Development of model systems that imitate human organs

Researchers in Dresden and Vienna are discovering the connection between the three-dimensional structures in tissues and the emergence of their architecture to help scientists design self-organizing tissues that mimic human organs.

The organs of the human body have a complex network of fluid-filled tubes and loops. They come in different shapes, and their three-dimensional structures are connected to each other in different ways depending on the organ. During embryonic development, organs develop their shape and tissue architecture from a simple group of cells. Due to a lack of concepts and tools, it is difficult to understand how the shape and complex network of tissues emerge during organ development. Organ development metrics were first identified by scientists at the Max Planck Institute for Molecular Cell Biology and Genetics (MPI-CBG) and the MPI for Physics of Complex Systems (MPI-PKS), both in Dresden, as well as the Research Institute for Molecular Pathology (IMP) in Vienna. In their study, an international team of researchers provides the necessary tools to transform the field of organoids — miniature organs — into an engineering discipline for developing model systems for human development.

The collective interaction of cells leads to the formation of an organism in the process of development. Different organs have different geometries and differently connected three-dimensional structures that determine the function of the fluid-filled tubes and loops in the organs. An example is the branched network architecture of the kidney, which supports efficient blood filtration. Embryo development is difficult to observe in a living system, which is why there are so few concepts that describe how networks of fluid-filled tubes and loops develop. While past studies have shown how cellular mechanics induce local shape changes during organismal development, it is unclear how tissue communication occurs.

Combining imaging and theory, researcher Keisuke Ishihara began working on this question first in Jan Brug’s group at MPI-CBG and MPI-PKS. He later continued his work with Eli Tanaka’s group at IMP. Together with his colleague Argyadip Mukherjee, a former researcher in Frank Jülicher’s group at MPI-PKS, and Jan Bruges, Keisuke used organoids derived from mouse stem cells, which form a complex network of epithelium that lines organs and acts as a barrier.

“I still remember the exciting moment when I discovered that some organoids had transformed into tissues with many buds that looked like a bunch of grapes. However, describing the changes in the 3D architecture during development proved to be a difficult task,” recalls Keisuke, adding, “I found that this organoid system creates strange internal structures with many loops or passages, resembling a toy ball with holes.”

The study of tissue development in organoids has several advantages: they can be observed using modern microscopy techniques, which allows us to see dynamic changes in the depth of the tissue. They can be created 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 changes in the internal structure of organoids over time.

Keisuke continues, “We found that tissue junctions occur by two different processes: either two separate epithelia fuse, or one epithelium itself fuses by fusing its two ends and thus creates a doughnut-shaped loop.” Based on the theory of epithelial surfaces, researchers hypothesize that epithelial flexibility is a key parameter that controls epithelial fusion and, in turn, the development of tissue junctions.

Study leaders Jan Bruges, Frank Jülicher and Eli Tanaka conclude: “We hope that our findings will lead to new insights into the complex architecture of tissues and the interplay between shape and network connectivity in organ development. Our experimental and analytical framework will help the organoid community to characterize and construct self-organizing tissues that mimic human organs. By revealing how cellular factors influence organ development, these results may also be useful for cell biologists interested in organizational principles.”

Reference: “Topological morphogenesis of neuroepithelial organelles” November 21, 2022. DOI: 10.1038/s41567-022-01822-6

Funding: Max-Planck-Gesellschaft, Joachim Herz Stiftung, Austrian Science Fund