27 November 2020 Thesis defense Susanne van den Brink: “From stressed satellite cells to mouse and human gastruloids” Back to news Susanne van den Brink, from the group of Alexander van Oudenaarden, successfully defended her thesis “From stressed satellite cells to mouse and human gastruloids: Applications of single-cell and spatial transcriptomics” on the 27th of November, with cum laude honors. Together with her colleagues, she discovered that the method with which cells are extracted from tissues induces a stress response in a subset of these cells. Additionally, they optimized the protocol with which embryo-like structures – gastruloids – can be generated from mouse embryonic stem cells and developed a first human version of this model. Their model system can be used to study a stage in the human embryonic development that is otherwise inaccessible for research. Van den Brink’s PhD consisted of two parts. During the first part, she focused on muscle stem cells. Muscle stem cells are always present in adult muscles, but they are normally inactive. Only when a muscle is damaged, for example after exercise or injury, the stem cells are activated and start to multiply to repair the muscle. Muscle stem cells in distress Before Van den Brink started her PhD, a paper was published that showed that there are two subtypes of muscle stem cells, each with a slightly different gene expression profile. However, during her PhD she discovered that both subtypes actually belong to the same population of cells; one of the groups simply showed a higher stress response than the other. This stress response was induced by the widely-used method – called FACS, with which researchers extract muscle stem cells from muscles. Discovery of an artefact Van den Brink’s research thus pointed to an artefact: the observed differences between muscle stem cells were not naturally present in muscles, but were the consequence of the research method that was used. Next, she discovered that this artefact is not specific for muscle stem cells: “We found similar results in other types of cells, suggesting that we found a general effect of the cell-extraction method. Scientists that use this method have to keep this effect in mind during their experiments”, Van den Brink explains. As a consequence of these findings, the results of a number of previously published studies needed to be reinterpreted. Her study was published in the leading journal Nature Methods. First embryo model from stem cells During the second part of her PhD, Van der Brink followed up on research that she conducted during her Master’s internship in Cambridge (UK) in 2013. “During that internship, I discovered how embryo-like structures can be grown from mouse embryonic stem cells, something that had never been achieved before. In the years following my internship, a whole new research field arose from this discovery”, she explains. The model – also called a gastruloid – resembled important aspects of mouse embryos, but there were also still important differences between gastruloids and actual mouse embryos. For instance, the gastruloids did not make so-called somites. Somites are blocks of tissue that give rise to the embryo’s vertebrae and muscles in a later stage of embryonic development. Picture of a gastruloid in which the somites, the precursors of the vertebrae and muscles, are stained in blue. Credit: Vincent van Batenburg, ©Hubrecht Institute. Floating gastruloids “During my PhD, I discovered, partly by coincidence, how we can induce the formation of somite-like structures in the gastruloid. During some of our experiments, we tried to film the gastruloids with a microscope. However, the gastruloids floated in a liquid and therefore continuously drifted out of view. We needed something to stabilize them.” A colleague suggested ‘Matrigel’, a gel-like substance. The gel turned out to indeed stabilize the gastruloids, but unexpectedly also induced the formation of somites, which resulted in embryo structures that more accurately resemble actual mouse embryos. It is not yet known why Matrigel has this effect on the gastruloids. Cartoon rendering of a mouse embryo (left) and a mouse gastruloid (embryo-like structure generated from stem cells - right). Pink-blue blocks represent somites, the embryonic precursors of the vertebrae and muscles. Credit: Núria Taberner, ©Hubrecht Institute. Human gastruloids After optimizing the gastruloids developed from mouse embryonic stem cells, Van den Brink and her colleagues from Cambridge developed a first protocol to grow gastruloids from human embryonic stem cells. These human gastruloids mimic aspects of the development of human embryos between 18 and 21 days old. “An important result, since research with actual human embryos older than 14 days is not allowed. This model thus allows scientists to study human embryonic development beyond day 14”, she says. Given that gastruloids do not form a brain and placenta and are therefore not viable, the development of gastruloids conforms to the current ethical standards. Patient models In the near future, the researchers are aiming to develop human embryo models from induced pluripotent stem cells. Such stem cells are generated by bringing adult stem cells, for example from the skin, back to an embryonic state. Van den Brink explains: “We hope that this will allow us to make patient models. Take, for instance, a child who is born with a certain heart disorder. If we would be able to take skin cells and make an embryonic model for that specific child, we could use that model to study the origin of the disorder and to find out what genes that are involved. We can then use this information to prevent heart disorders or to improve the screenings of embryos during IVF procedures.” Medical applications With the completion of her PhD, her time at the Hubrecht Institute comes to an end. Van den Brink had originally planned to move to Barcelona in September for a postdoc in the IMIM-institute, but her move got postponed until January 2021 due to the pandemic. In Barcelona, she plans to further optimize the gastruloid model and study potential medical applications of the gastruloid model system. “I am very excited about this next step, because it will allow us to explore whether the embryonic model that we developed can indeed be used for clinical applications”, says the brand-new doctor. Teamwork Van den Brink wants to emphasize that she could never have done her research by herself: an enormous amount of team effort and collaboration was involved. “That is what made my PhD so much fun; as a team, we shared all the ups and downs. This interaction with colleagues is what I miss now everyone is mostly working from home due to the current Covid-19 measures.” Her defense was partly digital and therefore also different than usual. And a reception or party afterwards is out of the question. “I think that, for now, it will be a zoom party. But who knows, maybe in a year or two we can organize a big party for everyone that finished their PhD at the Hubrecht during the pandemic. That would then also be a great reunion.” Susanne van den Brink starts a postdoc at the IMIM-institute in January 2021, where she will further optimize the gastruloid model and study to what extent it can be used for medical applications.