Recent advances and contraversies on the role of pulmonary neuroepithelial bodies as airway sensors

Cutz, Ernest; Pan, Jie; Yeger, Herman; Domnik, Nicolle J.; Fisher, John T.

doi:10.1016/j.semcdb.2012.09.003

Cited by 106 publications

(114 citation statements)

References 74 publications

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“…Subepithelial mast cells or blood platelets were proposed as a source of serotonin in the mouse trachea (König et al, 2009). In the mammalian tracheo-bronchial epithelium, single serotonin-producing cells (neuroendocrine cells) or cell clusters (neuroendocrine bodies) were described (Cutz et al, 2013;Linnoila, 2006;Van Lommel, 2001). Although serotonin secretion into the airway lumen has not been demonstrated, serotonin released from neuroendocrine cells might influence ciliary beating in neighboring ciliated cells.…”

Section: Discussionmentioning

confidence: 99%

A novel serotonin-secreting cell type regulates ciliary motility in the mucociliary epidermis of Xenopus tadpoles

et al. 2014

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The embryonic skin of Xenopus tadpoles serves as an experimental model system for mucociliary epithelia (MCE) such as the human airway epithelium. MCEs are characterized by the presence of mucus-secreting goblet and multiciliated cells (MCCs). A third cell type, ion-secreting cells (ISCs), is present in the larval skin as well. Synchronized beating of MCC cilia is required for directional transport of mucus. Here we describe a novel cell type in the Xenopus laevis larval epidermis, characterized by serotonin synthesis and secretion. It is termed small secretory cell (SSC). SSCs are detectable at early tadpole stages, unlike MCCs and ISCs, which are specified at early neurulation. Subcellularly, serotonin was found in large, apically localized vesicle-like structures, which were entirely shed into the surrounding medium. Pharmacological inhibition of serotonin synthesis decreased the velocity of cilia-driven fluid flow across the skin epithelium. This effect was mediated by serotonin type 3 receptor (Htr3), which was expressed in ciliated cells. Knockdown of Htr3 compromised flow velocity by reducing the ciliary motility of MCCs. SSCs thus represent a distinct and novel entity of the frog tadpole MCE, required for ciliary beating and mucus transport across the larval skin. The identification and characterization of SSCs consolidates the value of the Xenopus embryonic skin as a model system for human MCEs, which have been known for serotonindependent regulation of ciliary beat frequency.

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Section: Discussionmentioning

confidence: 99%

A novel serotonin-secreting cell type regulates ciliary motility in the mucociliary epidermis of Xenopus tadpoles

et al. 2014

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“…Although the functional relationship between solitary PNEC and NEB cell clusters is presently unclear, NEBs neuroepithelial bodies are presumed polymodal airway sensors responding to a variety of stimuli including hypoxia, hypercarbia, acidosis, and mechanical stretch. 9,20 PNEC/NEB produce amine (serotonin) and peptides, particularly bombesin in human lung and Figure 6 Tripple immunostaining of NEB containing up to 13 nuclei in lung of control 2-month-old infant. The section was first immunostained for bombesin (FITC, green), Mash1 (rhodamine, red), and HIF1α (ALEXA 680, pseudogreen); after stripping the section was re probed with antibodies against bombesin (rhodamine, red) and Prox1 (FITC green).…”

Section: Discussionmentioning

confidence: 99%

“…Although the precise function of NEBs neuroepithelial bodies is presently unknown, the predominant hypothesis suggests a role in respiratory control, particularly during the perinatal period when these cells are most prominent. 9,20 Whereas responses of NEB cells to acute hypoxia are mediated by ion channels, chronic sustained hypoxia involves the general cellular O 2 sensors, prolyl-hydroxylases, with downstream effects on expression of HIFs that in turn regulate expression of a large number of genes required for adaptation to a hypoxic environment. 21 Previous studies identified hyperplasia of solitary PNEC and PNEC clusters, NEBs, in a number of pediatric lung disorders including chronic lung disease of prematurity, BPD PNEC and NEBs, which is associated with high morbidity and mortality.…”

