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Intercellular communication is indispensable across multicellular organisms, and any aberration in this process can give rise to significant anomalies in developmental and homeostatic processes. Thus, a comprehensive understanding of its mechanisms is imperative for addressing human health-related concerns. Recent advances have expanded our understanding of intercellular communication by elucidating additional signaling modalities alongside established mechanisms. Notably, cellular protrusion-mediated long-range communication, characterized by physical contact through thin and elongated cellular protrusions between cells involved in signal transmission and reception, has emerged as a significant intercellular signaling paradigm. This chapter delves into the exploration of a signaling cellular protrusion termed 'airinemes,' discovered in the zebrafish skin. It covers their identified signaling roles and the cellular and molecular mechanisms that underpin their functionality.

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Actin-based protrusions are at the base of many fundamental cellular processes, such as cell adhesion, migration and intercellular communication. In recent decades, the discovery of new types of actin-based protrusions with unique functions has enriched our comprehension of cellular processes. However, as the repertoire of protrusions continues to expand, the rationale behind the classification of newly identified and previously known structures becomes unclear. Although current nomenclature allows good categorization of protrusions based on their functions, it struggles to distinguish them when it comes to structure, composition or formation mechanisms. In this Cell Science at a Glance article, we discuss the different types of actin-based protrusions, focusing on filopodia, cytonemes and tunneling nanotubes, to help better distinguish and categorize them based on their structural and functional differences and similarities.

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Tissue-resident macrophages are heterogeneous and perform location-dependent functions. Skin resident macrophages play intriguing roles in long-distance intercellular signaling by mediating cellular protrusions called airinemes in zebrafish. These macrophages relay signaling molecules containing airineme vesicles between pigment cells, and their absence disrupts airineme-mediated signaling and pigment pattern formation. It is unknown if the same macrophages control both these signaling and typical immune functions or if a separate subpopulation functions in intercellular communication. With high-resolution imaging and genetic ablation approaches, we identify a macrophage subpopulation responsible for airineme-mediated signaling. These seem to be distinct from conventional skin-resident macrophages by their ameboid morphology and faster or expansive migratory behaviors. They resemble ectoderm-derived macrophages termed metaphocytes. Metaphocyte ablation markedly decreases airineme extension and signaling. In addition, these ameboid/metaphocytes require matrix metalloproteinase-9 for their migration and airineme-mediated signaling. These results reveal a macrophage subpopulation with specialized functions in airineme-mediated signaling, which may play roles in other aspects of intercellular communication.

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In multicellular organisms, interactions between cells and intercellular communications form the very basis of the organism's survival, the functioning of its systems, the maintenance of homeostasis and adequate response to the environment. The accumulated experimental data point to the particular importance of intercellular communications in determining the fate of cells, as well as their differentiation and plasticity. For a long time, it was believed that the properties and behavior of cells were primarily governed by the interactions of secreted or membrane-bound ligands with corresponding receptors, as well as direct intercellular adhesion contacts. In this review, we describe various types of other, non-classical intercellular interactions and communications that have recently come into the limelight-in particular, the broad repertoire of extracellular vesicles and membrane protrusions. These communications are mediated by large macromolecular structural and functional ensembles, and we explore here the mechanisms underlying their formation and present current data that reveal their roles in multiple biological processes. The effects mediated by these new types of intercellular communications in normal and pathological states, as well as therapeutic applications, are also discussed. The in-depth study of novel intercellular interaction mechanisms is required for the establishment of effective approaches for the control and modification of cell properties both for basic research and the development of radically new therapeutic strategies.

