After damage, tissues face a difficult task: cells must become flexible enough to repair the injury, but then regain the right identities and spatial organization. Using intestinal organoids and mouse models, researchers in the Liberali lab and their collaborators studied how this transition is coordinated.

The team focused on YAP1, a protein that helps cells sense mechanical cues in their environment. During regeneration of the intestinal lining, YAP1 activity briefly varied from cell to cell before the emergence of progenitor cells that help rebuild the gut’s normal architecture.

The researchers found that this variability was not random noise but a physical state of the tissue. At a critical point in the tissue’s growth, subtle differences in cell packing and shape led to much larger differences in YAP1 activity from one cell to the next.

These differences helped cells take on different roles. Cells with higher YAP1 activity were more likely to start becoming secretory cells, a cell type needed to restore the gut lining. A protein called FOXA1 helped translate the physical cues sensed by YAP1 into changes in gene activity. It also helped connect this early signal to Delta-Notch signaling, a system cells use to communicate with their neighbors so they do not all become the same cell type.

This relay created a kind of memory: once some cells started becoming secretory cells, they could maintain that identity even after YAP1 activity faded. In this way, a brief mechanical signal was converted into a stable tissue pattern.

The study also showed that regeneration requires a timed burst of YAP1 variability: too little disrupted patterning, while prolonged YAP1 activity prevented normal organization.

“Our findings suggest that once an optimal tissue architecture is reached, new patterns can form,” says study senior author Prisca Liberali. Similar mechanisms, she adds, may help other organs restore structure after injury and could inform efforts to build or repair tissues in the lab.