April 25, 2019
Intestinal organoid development mimics regeneration
Intestinal organoids are three-dimensional structures derived from a single intestinal stem cell. They are great tools for applications ranging from fundamental biology to personalized and regenerative medicine. However, despite their relevance in research, it is still unclear how a single cell can give rise to a fully formed organoid. In a study published in Nature, the group of Prisca Liberali discovered the molecular events that lead to symmetry breaking – the most crucial step in organoid development.
Organoids are complex three-dimensional structures that contain multiple cell types, spatially arranged similarly to the cells in a specific tissue or organ. Researchers have been developing organoids for at least 60 years, initially to explore basic mechanisms of development. However, it's only in the past decade that, thanks to improved knowledge of mammalian development and growing experience in stem cell culture, they have been able to use the self-organizing properties of stem cells to create realistic in vitro models of human tissues. Organoid models have now been established for many organs: brain, liver, kidney, breast, retina, and different organs of the gastrointestinal tract, among others. Organoids hold great therapeutic promise, since they can be used not only as disease models and for drug testing, but also for regenerative medicine.
The group of Prisca Liberali is interested in the fundamental aspects of organ formations and regeneration, working with intestinal organoids as a model system. Despite the extensive use of organoids, it is still unclear how a single intestinal stem cell gives rise to a cell population with various cell types and the capacity to self-organize. Liberali explains her passion for the topic in simple terms: “I want to understand how it’s possible to make a structure as complex as an organoid in five days ‘without a body’”.
Using quantitative imaging approaches (high-content imaging and long-term time-lapse imaging by light sheet microscopy) combined with single-cell gene expression analysis, Denise Serra, Urs Mayr and Andrea Boni from the Liberali group characterized the development of intestinal organoids from a single cell. By following the fate of the initial cell, they could demonstrate that first the individual stem cells follow a regenerative response generating a symmetrical sphere-like structure. Then, between the 8-cells and 16-cells stage, symmetry is broken and a new type of cell emerges. From then on, the cells continue to multiply and differentiate in various cell types until they reach a size of 1000 cells and become a fully formed organoid by day 5.
The moment when symmetry breaks for the first time – when one cell among initially identical cells start to differentiate – is the most important step during pattern formation and a key rule of the logic of life (see, www.logicoflife.ch). The Liberali group elucidated the mechanism that led to symmetry breaking – the major finding in their study. In summary, they showed that a transient and variable Yap protein activation leads to symmetry breaking. Yap is known for getting activated when there is an injury and the tissues need to regenerate. It is also expressed in certain cancers.
“Because of the presence of Yap, we concluded that the pathway followed by the cells mimics a regenerative process, and not a developmental one,“ says Liberali. “Why is this important? By continuing to study how organoid development is regulated, we will get a better understanding of how tissues achieve self-repair. This will allow us to look for compounds that could regulate the recovery process and speed it up – for the benefit of patients with severe diarrhea for example, or those who underwent chemotherapy or bone marrow transplant.”
Denise Serra*, Urs Mayr*, Andrea Boni*, Ilya Lukonin, Markus Rempfler, Ludivine Challet Meylan, Michael B. Stadler, Petr Strnad, Panagiotis Papasaikas, Annick Waldt, Guglielmo Roma and Prisca Liberali (2019) Self-organization and symmetry breaking in intestinal organoid development. Nature (Advance online publication)
* these authors contributed equally.
Captions pictures below:
1: Symmetry-breaking in intestinal organoid
2-3: Fully-grown intestinal organoids