During development and tissue repair, progenitor cells are guided by both biochemical and biophysical cues of their microenvironment, including topographical signals. The topographical cues have been shown to play an important role in controlling the fate of cells. Systematic investigation of topographical structures with different geometries and sizes under the identical experimental conditions on the same chip will enhance the understanding of the role of shape and size in cell-topography interactions. A simple customizable multi-architecture chip (MARC) array is therefore developed to incorporate, on a single chip, distinct topographies of various architectural complexities, including both isotropic and anisotropic features, in nano- to micrometer dimensions, with different aspect ratios and hierarchical structures. Polydimethylsiloxane (PDMS) replicas of MARC are used to investigate the influence of different geometries and sizes in neural differentiation of primary murine neural progenitor cells (mNPCs). Anisotropic gratings (2 μm gratings, 250 nm gratings) and isotropic 1 μm pillars significantly promote differentiation of mNPCs into neurons, as indicated by expression of β-III-tubulin (59%, 58%, and 58%, respectively, compared to 30% on the control). In contrast, glial differentiation is enhanced on isotropic 2 μm holes and 1 μm pillars. These results illustrate that anisotropic topographies enhance neuronal differentiation while isotropic topographies enhance glial differentiation on the same chip under the same conditions. MARC enables simultaneous cost-effective investigation of multiple topographies, allowing efficient optimization of topographical and biochemical cues to modulate cell differentiation.
Cough is an essential defensive behavior for maintaining airway patency and to protect the lungs from potentially harmful agents. However, inflammatory pathologies can sensitize and activate the neural pathways regulating cough, leading to excessive and nonproductive coughing that serves little protective utility. Problematic cough continues to be one of the most common reasons for seeking medical advice, yet for many patients, it can be refractory to disease-specific treatments and currently available antitussive therapies. The effect of inflammation on cough neural processing occurs not only at the level of the bronchopulmonary sensory nerve terminals but also within the nervous system at multiple peripheral and central sites. Sensory nerves also actively regulate inflammation, and it is therefore a complex interplay between the immune and nervous systems that contributes to chronic cough and the associated sensory hypersensitivities. In this review we provide a brief overview of cough neurobiology in health and disease and then explore the peripheral and central nervous system sites at which neuroimmune interactions can occur. We present advancements in the development of effective antitussive therapies and suggest novel targets for future consideration.
Influenza A virus (IAV) is rapidly detected in the airways by the immune system, with resident parenchymal cells and leukocytes orchestrating viral sensing and the induction of antiviral inflammatory responses. The airways are innervated by heterogeneous populations of vagal sensory neurons which also play an important role in pulmonary defense. How these neurons respond to IAV respiratory infection remains unclear. Here, we use a murine model to provide the first evidence that vagal sensory neurons undergo significant transcriptional changes following a respiratory IAV infection. RNA sequencing on vagal sensory ganglia showed that IAV infection induced the expression of many genes associated with an antiviral and pro‐inflammatory response and this was accompanied by a significant increase in inflammatory cell recruitment into the vagal ganglia. Assessment of gene expression in single‐vagal sensory neurons confirmed that IAV infection induced a neuronal inflammatory phenotype, which was most prominent in bronchopulmonary neurons, and also evident in some neurons innervating other organs. The altered transcriptome could be mimicked by intranasal treatment with cytokines and the lung homogenates of infected mice, in the absence of infectious virus. These data argue that IAV pulmonary infection and subsequent inflammation induces vagal sensory ganglia neuroinflammation and this may have important implications for IAV‐induced morbidity.
Overview of cough and cough hypersensitivity syndromeCough is an important physiological response to airway irritation but can become excessive and problematic in disease. The characteristic cough motor pattern is relatively simple, consisting of an initial inspiration, a brief expiration against a closed glottis and finally forced expiration with the glottis open (1,2). This motor pattern generates large airflow velocities that effectively clear the airways of irritant material. Accordingly, cough plays an essential role in maintaining airway patency in both health and disease. However, despite the simplicity of an observable cough, the underlying neural mechanisms that lead to the production of a cough motor pattern can be quite complex. Firstly, cough can be initiated purely reflexively, mediated by the detection of irritant stimuli in the airway tree by vagal sensory nerve fibres leading to cough induction via the brainstem without any conscious control or regulation (3,4). Additionally, cough can occur with varying levels of volitional or cognitive control. Indeed, cough can be initiated at will, with or without any sensory input from the airways, and it can also be effectively suppressed, both consciously and subconsciously, even at times of strong peripheral sensory drive (5,6). This highlights some of the complexities in understanding the neural processes that control coughing, which is further complicated by multiple types of sensory neurons and receptors in the airways for detecting different Review Article on the 3rd International Cough Conference
Key pointsr Airway projecting sensory neurons arising from the jugular vagal ganglia terminate centrally in the brainstem paratrigeminal nucleus, synapsing upon neurons expressing the neurokinin 1 receptor.r This study aimed to assess the involvement of paratrigeminal neurokinin 1 receptor neurons in the regulation of cough, breathing and airway defensive responses.r Lesioning neurokinin 1 receptor expressing paratrigeminal neurons significantly reduced cough evoked by inhaled bradykinin but not inhaled ATP or tracheal mechanical stimulation.r The reduction in bradykinin-evoked cough was not accompanied by changes in baseline or evoked respiratory variables (e.g. frequency, volume or timing), animal avoidance behaviours or the laryngeal apnoea reflex.r These findings warrant further investigations into targeting the jugular ganglia and paratrigeminal nucleus as a therapy for treating cough in disease.Abstract Jugular vagal ganglia sensory neurons innervate the large airways and are thought to mediate cough and associated perceptions of airway irritations to a range of chemical irritants. The central terminals of jugular sensory neurons lie within the brainstem paratrigeminal nucleus, where postsynaptic neurons can be differentiated based on the absence or presence of the neurokinin 1 (NK1) receptor. Therefore, in the present study, we set out to test the hypothesis that NK1 receptor expressing paratrigeminal neurons play a role in cough evoked by inhaled chemical irritants. To test this, we performed selective neurotoxin lesions of NK1 receptor expressing neurons in the paratrigeminal nucleus in guinea-pigs using substance P conjugated to saporin Alexandria Driessen's research interests are centred around understanding the neurobiology of somatic and visceral sensations and the mechanisms for pathological hypersensitivities. She has spent the last 5 years investigating the neuroanatomy and neurophysiology of vagal sensory pathways, providing novel insights into airway sensory processing in the brain. Dr Driessen's studies have challenged a central dogma in the field and are identifying novel targets for relieving difficult-to-treat sensations associated with respiratory disease.A. K. Driessen and others J Physiol 598.11 (SSP-SAP). Sham lesion control or SSP-SAP lesion guinea-pigs received nebulised challenges, with the pan-nociceptor stimulant bradykinin or the nodose ganglia specific stimulant adenosine 5 -triphosphate (ATP), in conscious whole-body plethysmography to study cough and associated behaviours. Laryngeal apnoea reflexes and cough evoked by mechanical stimulation of the trachea were additionally investigated in anaesthetised guinea-pigs. SSP-SAP significantly and selectively reduced the number of NK1 receptor expressing neurons in the paratrigeminal nucleus. This was associated with a significant reduction in bradykinin-evoked cough, but not ATP-evoked cough, mechanical cough or laryngeal apnoeic responses. These data provide further evidence for a role of jugular vagal pathways in cough, and addition...
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