Transcriptomic and epigenetic mechanisms controlling cholangiocyte transdifferentiation into hepatocytes

Area of Science:

• Hepatology and regenerative medicine.
• Cellular plasticity and differentiation.
• Epigenetics and gene regulation in liver disease.

Background:

• Liver regeneration mechanisms in chronic liver disease are not fully understood.
• Transdifferentiation between cholangiocytes and hepatocytes is a potential regenerative pathway.
• This study investigates the molecular drivers of this process in human patients.

Purpose of the Study:

• To uncover the molecular mechanisms driving cholangiocyte-to-hepatocyte transdifferentiation in humans.
• To identify key molecular players and epigenetic regulations involved in this cellular plasticity.
• To explore the therapeutic potential of enhancing this regenerative process.

Main Methods:

• Derived intrahepatic cholangiocyte organoids from patients with metabolic dysfunction-associated steatohepatitis.
• Induced differentiation into biphenotypic cells mimicking in vivo transdifferentiation.
• Utilized single-nuclei RNA sequencing and ATAC sequencing to analyze molecular pathways and epigenetic modifications.
• Performed functional validation of identified transcription factors.

Main Results:

• Cholangiocyte plasticity was observed to be independent of liver lobe origin.
• Single-nuclei ATAC sequencing revealed chromatin remodeling as a mechanism for plasticity.
• The transcription factor HNF4G was identified as a key player in inducing hepatocyte markers.
• Findings were validated using human liver biopsy data.

Conclusions:

• Cholangiocytes can transdifferentiate into hepatocytes, a process confirmed in human organoids.
• Hepatocyte Nuclear Factor 4 Gamma (HNF4G) promotes this transdifferentiation.
• Epigenetic remodeling and chromatin reorganization are crucial for cholangiocyte plasticity.
• Targeting HNF4G offers a potential therapeutic strategy for enhancing liver regeneration.