMH-related pathologies in smokers and patients with COPD.

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“…Through the use of DAPT, a gamma secretase inhibitor (GSI) that prevents gamma secretase-mediated cleavage of Notch receptors [41], Tsao at el. demonstrated that the blockade of proteolytical Notch processing in murine lung primordium explants resulted in lung outgrows that exhibited significantly reduced levels of Sox2 [5], a factor present in proximal progenitors that are necessary for the generation and maintenance of several cell lineages, including basal and club cells [42]. In these studies, it was markedly shown that while lung buds were formed by E8.5 and the distal region appeared substantially enlarged, impaired growth in the proximal region was observed [5].…”

Section: Notch Signaling In Lung Developmentmentioning

confidence: 90%

Notch Transduction in Non-Small Cell Lung Cancer

Sharif

Shaji

Chammaa

et al. 2020

IJMS

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The evolutionarily-conserved Notch signaling pathway plays critical roles in cell communication, function and homeostasis equilibrium. The pathway serves as a cell-to-cell juxtaposed molecular transducer and is crucial in a number of cell processes including cell fate specification, asymmetric cell division and lateral inhibition. Notch also plays critical roles in organismal development, homeostasis, and regeneration, including somitogenesis, left-right asymmetry, neurogenesis, tissue repair, self-renewal and stemness, and its dysregulation has causative roles in a number of congenital and acquired pathologies, including cancer. In the lung, Notch activity is necessary for cell fate specification and expansion, and its aberrant activity is markedly linked to various defects in club cell formation, alveologenesis, and non-small cell lung cancer (NSCLC) development. In this review, we focus on the role this intercellular signaling device plays during lung development and on its functional relevance in proximo-distal cell fate specification, branching morphogenesis, and alveolar cell determination and maturation, then revise its involvement in NSCLC formation, progression and treatment refractoriness, particularly in the context of various mutational statuses associated with NSCLC, and, lastly, conclude by providing a succinct outlook of the therapeutic perspectives of Notch targeting in NSCLC therapy, including an overview on prospective synthetic lethality approaches.

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Notch signaling in the mammalian respiratory system, specifically the trachea and lungs, in development, homeostasis, regeneration, and disease

Cited by 90 publications

References 66 publications

Epithelial barriers in allergy and asthma

Epithelial barriers in allergy and asthma

Cigarette Smoke Activates NOTCH3 to Promote Goblet Cell Differentiation in Human Airway Epithelial Cells

Notch Transduction in Non-Small Cell Lung Cancer

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