Section: Discussionmentioning

confidence: 99%

Multilabel immunofluorescence and antigen reprobing on formalin-fixed paraffin-embedded sections: novel applications for precision pathology diagnosis

et al. 2016

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We report new methods for multilabel immunofluorescence (MIF) and reprobing of antigen epitopes on the same formalin-fixed paraffin-embedded (FFPE) sections. The MIF method includes an antigen-retrieval step followed by multilabel immunostaining and examination by confocal microscopy. As examples, we illustrate epitopes localized to the apical and basolateral membranes, and the cytoplasm of enterocytes of normal small intestine and in cases of congenital enteropathies (microvillous inclusion disease and congenital tufting enteropathy). We also demonstrate localization of the bile salt excretion pump protein (BSEP) in bile canalicular membrane of normal hepatocytes and in cases of primary sclerosing cholangitis. To demonstrate colocalization of cytoplasmic and nuclear epitopes we analyzed normal control and hyperplastic pulmonary neuroendocrine cells (PNEC) and neuroepithelial bodies (NEBs), presumed airway sensors in the lungs of infants with bronchopulmonary dysplasia (BPD). As cytoplasmic markers we used anti-bombesin or anti-synaptic vesicle protein 2 (SV2) antibody, respectively, and for nuclear localization, antibodies against neurogenic genes mammalian achaete-scute homolog (Mash1) and prospero homeobox 1 (Prox1), essential for NEB cells differentiation and maturation, hypoxia-inducible factor 1α (HIF1α) a downstream modulator of hypoxia response and a proliferation marker Ki67. The reprobing method consisted of removal of the previously immunolabeled target and immunostaining with different antibodies, facilitating colocalization of enterocyte brush border epitopes as well as HIF1α, Mash1 and Prox1 in PNEC/NEB PNEC and NEBs. As these methods are suitable for routine FFPE pathology samples from various tissues, allowing visualization of multiple epitopes in the same cells/sections with superior contrast and resolution, they are suitable for a wide range of applications in diagnostic pathology and may be particularly well suited for precision medicine diagnostics.

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“…NE cells are particular in their distribution, as they can be solitary or form small or large groups (Fig. 4A) (Cutz et al, 2013). In pathological conditions, their unclustering is associated with increased neuropeptide release and increased immune response (Branchfield et al, 2016).…”

Section: Lung Epithelial Neuroendocrine Mini-organs: Slithering Untilmentioning

confidence: 99%

“…A plethora of studies have provided insights into the key molecular mechanisms that underlie cell induction and differentiation during the formation of these miniorgans (reviewed by Ahn, 2015;Aman and Piotrowski, 2011;Barlow, 2015;Biggs and Mikkola, 2014;Chitnis et al, 2012;Cutz et al, 2013;Fuchs, 2015;Fuchs and Nowak, 2008;Heller and Fuchs, 2015;Lee and Tumbar, 2012;Montell, 2008). However, it is only during the last few years that methodological improvements have rendered these organs accessible for in vivo imaging techniques.…”

Section: Introductionmentioning

confidence: 99%

Epithelial cell behaviours during neurosensory organ formation

Kapsimali

2017

Development

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Perception of the environment in vertebrates relies on a variety of neurosensory mini-organs. These organs develop via a multi-step process that includes placode induction, cell differentiation, patterning and innervation. Ultimately, cells derived from one or more different tissues assemble to form a specific mini-organ that exhibits a particular structure and function. The initial building blocks of these organs are epithelial cells that undergo rearrangements and interact with neighbouring tissues, such as neural crest-derived mesenchymal cells and sensory neurons, to construct a functional sensory organ. In recent years, advances in in vivo imaging methods have allowed direct observation of these epithelial cells, showing that they can be displaced within the epithelium itself via several modes. This Review focuses on the diversity of epithelial cell behaviours that are involved in the formation of small neurosensory organs, using the examples of dental placodes, hair follicles, taste buds, lung neuroendocrine cells and zebrafish lateral line neuromasts to highlight both well-established and newly described modes of epithelial cell motility.

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Recent advances and contraversies on the role of pulmonary neuroepithelial bodies as airway sensors

Cited by 106 publications

References 74 publications

A novel serotonin-secreting cell type regulates ciliary motility in the mucociliary epidermis of Xenopus tadpoles

A novel serotonin-secreting cell type regulates ciliary motility in the mucociliary epidermis of Xenopus tadpoles

Multilabel immunofluorescence and antigen reprobing on formalin-fixed paraffin-embedded sections: novel applications for precision pathology diagnosis

Epithelial cell behaviours during neurosensory organ formation

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