How do cells communicate? Cells use different languages to communicate with each other, while they can also vary the volume or duration of these signals to send information, which ultimately affects the fate and behaviour of cells. We spoke to Dr Katharina Sonnen and Sonja Weterings about their work in using new technologies to investigate how cells talk to each other, which could open up new therapeutics avenues in future. The fields of developmental biology and
Cell signalling
adult tissue homeostasis have traditionally been viewed as separate, with scientists tending to communicate primarily with peers in their own area of research. However, similar cell signalling processes are involved in development and tissue maintenance. “There are certain principles in an adult organism that control whether a cell duplicates, or whether it becomes a muscle cell or a skin cell for example. These principles also apply in development, which starts with a single cell, which then makes the whole organism,” explains Dr Katharina Sonnen, Group Leader in the Sonnen Lab at the Hubrecht Institute in Utrecht. The focus in Dr Sonnen’s lab is on investigating the underlying basis of cell signalling, using new technologies to build a fuller picture. “Improved microscopes allow us to visualise cell-cell communications within tissue, in a dish. There are also technologies now to change or modify cell signals, which allow us to decode cell-cell communication,” she outlines.
As the head of the laboratory, Dr Sonnen is now working to gain deeper insights into cell signalling pathways and the transmission of biological information, using two model systems. The first of these model systems is somitogenesis, a phase of embryonic development. “In this phase the vertebrae are formed in a step-wise way, while several different organs form at the same
simplified model of the small intestine,” outlines Sonja Weterings, a PhD student in the lab. “We dissect the small intestine of a mouse and then grow these cells as mini-guts in a dish, which we then use in our research into cell signalling.” A variety of different techniques are being used in this research to visualize and investigate the mode-of-action of cell-cell communication, one of which is fluorescence real-time
We’ve seen that cell communication in the embryo is dynamic, and we want to understand how it works. What is really going
on? How does it control cell proliferation? And is the mechanism similar in adult tissues? time,” says Dr Sonnen. A second model system that Dr Sonnen and her colleagues in the group are using is a novel model of the small intestine, an organ in which there is a regular turnover of different types of cells throughout adult-life. “In the lab, we can make little organs in a dish called organoids. We make use of what is essentially a
imaging. Cells are fluorescently labelled, then researchers can follow these coloured cells using a microscope which can effectively zoom in to look at single cells. “This also allows us to record the communication between cells. We can get cells to produce a colour when another cell talks to it. So a cell receives a signal – from
Figure 1: Study of signalling dynamics in embryonic development and tissue homeostasis.
a neighbouring cell or one further away – then it will start to produce a colour,” explains Dr Sonnen. The nature of that signal can then be related to the subsequent behaviour of the cell. “We can look at the signal the cell receives, and then at what happens next. Does it proliferate, or die, or do something else entirely?” continues Dr Sonnen. “Then we change the signal and see what happens then. The main aim for us is to understand the communication system, to understand how cells talk to each other.” This might be between neighbouring cells or over larger distances, with cells effectively using different languages to communicate with each other at different ranges. Cells can also vary a single sound to transmit information, in what has been described as the Morse code of biology. “With Morse code, varying a single sound – making it long or short, or combining long or short – allows you to transmit information,” says Dr Sonnen. Through the use of a technique called microfluidics, Dr Sonnen is able to change the nature of cell communication, then she can assess the effects. “We don’t just look at what’s going on, but can now also change the signal and then see what’s going on. We basically combine fluorescence realtime imaging with microfluidics,” she explains. “We can inactivate communication for some time then activate it, and in this way we can externally control the periodic activation.”
Translational impact A deeper understanding of cell signalling could also help researchers develop treatments for conditions associated with certain aberrations in cell function. Researchers in Dr Sonnen’s group are investigating how cell-cell communication is changed in the context of cancer. “In this context there is too much cellular proliferation and too little cell specification or cell death, so the control mechanisms don’t work properly any more. How is that changed in a tumour? Can we maybe change it back to induce differentiation for instance, so that
the cell doesn’t proliferate?” she outlines. Certain chemotherapeutics are available that block this cell communication, yet internal mechanisms may keep a system running, while these treatments also typically cause adverse side-effects; now Dr Sonnen is investigating the possibility of a more targeted approach. “If we target the signalling dynamics more specifically it may be that we have a better outcome and less severe side-effects for the patient as well,” she says. This research provides a solid foundation for potential translational work in future, yet this rests first on a thorough understanding of cell signalling under healthy conditions. While very much aware of the long-term therapeutic possibilities which could arise from her research, Dr Sonnen says the priority in the lab at this stage is to dig deeper into cell signalling mechanisms, both in somitogenesis and the small intestine. “We’ve seen that cell communication in the embryo is dynamic, and we want to understand how it works. What is really going on? How does it control cell proliferation? And is the mechanism similar in adult tissues?” she says. Similar cell signalling dynamics have been observed in adult tissue, now researchers aim to heighten awareness of these similarities. “We go to conferences on development, as well as those that are more related to organoids or adult tissues,” continues Dr Sonnen. “We’re trying to basically build a bridge between research into development and homeostasis.” The project is currently at around the midway point of its funding term, and various different tools have been set up which will help researchers gain deeper insights. These signals have been shown to play a significant role in the development of cancer, underlining the wider importance of the project’s work. “More research is required before we can move towards translational work. But in the longer term, understanding cell signalling could allow us to control differentiation,” says Dr Sonnen.
Figure 2: The “morse code of biology”
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SignalingDynamics Signaling dynamics in the control of cell proliferation and differentiation during development and homeostasis Project Objectives
The objectives of SignalingDynamics are to understand how signalling dynamics control cell proliferation and cell differentiation in the context of embryonic development and adult tissue homeostasis. To this end, the segmenting vertebrate embryo is used as model system of embryonic development and the small intestine as model system of tissue homeostasis. By comparing these two systems, we aim to derive general principles of cell-cell communication in multicellular systems.
Project Funding
This project has received funding from the European Union’s Horizon 2020 research and innovation programme, Starting Grant (StG), LS3, ERC-2019-STG. Grant agreement ID: 850554
Contact Details
Project Coordinator: Katharina Sonnen, PhD, Group Leader Hubrecht Institute Uppsalalaan 8 3584 CT Utrecht The Netherlands T: +31 (0) 30 212 18 00 E: k.sonnen@hubrecht.eu W: https://www.sonnenlab.org/ W: https://cordis.europa.eu/project/id/850554 Katharina Sonnen
Sonja Weterings
Katharina Sonnen: After a PhD in cell biology (University of Basel), Ina did a Postdoc at EMBL Heidelberg to study cell-cell communication in vertebrate embryos. In 2018, she established her own research group at the Hubrecht Institute to study how cells communicate with each other both during embryonic development and in adult tissues. For this work she received an ERC starting grant in 2019. Sonja Weterings: Sonja is one of the PhD students working on the ERC-funded project SignalingDynamics. Her work focusses on signaling dynamics in adult tissues, mainly the small intestine. She studied Molecular Biology and Biomedical Sciences in Utrecht.
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