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The function of Hedgehog (Hh) as a morphogen results from its long-distance distribution from producing to neighboring receiving cells within the developing tissue. This signal distribution enables, for example, the formation of a concentration gradient eliciting distinct cellular responses that will give rise to spatial patterning. Hh is a lipid modified protein and its dispersion is better guaranteed through cytonemes, cell protrusions that allow direct cell membrane contact and signal transfer at a distance. Hh and its receptor Patched (Ptc) meet at cytoneme contacts in a way that reminds synapses. Both Hh and Ptc require a recycling process prior to presentation in cytonemes. Increasing research on the role of cytonemes in Hh signaling is revealing cellular mechanisms that link signal transport through dynamic cytonemes with concurrent regulation of cell adhesion. The equilibrium between these two processes is being unveiled as crucial to both patterned morphogen distribution and signal transfer. In addition, these discoveries are pushing forward our understanding of the role of extracellular elements involved in the Hh pathway, such as the Hh coreceptors Ihog and Boi and the glypicans Dally and Dally-like protein (Dlp).

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So far, only two retroviruses, human immunodeficiency virus (HIV) (type 1 and 2) and human T-cell lymphotropic virus type 1 (HTLV-1), have been recognized as pathogenic for humans. Both viruses mainly infect CD4+ T lymphocytes. HIV replication induces the apoptosis of CD4 lymphocytes, leading to the development of acquired immunodeficiency syndrome (AIDS). After a long clinical latency period, HTLV-1 can transform lymphocytes, with subsequent uncontrolled proliferation and the manifestation of a disease called adult T-cell leukemia (ATLL). Certain infected patients develop neurological autoimmune disorder called HTLV-1-associated myelopathy, also known as tropical spastic paraparesis (HAM/TSP). Both viruses are transmitted between individuals via blood transfusion, tissue/organ transplantation, breastfeeding, and sexual intercourse. Within the host, these viruses can spread utilizing either cell-free or cell-to-cell modes of transmission. In this review, we discuss the mechanisms and importance of each mode of transmission for the biology of HIV-1 and HTLV-1.

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WNT signaling is a key developmental pathway in tissue organization. A recent focus of research is the secretion of WNT proteins from source cells. Research over the past decade on how WNTs are produced and released into the extracellular space has unravelled very specific control mechanisms in the early secretory pathway, specialized trafficking routes, and redundant forms of packaging for delivery to target cells. In this review I discuss the findings that WNT proteins have been found on extracellular vesicles (EVs) such as exosomes and possible functional implications. There is an ongoing debate in the WNT signaling field whether EV are relevant in vivo and can fulfill specific functions, also fueled by the general preconception of EV secretion as cellular garbage disposal. As part of the EV research community, I want to give an overview of what we know and don't know about WNT secretion on EVs and offer a more unifying model that can explain current discrepancies in observations regarding WNT secretion.

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The conserved family of Hedgehog (Hh) signaling proteins plays a key role in cell-cell communication in development, tissue repair, and cancer progression, inducing distinct concentration-dependent responses in target cells located at short and long distances. One simple mechanism for long distance dispersal of the lipid modified Hh is the direct contact between cell membranes through filopodia-like structures known as cytonemes. Here we have analyzed in Drosophila the interaction between the glypicans Dally and Dally-like protein, necessary for Hh signaling, and the adhesion molecules and Hh coreceptors Ihog and Boi. We describe that glypicans are required to maintain the levels of Ihog, but not of Boi. We also show that the overexpression of Ihog, but not of Boi, regulates cytoneme dynamics through their interaction with glypicans, the Ihog fibronectin III domains being essential for this interaction. Our data suggest that the regulation of glypicans over Hh signaling is specifically given by their interaction with Ihog in cytonemes. Contrary to previous data, we also show that there is no redundancy of Ihog and Boi functions in Hh gradient formation, being Ihog, but not of Boi, essential for the long-range gradient.

