Acute severe liver injury impairs hepatocyte regeneration through the induction of senescence, according to new research. Strikingly, senescence was found to spread between neighbouring hepatocytes through paracrine TGFβ signalling.

Hepatocytes (red) and markers of senescence (green) around area of liver damage. Image courtesy of T. Bird, University of Edinburgh, UK

The liver has a remarkable capacity to regenerate after moderate damage. However, liver regeneration can fail after severe insults, such as acute paracetamol-related injury. “It was apparent for some patients requiring liver transplantation for sudden forms of liver failure that their livers were unable to regenerate despite the raw material for regeneration still being present,” explains author Thomas Bird. “We asked why regeneration fails in these otherwise regenerative hepatocytes, even after the toxins causing damage are no longer detectable.”

As previous research had suggested that cellular senescence might occur after years of liver injury, Bird and colleagues assessed human liver specimens obtained from patients at the onset of severe acute injury. Hepatocytes from these previously healthy livers expressed high levels of senescence markers, and levels correlated with the extent of hepatic necrosis. These results were confirmed in paracetamol and carbon tetrachloride mouse models of acute liver injury. Notably, knockout of p21, a key protein involved in senescence formation, improved hepatocyte regeneration, indicating that senescence impairs liver recovery.

Using genetically engineered mouse models, the authors discovered that senescence spreads between adjacent cells via the secretion of paracrine factors; further functional studies revealed that macrophage-derived TGFβ was required for optimal senescence induction. “Most importantly, we showed, in proof-of-principle studies in mice, that targeting the TGFβ senescence pathway can lead to clinically meaningful improvements in liver regeneration, function and overall survival following paracetamol poisoning,” says Bird.

targeting the TGFβ senescence pathway can lead to clinically meaningful improvements in liver regeneration

Given the urgent need for effective therapies for acute liver failure, the investigators plan to move forward to clinical trials of TFGβ inhibitor therapy in this setting. “We have the advantage that other drugs in this class are already in phase I and phase II clinical oncology trials, so we hope to quickly move these treatments towards the clinic,” Bird concludes.