Why do lymphatic endothelial cells look like puzzle pieces?
The lymphatic system plays a crucial role in maintaining fluid balance in tissues and supporting immune function. Its smallest vessels, known as lymphatic capillaries, are made up of a single layer of lymphatic endothelial cells that allow fluids, cells, and large molecules to enter from surrounding tissues. These vessels must be highly permeable to efficiently take up fluid, yet also flexible enough to withstand sudden changes in tissue volume—such as swelling—without rupturing.
In a new study published in the journal Nature, researchers have uncovered how the thin layer of lymphatic endothelial cells manages to maintain its integrity under changing pressure conditions. The key lies in the cells’ ability to continuously adjust their unique shape.
“It has long been known that capillary lymphatic endothelial cells have a lobate shape, resembling oak leaves or jigsaw puzzle pieces. However, the reason for this peculiar morphology has remained a mystery, and it has never been successfully replicated in cultured cells,” says Taija Mäkinen, director of the Wihuri Research Institute and professor at University of Helsinki, who led the study. “In our research, we found that exposing cultured lymphatic endothelial cells to intermittent multidirectional stretching caused them to adopt this puzzle-like shape, increasing their overlap with neighboring cells.”
Interestingly, a similar puzzle-shaped structure is found in an entirely different type of cell—on the surface of plant leaves. In plants, this shape helps the cells withstand internal fluid pressure (turgor pressure), which is essential for growth and maintaining an upright position.
“The puzzle shape of plant cells is controlled by a specific signaling pathways that regulate their cell cytoskeleton, and a corresponding pathway is also present in lymphatic endothelial cells,” Taija Mäkinen explains. “When we blocked this pathway in cultured lymphatic endothelial cells, the stretch-induced overlap between cells was reduced. In mice lacking one of the key signaling molecules in this pathway, not only was the shape of lymphatic endothelial cells altered, but the integrity and function of the vessels were also impaired. This suggests that the overlapping puzzle-like organisation between endothelial cells is essential for lymphatic vessels to expand safely under pressure without rupturing.”
The discovery that puzzle-shaped cells serve a similar function in both plants and mammals suggests a fundamental biological principle: this distinctive morphology enhances structural stability across different life forms. Interestingly, this principle has also been applied in human engineering—pavement blocks often have an interlocking, undulating shape to enhance durability and resistance to wear and tear. By revealing a shared design strategy for withstanding pressure, the study offers new insights into how lymphatic vessels function in health and disease.
“The key findings in our study came from experiments where we labeled individual endothelial cells in different colours or their cytoskeleton and tracked their behavior at the single-cell level in living mice over minutes, hours, or even months using two-photon microscopy. This approach allowed us to repeatedly image the same cells in the same mouse over time, providing unprecedented insight into their dynamic adaptations,” says Taija Mäkinen. These critical experiments were conducted at Uppsala University from where the group has moved, but thanks to private-public partnership and funding from the Wihuri Research Institute, Academy of Finland and University of Helsinki, a state-of-the-art two-photon microscope has been acquired in Helsinki. This will empower researchers in Helsinki to push the boundaries of discovery and explore new frontiers using cutting-edge imaging technologies.
Taija Mäkinen Lab 