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The Wnt-pathway is part of a signalling network that regulates many aspects of cell biology. Recently, we discovered crosstalk between AMPA/Kainate-type ionotropic glutamate receptors (iGluRs) and the Wnt-pathway during the initial Wnt3a-interaction at the cytonemes of mouse embryonic stem cells (ESCs). Here, we demonstrate that this crosstalk persists throughout the Wnt3a-response in ESCs. Both AMPA and Kainate receptors regulate early Wnt3a-recruitment, dynamics on the cell membrane, and orientation of the spindle towards a Wnt3a-source at mitosis. AMPA receptors specifically are required for segregating cell fate components during Wnt3a-mediated asymmetric cell division (ACD). Using Wnt-pathway component knockout lines, we determine that Wnt co-receptor Lrp6 has particular functionality over Lrp5 in cytoneme formation, and in facilitating ACD. Both Lrp5 and 6, alongside pathway effector ß-catenin act in concert to mediate the positioning of the dynamic interaction with, and spindle orientation to, a localised Wnt3a-source. Wnt-iGluR crosstalk may prove pervasive throughout embryonic and adult stem cell signalling.

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Understanding the mechanisms of cell-to-cell communication is one of the fundamental questions in biology and medicine. In particular, long-range signalling where cells communicate over several cell diameters is vital during development and homeostasis. The major morphogens, their receptors and intracellular signalling cascades have largely been identified; however, there is a gap in our knowledge of how such signalling factors are propagated over a long distance. In addition to the diffusion-based propagation model, new modalities of disseminating signalling molecules have been identified. It has been shown that cells can communicate with direct contact through long, thin cellular protrusions between signal sending and receiving cells at a distance. Recent studies have revealed a type of cellular protrusion termed 'airinemes' in zebrafish pigment cell types. They share similarities with previously reported cellular protrusions; however, they also exhibit distinct morphology and features. Airinemes are indispensable for pigment pattern development by mediating long-distance Delta-Notch signalling between different pigment cell types. Notably, airineme-mediated signalling is dependent on skin-resident macrophages. Key findings of airineme-mediated intercellular signalling in pattern development, their interplay with macrophages and their implications for the understanding of cellular protrusion-mediated intercellular communication will be discussed.

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Disease progression in many tumor types involves the interaction of genetically abnormal cancer cells with normal stromal cells. Neoplastic transformation in a Drosophila genetic model of epidermal growth factor receptor (EGFR)-driven tumorigenesis similarly relies on the interaction between epithelial and mesenchymal cells, providing a simple system to investigate mechanisms used for the cross-talk. Using the Drosophila model, we show that the transformed epithelium hijacks the mesenchymal cells through Notch signaling, which prevents their differentiation and promotes proliferation. A key downstream target in the mesenchyme is Zfh1/ZEB. When Notch or zfh1 are depleted in the mesenchymal cells, tumor growth is compromised. The ligand Delta is highly upregulated in the epithelial cells where it is found on long cellular processes. By using a live transcription assay in cultured cells and by depleting actin-rich processes in the tumor epithelium, we provide evidence that signaling can be mediated by cytonemes from Delta-expressing cells. We, thus, propose that high Notch activity in the unmodified mesenchymal cells is driven by ligands produced by the cancerous epithelial. This long-range Notch signaling integrates the two tissues to promote tumorigenesis, by co-opting a normal regulatory mechanism that prevents the mesenchymal cells from differentiating.

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Hedgehog (Hh) signal molecules play a fundamental role in development, adult stem cell maintenance and cancer. Hh can signal at a distance, and we have proposed that its graded distribution across Drosophila epithelia is mediated by filopodia-like structures called cytonemes. Hh reception by Patched (Ptc) happens at discrete sites along presenting and receiving cytonemes, reminiscent of synaptic processes. Here, we show that a vesicle fusion mechanism mediated by SNARE proteins is required for Ptc placement at contact sites. Transport of Ptc to these sites requires multivesicular bodies (MVBs) formation via ESCRT machinery, in a manner different to that regulating Ptc/Hh lysosomal degradation after reception. These MVBs include extracellular vesicle (EV) markers and, accordingly, Ptc is detected in the purified exosomal fraction from cultured cells. Blockage of Ptc trafficking and fusion to basolateral membranes result in low levels of Ptc presentation for reception, causing an extended and flattened Hh gradient.

