Chronic replicative stress induced by CCl4 in TRF1 knockout mice recapitulates the origin of large liver cell changes

Large liver cell changes (LLCC) are characterized by pleomorphic large nuclei frequently found in liver diseases as chronic viral hepatitis and liver cirrhosis. The origin of this lesion remains cryptic, but the presence of LLCC is correlated with an increased risk of hepatocellular carcinoma. Telomeric repeat binding factor 1 (TRF1) is part of the shelterin complex and is essential for telomere protection. Ablation of TRF1 induces telomere fragility and fusions and chromosomal instability.

In this study, we addressed the role of TRF1 in liver regeneration generating a mouse model with conditional deletion of TRF1 in the liver.

TRF1 deletion has no deleterious effects in liver and leads to increased ploidy of hepatocytes after 2/3 hepatectomy. Mice lacking TRF1 in the liver can survive for over one year without any evidence for altered liver function. Importantly, applying chronic replicative stress by frequent carbon tetrachloride (CCl4) injections, TRF1 deleted mice undergo ploidy changes consistent with endoreduplication and develop LLCC like lesions in the liver positive for p21, Cyclin D1 and PCNA as observed in humans.

In summary, we provide mechanistic insight into the role of TRF1 in liver regeneration and provide a mouse model recapitulating the clinical features of LLCC.