Three-Dimensional Architecture of the Liver Structural Organization, Methodological Advances, and Functional...

Area of Science:

• Hepatology and Liver Biology
• Cellular and Molecular Biology
• Biomedical Engineering

Background:

• The liver, despite its small body mass percentage, performs over 500 biochemical tasks using hepatocytes.
• Liver function is intricately linked to its three-dimensional architecture and resulting zonal gradients.
• Understanding liver zonation is crucial as it influences disease susceptibility and drug responses.

Purpose of the Study:

• To review methods for studying liver architecture across multiple scales.
• To explore how liver zonation dictates hepatocyte function and disease pathology.
• To discuss the potential of regenerative medicine and bioengineering for liver repair.

Main Methods:

• Vascular corrosion casting, serial sectioning, micro-CT, and tissue clearing for structural analysis.
• Light-sheet microscopy, single-cell, and spatial transcriptomics for functional and molecular insights.
• Computational modeling to integrate multi-scale data and predict tissue behavior.

Main Results:

• Liver architecture creates zonal gradients, particularly along the portal-to-central axis, influencing gene expression in approximately half of hepatocytes.
• Specific zones are preferentially affected by drug toxicities, steatosis, and fibrosis.
• Liver regeneration in adults mirrors developmental processes, offering therapeutic avenues.

Conclusions:

• Liver zonation is a fundamental principle governing its complex functions and disease susceptibility.
• Advanced imaging and transcriptomic techniques are revealing liver architecture and function at unprecedented resolution.
• Bioengineering and synthetic biology hold promise for future liver tissue repair and regeneration, though clinical application requires further development.