Objective Uncertainty about acute liver failure (ALF) pathogenesis limits therapy. We postulate that ALF results from excessive reactivation of a fetal liver programme that is induced in hepatocytes when acutely injured livers regenerate. To evaluate this hypothesis, we focused on two molecules with known oncofetal properties in the liver, Yes-associated protein-1 (YAP1) and Insulin-like growth factor-2 RNA-binding protein-3 (IGF2BP3).
Design We compared normal liver with explanted livers of patients with ALF to determine if YAP1 and IGF2BP3 were induced; assessed whether these factors are upregulated when murine livers regenerate; determined if YAP1 and IGF2BP3 cooperate to activate the fetal programme in adult hepatocytes; and identified upstream signals that control these factors and thereby hepatocyte maturity during recovery from liver injury.
Results Livers of patients with ALF were massively enriched with hepatocytes expressing IGF2BP3, YAP1 and other fetal markers. Less extensive, transient accumulation of similar fetal-like cells that were proliferative and capable of anchorage-independent growth occurred in mouse livers that were regenerating after acute injury. Fetal reprogramming of hepatocytes was YAP1-dependent and involved YAP1-driven reciprocal modulation of let7 microRNAs and IGF2BP3, factors that negatively regulate each other to control fate decisions in fetal cells. Directly manipulating IGF2BP3 expression controlled the fetal-like phenotype regardless of YAP1 activity, proving that IGF2BP3 is the proximal mediator of this YAP1-directed fate.
Conclusion After acute liver injury, hepatocytes are reprogrammed to fetal-like cells by a YAP1-dependent mechanism that differentially regulates let7 and IGF2BP3, identifying novel therapeutic targets for ALF.
- acute liver failure
- cell biology
- liver regeneration
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Contributors JH: helping with the design of the research studies, conducting the experiments, acquiring data, analysing data, providing reagents, writing the manuscript. S-HO: conducting the experiments, acquiring the data. RTP: conducting the experiments, acquiring the data. CDG: providing human liver samples. CLB: providing human liver samples. AMD: designing the research studies, analysing the data, writing the manuscript, securing funding for the research.
Funding This work was supported by NIH grants DK106633, AA010154 and DK077794, the Florence McAlister Professorship of Medicine (AMD) and an award from the Duke Regeneration Next Initiative (JH).
Competing interests None declared.
Ethics approval Animal studies were conducted under an approved Duke University IACUC protocol as per the National Research Council ’Guide for the Care and Use of Laboratory Animals'. Human livers were obtained and analysed in accordance with a Duke Institutional Review Board-approved protocol (Pro00087196).
Provenance and peer review Not commissioned; externally peer reviewed.
Patient consent for publication Not required.
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