Limited Contribution of Hepatic Progenitor Cells to Hepatocyte Replenishment After Acetaminophen Overdose
Year: 2026
Type: preprint
Abstract: Liver regeneration is critical determinant of survival following acetaminophen (APAP) overdose, is driven primarily by proliferation of surviving hepatocytes. Hepatic progenitor cells (HPCs) are bipotential cells activated when hepatocyte proliferation is impaired. Contribution of HPCs to liver regeneration after APAP overdose remains unclear. This study investigated the contribution of HPCs to hepatocyte repopulation after severe APAP overdose using lineage tracing mouse models. Two-month-old male C57BL/6J mice were fasted overnight and then administered a 600 mg/kg overdose of APAP (600APAP). For lineage tracing, male ROSAmT-mG mice were injected with AAV8-TBG-Cre to label hepatocytes. Two weeks after AAV administration, mice were fasted overnight and then administered a 600 mg/kg overdose of APAP. Liver and blood samples were collected multiple times. C57BL/6J mice treated with severe acetaminophen overdose (600APAP) show substantial liver injury, with peak serum ALT and hepatic necrosis at 72 h, followed by progressive recovery. HPC activation was evidenced by increased expression of EpCAM, A6, and CK19 during recovery phase. APAP administration to ROSAmT-mG mice induced liver injury and subsequent regeneration and recovery comparable to wild type mice. Detection of HNF4α/tdTomato double-positive cells, hepatocytes originating from HPCs, were detected after injury but represented only 0.3–0.6% of total hepatocytes. Taken together, this study indicates that despite an increase of HPCs markers, lineage tracing model demonstrate that HPCs transdifferentiation contribute minimally to hepatocyte replenishment following severe APAP-induced liver injury.
Source: Preprints.org
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7212239084
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