Senescence induces clonal failure of hepatocyte plasticity and reshapes regenerative lineages.

Telomere-induced senescence in mouse hepatocytes causes clonal imbalance and blocks hepatocyte-to-ductal metaplasia during chronic liver injury, reshaping regenerative lineages.

• Why it matters: Chronic liver disease features telomere shortening, but it is unclear how physiological telomeric dysfunction limits regeneration without directly killing hepatocytes.
• What they did: Using an AAV-CRISPR approach to induce resolvable telomeric breaks while preserving endogenous telomere maintenance, the study combined clonal dynamics, lineage tracing, single-nucleus transcriptomics, and a telomere-stress in vivo CRISPR screen.
• The result: Senescent hepatocytes showed limited entry into dedifferentiation and incomplete ductal program activation, disrupting epithelial composition and amplifying the ductular reaction; human cirrhotic samples linked preserved telomere integrity to bipotent hepatocyte states.

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