Lab-grown intestinal organoids mimic gut structures, including crypts, which are crucial for gut regeneration as they are home to stem cells. However, the exact mechanical processes driving crypt formation have remained unclear.

Researchers in the Liberali lab and their collaborators at the Institute of Science and Technology Austria created a model to explain how crypts form in intestinal organoids by linking mechanical forces and cell responses to tissue shape.

The model suggests that changes in the volume of intestinal cells and lumen—the fluid-filled cavity inside gut organoids—play a crucial role in modulating the mechanical forces within the tissue. As the lumen shrinks, it reduces the energy needed to bend the tissue while increasing tension differences between cell layers. This mechanical feedback is a key driver of crypt formation.

“As the organoid’s lumen volume decreases, the tissue bends, and crypts emerge,” Liberali says.

To test their model, the researchers artificially increased lumen volume. In early-stage organoids, developing crypts reopened, while fully formed crypts remained unchanged. Further experiments showed that in developing crypts, volume changes altered the distribution of myosin, a key protein in cell contraction, and weakened tension. In mature crypts, myosin remained stable, locking the structure in place.

The researchers also found that lumen pressure acts as a long-range signal that can synchronize crypt formation across an organoid. This means that all crypts in a single organoid respond to changes in fluid pressure, ensuring coordinated development.

Similar mechanical feedback loops might be at play in other tissue models, Liberali says. “This work helps explain how mechanical forces influence organ development and may have broader implications for regenerative medicine and tissue engineering.”