Upholding telomeres prevents hepatic stellate cell transdifferentiation and liver fibrogenesis

Hepatic stellate cells (HSCs) are principal drivers of liver cirrhosis. Whether and how telomere dysfunction affects HSC function remain unclear. This study was undertaken to investigate the role of telomere maintenance in HSCs during fibrogenesis and to evaluate its therapeutic potential by genetic and pharmacological means.

Liver fibrosis was established in mice treated with carbon tetrachloride (CCl4) or bile duct ligation (BDL), and characterized by tissue and molecular pathology and biochemistry, followed by HSC isolation using flow cytometry. Animals were engineered for HSC-specific overexpression of the telomerase reverse transcriptase (TERT) gene or Acd (encoding the shelterin component TPP1). Alternatively, mice were intraperitoneally injected with telomere dysfunction inhibitor (TELODIN), a D-amino acid octapeptide that stabilizes the telomerase activator TPP1. HSC-specific TERT expression alleviated hepatic fibrosis by suppressing HSC activation, proliferation, and transdifferentiation. Likewise, HSC-specific TPP1 overexpression mitigated hepatic fibrosis by preventing telomere dysfunction and shortening. Pharmacological stabilization of TPP1 by intraperitoneal administration of TELODIN counteracted hepatic fibrogenesis while maintaining HSC quiescence. Mechanistically, TELODIN stabilized TPP1, reduced telomere dysfunction, and decreased HSC transdifferentiation into profibrotic myofibroblasts.

Telomere dysfunction mediates HSC transdifferentiation during experimental hepatic fibrogenesis. Targeted interventions - that increase telomerase activity or TPP1 mediated telomerase recruitment and activation - alleviate HSC-mediated fibrosis. Pharmacological administration of TELODIN effectively attenuates experimental liver fibrosis by restoring telomere homeostasis in HSCs.