Emerging role of contact-mediated cell communication in tissue development and diseases

Histochemistry and Cell Biology https://doi.org/10.1007/s00418-018-1732-3 REVIEW Emerging role of contact-mediated cell communication in tissue development and diseases Benjamin Mattes1 · Steffen Scholpp1 Accepted: 18 September 2018 © The Author(s) 2018 Abstract Cells of multicellular organisms are in continuous conversation with the neighbouring cells. The sender cells signal the receiver cells to influence their behaviour in transport, metabolism, motility, division, and growth. How cells communicate with each other can be categorized by biochemical signalling processes, which can be characterised by the distance between the sender cell and the receiver cell. Existing classifications describe autocrine signals as those where the sender cell is identical to the receiver cell. Complementary to this scenario, paracrine signalling describes signalling between a sender cell and a different receiver cell. Finally, juxtacrine signalling describes the exchange of information between adjacent cells by direct cell contact, whereas endocrine signalling describes the exchange of information, e.g., by hormones between distant cells or even organs through the bloodstream. In the last two decades, however, an unexpected communication mechanism has been identified which uses cell protrusions to exchange chemical signals by direct contact over long distances. These signalling protrusions can deliver signals in both ways, from sender to receiver and vice versa. We are starting to understand the morphology and function of these signalling protrusions in many tissues and this accumulation of findings forces us to revise our view of contact-dependent cell communication. In this review, we will focus on the two main categories of signalling protrusions, cytonemes and tunnelling nanotubes. These signalling protrusions emerge as essential structural components of a vibrant communication network in the development and tissue homeostasis of any multicellular organism. Keywords Cytoneme · Tunnelling nanotubes · Contact-dependent signalling · Paracrine signalling · Wnt · Hedgehog · Trafficking An introduction into contact‑dependent cell communication Cell–cell communication by interaction of the receptors and ligands of directly adjacent cells is generally defined as juxtacrine signalling. Here, signalling components bind to their counterparts on the neighbouring cells. Notch–Delta signalling is one of the best-studied examples for such a fundamental communication mechanism that governs the differentiation of many cell types (Fortini 2009). The core Notch signalling pathway contains only a small number of signalling components such as the Notch receptors and its ligands from, for example, the Delta-like and Jagged * Steffen Scholpp 1 Living Systems Institute, School of Biosciences, College of Life and Environmental Science, University of Exeter, Exeter EX4 4QD, UK families. Activation of the Notch receptor by ligand binding triggers its own proteolytic cleavage, leading to subsequent translocation of the intracellular domain of the receptor to the nucleus to initiate the transcription of Notch target genes. Remarkably, both of the main signalling components, the Notch receptors as well as the ligands, are membrane-bound. Initiation of signalling requires, therefore, a close physical interaction of the sender cell with the receiver cell and a precise steric orientation of the transmembrane signalling components to allow interactions between cells (in trans). However, this classical example for juxtacrine signalling process has been called into question. Notch–Delta interaction has also been observed to operate between distant cells in a tissue. How can we solve this contradictory observation compared to the definition of juxtacrine signalling of adjacent cells? An alternative means to localize Notch activation is by positioning Notch signalling components at cellular protrusions, which leads to the activation of signalling at distance (De Joussineau et al. 2003; Cohen et al. 2010). These 13 Vol.:(0123456789) Histochemistry and Cell Biology signalling filopodia can span over several cell diameters and have been defined as cytonemes (Ramírez-Weber and Kornberg 1999). Cytonemes transport a large variety of signalling components in many tissues and organisms (Kornberg and Roy 2014). Our knowledge of cytonemal transport has steadily increased in the last years and we will discuss recent advances in this review. Another form of contact-dependent and long-range signalling requires the formation of thin membranous, cytoplasmic connections (Gerdes and Carvalho 2008). Through cytoplasmic connections, various types of information can be transmitted. Various experimental settings demonstrate that the biochemical signals—soluble and membrane tethered—can be selectively transported through membranous tubes between cells, which suggest that their membranes and cytoplasm are continuously connected. Due to their structure, these conduits have been termed as tunnelling nanotubes (TNTs). Low molecular weight biochemical signals were not the only components observed in these conduits: vesicles and even organelles enter these tubes on one side, then transport along the tube, and exit into the connected cell (Sisakhtnezhad and Khosravi 2015). During this unidirectional transfer, a continuous and rapid translocation of these structures could be detected at any given point along the conduit, which was consistent with the existence of a direct intercellular transfer mechanism based on membrane continuity. In addition to biochemical signals and organelles, these thin cytoplasm-filled bridges can also be used to transfer electrical and mechanical stimuli from one cell to another. In a following section, we will discuss the function of these TNTs with regard to information exchange. After examining the recent advances in our understanding of cytonemes and TNTs, we will compare these two kinds of signalling protrusions. We hypothesize that they serve as an underlying structure of an emerging information grid between cells. This information network connects cells with an end-to-end principal for precise collecting, disseminating, and managing information. This is crucial during development of embryonic tissues, for maintaining balance of mature tissues and to facilitate tissue response to a disease in multicellular organism. The multiple functions of filopodia Filopodia are actin-rich membrane protrusions that extend from cells (Mattila and Lappalainen 2008; Jacquemet et al. 2015). These finger-like structures are thin with a diameter of about 100–300 nm. On average, filopodia vary in lengths and reach on average a length of about several micrometres. Very short protrusions emergent from the cell cortex and lamellipodia are often called ‘microspikes’ which can be observed in large numbers. However, in some circumstances 13 filopodia can also extend over several hundreds of micrometres. Filopodia contain paral (...truncated)