Hippo pathway activity influences liver cell fate

Area of Science:

• Cell biology
• Developmental biology
• Hepatology

Background:

• The Hippo-signaling pathway regulates organ size and cell proliferation.
• Its role in controlling cell fate decisions, particularly in hepatocytes, remains largely unexplored.

Purpose of the Study:

• To investigate the function of the Hippo-signaling pathway in maintaining hepatocyte differentiation and cell fate.
• To explore the potential of mature hepatocytes to revert to progenitor states.

Main Methods:

• Lineage tracing
• Clonal analysis
• In vivo organoid culture
• Acute inactivation of Hippo pathway signaling

Main Results:

• Hippo pathway activity is crucial for maintaining the differentiated state of adult hepatocytes.
• Acute Hippo pathway inactivation in vivo efficiently induces dedifferentiation of hepatocytes into progenitor-like cells.
• These induced progenitor cells exhibit self-renewal and single-cell engraftment capabilities.
• The NOTCH-signaling pathway was identified as a key downstream effector of YAP, a Hippo pathway transducer.

Conclusions:

• Hippo/YAP signaling plays a critical role in governing liver cell fate.
• Mature hepatocytes possess significant phenotypic plasticity, capable of dedifferentiation into progenitor cells.
• These findings offer new insights into liver regeneration mechanisms and potential therapeutic strategies.