Study Defines Metrics for Shape and Connectivity in Organ Development

Researchers in Germany and Austria have, for the first time, defined metrics for organ development that will help scientists engineer self-organizing tissues that mimic human organs. The emergence of such tissues, dubbed organoids, has the potential to greatly advance understanding of biology and disease.

As embryos mature, simple groups of cells become fluid-filled tubes and loops and eventually assemble into various shapes and three-dimensional structures with different types of connections. These shapes and connections underpin organ function, an example being the branched network architecture of the kidney that supports the efficient filtration of blood. 

Observing embryonic development in a living system to better understand organ development is difficult, however, and there are few concepts describing how these networks of fluid-filled tubes and loops organize.

For this reason, the team from the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) and the MPI for the Physics of Complex Systems (MPI-PKS)—both located in Dresden—and the Research Institute of Molecular Pathology (IMP) in Vienna set out to understand how the collective interaction of cells leads to the shaping of an organism during development.

Past studies have shown how cell mechanics induce local shape changes during the development of an organism, it is not clear how the connectivity of tissues emerges. By combining imaging and theory, researcher Keisuke Ishihara started to work on this question first in the group of Jan Brugues at the MPI-CBG and MPI-PKS. He later continued his work in the group of Elly Tanaka at the IMP. Together with his colleague Arghyadip Mukherjee, formerly a researcher in the group of Frank Jülicher at MPI-PKS, and Jan Brugués, Keisuke used organoids derived from mouse embryonic stem cells that form a complex network of epithelia, which line organs and function as a barrier.

“I still remember the exciting moment when I found that some organoids had transformed into tissues with multiple buds that looked like a bunch of grapes. Describing the change in the three-dimensional architecture during development proved to be challenging, though,” says Keisuke. “I found that this organoid system generates astonishing internal structures with many loops or passages, resembling a toy ball with holes.”

Studying the development of tissues in organoids has several advantages. Organoids can be observed with advanced microscopy methods, making it possible to see dynamic changes deep inside 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. “We discovered that tissue connectivity emerges from two different processes: either two separate epithelia fuse or a single epithelium self-fuses by fusing its two ends, and thereby creating a doughnut shaped loop,” Keisuke says.  

The researchers suggest, based on theory of epithelial surfaces, that the inflexibility of epithelia is a key parameter that controls epithelial fusion and in turn the development of tissue connectivity.

The authors hope the findings will lead to a fresh view of complex tissue architectures and the interplay between shape and network connectivity in organ development. The framework will help the organoid community to characterize and engineer self-organizing tissues that mimic human organs.

The findings were published recently in Nature Physics.