Organs in the human body have complex networks of fluid-filled tubes and loops. They come in different shapes and their three-dimensional structures are connected differently depending on the organ. During the development of an embryo, organs develop their shape and tissue architecture from a simple group of cells. Due to a lack of concepts and tools, it is challenging to understand how shape and the complex tissue network arise during organ development. Organ development metrics have now been defined for the first time by scientists at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) and the MPI for the Physics of Complex Systems (MPI-PKS), both in Dresden, as well as the Research Institute of Molecular Pathology (IMP) in Vienna. In their study, the international team of researchers provides the necessary tools to transform the field of organoids – miniature organs – into an engineering discipline to develop model systems for human development.
The collective interaction of cells during development leads to the formation of an organism. The different organs have different geometries and differently connected three-dimensional structures that determine the function of fluid-filled tubes and loops in organs. An example is the branched network architecture of the kidney, which supports the efficient filtration of blood. Observing embryonic development in a living system is difficult, which is why there are so few concepts describing how the networks of fluid-filled tubes and loops develop. While previous studies have shown how cell mechanics cause local shape changes during an organism’s development, how tissue connectivity emerges is not clear. By combining imaging and theory, researcher Keisuke Ishihara first set to work on this question in Jan Brugues’ group at the MPI-MEB and MPI-PKS. He later continued his work in Elly Tanaka’s group at the IMP. Together with his colleague Arghyadip Mukherjee, formerly a researcher in Frank Jülicher’s group at MPI-PKS, and Jan Brugués, Keisuke used organoids derived from mouse embryonic stem cells that form a complex network of epithelium, which forms organs and acts as a barrier. . “I still remember the exciting moment when I discovered that some organoids had transformed into multi-bud tissues that resembled a bunch of grapes. However, describing the change in three-dimensional architecture during development proved challenging,” recalls Keisuke, adding added: “I found that this organoid system generates amazing internal structures with many loops or passages, resembling a toy ball with holes.”
Studying the development of tissues in organoids has several advantages: they can be observed with advanced microscopy methods, allowing the observation of dynamic changes deep within the tissue. They can be generated in large numbers and the environment can be controlled to influence development. The researchers were able to study the shape, number and connectivity of the epithelium. They tracked the changes in the internal structure of organoids over time. Keisuke continues, “We found that tissue connectivity arises from two different processes: either two separate epithelia fuse or a single epithelium self-fuses by fusing the two ends together to create a doughnut-shaped loop.” The researchers suggest, based on the theory of epithelial surfaces, that the inflexibility of epithelium is a key parameter regulating epithelial fusion and, in turn, the development of tissue connectivity.
The study’s supervisors, Jan Brugues, Frank Jülicher and Elly Tanaka conclude: “We hope that our findings will lead to a fresh look at complex tissue architectures and the interplay between shape and network connectivity in organ development. Our experimental and analytical framework will organoid community help characterize and develop self-organizing tissues that mimic human organs. By revealing how cellular factors influence organ development, these results may also be useful to developmental cell biologists interested in organizational principles.”
Ishihara, K., et al. (2022) Topological morphogenesis of neuroepithelial organoids. nature physics. doi.org/10.1038/s41567-022-01822-6.