Dataset Information

Influence of ?-Particle Radiation on Intercellular Communication Networks of Tunneling Nanotubes in U87 Glioblastoma Cells.

ABSTRACT: Cellular communication plays a crucial role in the coordination and organization of cancer cells. Especially processes such as uncontrolled cell growth, invasion, and therapy resistance (development), which are features of very malignant tumors like glioblastomas, are supported by an efficient cell-to-cell communication in the tumor environment. One powerful way for cells to communicate are tunneling nanotubes (TNTs). These tiny membrane tunnels interconnect cells over long distances and serve as highways for information exchange between distant cells. Here, we study the response of cellular communication via TNTs in U87 glioblastoma cells to homogeneous irradiation with ?-particles as a stress factor. We describe the development of TNT networks in certain time steps after irradiation using confocal live-cell imaging and suggest an evaluation method to characterize these communication networks. Our results show that irradiated cells establish their network faster and have more cell-to-cell connections with high TNT content than sham-irradiated controls within the first 24 h. These findings suggest that there is an additional trigger upon radiation damage which results in fast and intensive network formation by TNTs as a radiation damage response mechanism.

SUBMITTER: Matejka N

PROVIDER: S-EPMC7509401 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Influence of α-Particle Radiation on Intercellular Communication Networks of Tunneling Nanotubes in U87 Glioblastoma Cells.

Matejka Nicole N Reindl Judith J

Frontiers in oncology 20200904

Cellular communication plays a crucial role in the coordination and organization of cancer cells. Especially processes such as uncontrolled cell growth, invasion, and therapy resistance (development), which are features of very malignant tumors like glioblastomas, are supported by an efficient cell-to-cell communication in the tumor environment. One powerful way for cells to communicate are tunneling nanotubes (TNTs). These tiny membrane tunnels interconnect cells over long distances and serve a ...[more]

PMID: 33014842

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Project description:Tunneling nanotubes (TNTs) are long bridge-like structures that connect eukaryotic cells and mediate intercellular communication. We found earlier that the conserved alphaherpesvirus US3 protein kinase induces long cell projections that contact distant cells and promote intercellular virus spread. In this report, we show that the US3-induced cell projections constitute TNTs. In addition, we report that US3-induced TNTs mediate intercellular transport of information (e.g., green fluorescent protein [GFP]) in the absence of other viral proteins. US3-induced TNTs are remarkably stable compared to most TNTs described in the literature. In line with this, US3-induced TNTs were found to contain stabilized (acetylated and detyrosinated) microtubules. Transmission electron microscopy showed that virus particles are individually transported in membrane-bound vesicles in US3-induced TNTs and are released along the TNT and at the contact area between a TNT and the adjacent cell. Contact between US3-induced TNTs and acceptor cells is very stable, which correlated with a marked enrichment in adherens junction components beta-catenin and E-cadherin at the contact area. These data provide new structural insights into US3-induced TNTs and how they may contribute to intercellular communication and alphaherpesvirus spread.IMPORTANCE Tunneling nanotubes (TNT) represent an important and yet still poorly understood mode of long-distance intercellular communication. We and others reported earlier that the conserved alphaherpesvirus US3 protein kinase induces long cellular protrusions in infected and transfected cells. Here, we show that US3-induced cell projections constitute TNTs, based on structural properties and transport of biomolecules. In addition, we report on different particular characteristics of US3-induced TNTs that help to explain their remarkable stability compared to physiological TNTs. In addition, transmission electron microscopy assays indicate that, in infected cells, virions travel in the US3-induced TNTs in membranous transport vesicles and leave the TNT via exocytosis. These data generate new fundamental insights into the biology of (US3-induced) TNTs and into how they may contribute to intercellular virus spread and communication.

Project description:BACKGROUND: Tunneling nanotubes (TNTs) may offer a very specific and effective way of intercellular communication. Here we investigated TNTs in the human retinal pigment epithelial (RPE) cell line ARPE-19. Morphology of TNTs was examined by immunostaining and scanning electron microscopy. To determine the function of TNTs between cells, we studied the TNT-dependent intercellular communication at different levels including electrical and calcium signalling, small molecular diffusion as well as mitochondrial re-localization. Further, intercellular organelles transfer was assayed by FACS analysis. METHODOLOGY AND PRINCIPAL FINDINGS: Microscopy showed that cultured ARPE-19 cells are frequently connected by TNTs, which are not attached to the substratum. The TNTs were straight connections between cells, had a typical diameter of 50 to 300 nm and a length of up to 120 µm. We observed de novo formation of TNTs by diverging from migrating cells after a short time of interaction. Scanning electron microscopy confirmed characteristic features of TNTs. Fluorescence microscopy revealed that TNTs between ARPE-19 cells contain F-actin but no microtubules. Depolymerisation of F-actin, induced by addition of latrunculin-B, led to disappearance of TNTs. Importantly, these TNTs could function as channels for the diffusion of small molecules such as Lucifer Yellow, but not for large molecules like Dextran Red. Further, organelle exchange between cells via TNTs was observed by microscopy. Using Ca²? imaging we show the intercellular transmission of calcium signals through TNTs. Mechanical stimulation led to membrane depolarisation, which expand through TNT connections between ARPE-19 cells. We further demonstrate that TNTs can mediate electrical coupling between distant cells. Immunolabelling for Cx43 showed that this gap junction protein is interposed at one end of 44% of TNTs between ARPE-19 cells. CONCLUSIONS AND SIGNIFICANCE: Our observations indicate that human RPE cell line ARPE-19 cells communicate by tunneling nanotubes and can support different types of intercellular traffic.

Dataset Information

Influence of ?-Particle Radiation on Intercellular Communication Networks of Tunneling Nanotubes in U87 Glioblastoma Cells.

Publications

Influence of α-Particle Radiation on Intercellular Communication Networks of Tunneling Nanotubes in U87 Glioblastoma Cells.

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