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Intercellular communication is a fundamental property of multicellular organisms, necessary for their adequate responses to changing environment. Tunneling nanotubes (TNTs) represent a novel means of intercellular communication being a long cell-to-cell conduit. TNTs are actively formed under a broad range of stresses and are also proposed to exist under physiological conditions. Development is a physiological condition of particular interest, as it requires fine coordination. Here we discuss whether protrusions shown to exist during embryonic development of different species could be TNTs or if they represent other types of cell structure, like cytonemes or intercellular bridges, that are suggested to play an important role in development.

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Ephrins can elicit either contact-mediated cell-cell adhesion or repulsion, depending on the efficiency of the removal of their ligand-receptor complexes from the cell surface, thus controlling tissue morphogenesis and oncogenic development. However, the dynamic of the turnover of newly assembled ephrin-Eph complexes during cell-cell interactions remains mostly unexplored. Here, we show that ephrin-A1-EphA2 complexes are locally formed at the tip of the filopodia, at cell-to-cell contacts. Clusters of ephrin-A1 from donor cells surf on filopodia associated to EphA2-bearing subdomains of acceptor cells. Full-length ephrin-A1 is transferred to acceptor cells by trans-endocytosis through a proteolysis-independent mechanism. Trans-endocytosed ephrin-A1 bound to its receptor enables signaling to be emitted from endo-lysosomes of acceptor cells. Localized trans-endocytosis of ephrin-A1 sustains contact-mediated repulsion on cancer cells. Our results uncover the essential role played by local concentration at the tip of filopodia and the trans-endocytosis of full-length ephrin to maintain long-lasting ephrin signaling.

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Increasing evidence during the past two decades shows that cells interconnect and communicate through cytonemes. These cytoskeleton-driven extensions of specialized membrane territories are involved in cell-cell signaling in development, patterning, and differentiation, but also in the maintenance of adult tissue homeostasis, tissue regeneration, and cancer. Brain tumor cells in glioblastoma extend ultralong membrane protrusions (named tumor microtubes, TMs), which contribute to invasion, proliferation, radioresistance, and tumor progression. Here we review the mechanisms underlying cytoneme formation, regulation, and their roles in cell signaling and communication in epithelial cells and other cell types. Furthermore, we discuss the recent discovery of glial cytonemes in the Drosophila glial cells that alter Wingless (Wg)/Frizzled (Fz) signaling between glia and neurons. Research on cytoneme formation, maintenance, and cell signaling mechanisms will help to better understand not only physiological developmental processes and tissue homeostasis but also cancer progression.

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Cell membrane nanotubes, variously referred to as tunneling nanotubes and cytonemes, are currently the focus of much interest. They are of ancient origin, as indicated by their opportunistic use for cell invasion by pathogens, including bacteria and virus, and by their employment in bacterial networking. They play a significant role in cancer invasion and in the explanation of glioblastoma resistance to treatment. Their structure and properties have been investigated with optical tweezers. They have been detected in vivo. Their role in the immune system was early verified. Very recently, it was shown that they share many properties with nerve synapses, including the roles of glutamate and Ca ions. Similar features have also been observed in primitive plants. These results support the conjecture that, besides their roles in immunology, developmental biology and cancer, cell membrane nanotubes are the ancestors of the nervous system.

