How tissues grow back: Uncovering distinct roles of key repair signals

New study in a collaboration between the Gram Hansen and Feng labs finds that tissue regeneration is not controlled by a single “on/off” switch, but by a well-orchestrated network of signals. This network is influenced by injury severity, timing, and the body’s immune system. Understanding how this network of signals work together, provides insights for how to safely promote regeneration such as for scar-free wound healing.

Our bodies rely on carefully controlled signals to grow, develop, and repair damaged tissues. These are controlled by signalling systems.

One of these signalling systems, called the Hippo pathway, acts like a master switch that helps cells decide when to grow, divide, or stop. Although this pathway is known to be important, for example in scar tissue and cancer formation, we still do not fully understand how its individual components work together during development and tissue repair.

Understanding these differences is essential for safely harnessing regenerative pathways in medicine, for example to promote scar free healing without increasing cancer risk.

Led by the Gram Hansen lab, researchers within the IRR used zebrafish larvae, a powerful model for studying regeneration, to systematically switch off different Hippo pathway genes and observe the effects. Zebrafish can rapidly regrow damaged tissues, making them ideal for uncovering how regeneration works in living animals.

The IRR-based team discovered that different Hippo pathway components have distinct and sometimes unexpected roles. Two closely related proteins, Yap and Taz, were found to behave very differently.

They found that Yap was crucial for normal development and for responding quickly to injury, while Taz played a more specialised role during later stages of regeneration. Importantly, the type of injury mattered: mild damage and severe damage triggered different repair programs, each relying on different Hippo pathway components.

This study also revealed a strong link between Hippo signalling and the immune system. When Yap or Taz are lost, fewer healing-associated immune cells (called macrophages) were recruited to injured tissue, and the normal transition from inflammation to repair was disrupted. This impaired immune response was closely linked to poor tissue regrowth.

Overall, these findings show that tissue regeneration is not controlled by a single “on/off” switch, but by a finely tuned network of signals that depend on injury severity, timing, and immune involvement.

This work was funded by Wellcome Trust, MRC, Cancer Research UK, Worldwide Cancer Research and CSO-LifeArc.

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