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Mast cells (MCs) are critical mediators of inflammation; however, their microbicidal activity against invading pathogens remains largely unknown. Here, we describe a nonpreviously reported antibacterial mechanism used by MCs against Coxiella burnetii, the agent of Q fever. We show that C. burnetii interaction with MCs does not result in bacterial uptake but rather induces the formation of extracellular actin filaments named cytonemes. MC cytonemes express cathelicidin and neutrophil elastase and mediate the capture and destruction of entrapped bacteria. We provide evidence that MC cytoneme formation and microbicidal activity are dependent on the cooperation of the scavenger receptor CD36 and Toll-like receptor 4. Taken together, our results suggest that MCs use an extracellular sophisticated mechanism of defense to eliminate intracellular pathogens, such as C. burnetii, before their entry into host cells.IMPORTANCE Mast cells (MCs) are found in tissues that are in close contact with external environment, such as skin, lungs, or intestinal mucosa but also in the placenta during pregnancy. If their role in mediating allergic conditions is established, several studies now highlight their importance during infection with extracellular pathogens. This study showed a new and effective antimicrobial mechanism of MCs against Coxiella burnetii, an intracellular bacterium whose infection during pregnancy is associated with abortion, preterm labor, and stillbirth. The data reveal that in response to C. burnetii, MCs release extracellular actin filaments that contain antimicrobial agents and are capable to trap and kill bacteria. We show that this mechanism is dependent on the cooperation of two membrane receptors, CD36 and Toll-like receptor 4, and may occur in the placenta during pregnancy by using ex vivo placental MCs. Overall, this study reports an unexpected role for MCs during infection with intracellular bacteria and suggests that MC response to C. burnetii infection is a protective defense mechanism during pregnancy.

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The Hedgehog (Hh) family of morphogens direct cell fate decisions during embryogenesis and signal to maintain tissue homeostasis after birth. Hh ligands harbor dual lipid modifications that anchor the proteins into producing cell membranes, effectively preventing ligand release. The transporter-like protein Dispatched (Disp) functions to release these membrane tethers and mobilize Hh ligands to travel toward distant cellular targets. The molecular mechanisms by which Disp achieves Hh deployment are not yet fully understood, but a number of recent publications provide insight into the complex process of Hh release. Herein we review this literature, integrate key discoveries, and discuss some of the open questions that will drive future studies aimed at understanding Disp-mediated Hh ligand deployment.

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BACKGROUND: Nitric Oxide (NO) is a key signalling molecule that has an important role in inflammation. It can be secreted by endothelial cells, neutrophils, and other cells, and once in circulation, NO plays important roles in regulating various neutrophil cellular activities and fate. OBJECTIVE: To describe neutrophil cellular responses influenced by NO and its concomitant compound peroxynitrite and signalling mechanisms for neutrophil apoptosis. METHODS: Literature was reviewed to assess the effects of NO on neutrophils. RESULTS: NO plays an important role in various neutrophil cellular activities and interaction with other cells. The characteristic cellular activities of neutrophils are adhesion and phagocytosis. NO plays a protective role in neutrophil-endothelial interaction by preventing neutrophil adhesion and endothelial cell damage by activated neutrophils. NO suppresses neutrophil phagocytic activity but stimulates longdistance contact interactions through tubulovesicular extensions or cytonemes. Neutrophils are the main source of superoxide, but NO flow results in the formation of peroxynitrite, a compound with high biological activity. Peroxynitrite is involved in the regulation of eicosanoid biosynthesis and inhibits endothelial prostacyclin synthase. NO and peroxynitrite modulate cellular 5-lipoxygenase activity and leukotriene synthesis. Long-term exposure of neutrophils to NO results in the activation of cell death mechanisms and neutrophil apoptosis. CONCLUSION: Nitric oxide and the NO/superoxide interplay fine-tune mechanisms regulating life and death in neutrophils.

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Conserved morphogenetic signaling proteins disperse across tissues to generate signal and signaling gradients, which in turn are considered to assign positional coordinates to the recipient cells. Recent imaging studies in Drosophila model have provided evidence for a "direct-delivery" mechanism of signal dispersion that is mediated by specialized actin-rich signaling filopodia, named cytonemes. Cytonemes establish contact between the signal-producing and target cells to directly exchange and transport the morphogenetic proteins. Although an increasing amount of evidence supports the critical role of these specialized signaling structures, imaging these highly dynamic 200 nm-thin structures in the complex three-dimensional contour of living tissues is challenging. Here, we describe the imaging methods that we optimized for studying cytonemes in Drosophila embryos.

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