hESCs-derived Organoids Achieve Liver Zonation Features through LSEC Modulation

Area of Science:

• Stem cell biology
• Hepatology
• Organoid technology

Background:

• Liver zonation is critical for physiological functions but absent in current organoid models.
• Existing organoids fail to accurately recapitulate liver development and disease pathogenesis.
• There is a need for advanced in vitro models that mimic liver heterogeneity.

Purpose of the Study:

• To develop zonated liver organoids by co-culturing human embryonic stem cell-derived hepatocytes (hESC-HEP) and liver sinusoidal endothelial cells (LSECs).
• To investigate the role of WNT2 signaling in LSECs on hepatocyte zonation and metabolic function.
• To construct biomimetic zonated organoids for studying metabolic dysfunction-associated steatotic liver disease (MASLD) and evaluate therapeutic potential.

Main Methods:

• Co-culture of hESC-HEP with LSECs exhibiting pericentral (PC) or periportal (PP) characteristics.
• Modulation of WNT2 signaling in LSECs to influence hepatocyte zonation.
• Construction of zonated MASLD organoids to study lipid metabolism.
• Assessment of glucagon-like peptide-1 receptor agonist (GLP-1RA) targeting of LSECs.

Main Results:

• Zonated LSECs with variable WNT2 signaling successfully regulated hepatocyte zonation and metabolic functions.
• PC and PP organoids exhibited distinct lipid metabolism profiles.
• Biomimetic zonated MASLD organoids were successfully constructed.
• GLP-1RA was found to directly target LSECs in zonated MASLD organoids.

Conclusions:

• Non-parenchymal cells, specifically LSECs, are crucial for recapitulating niche heterogeneity in liver organoids.
• This approach enables the development of more physiologically relevant liver organoids for studying liver zonation and disease.
• The findings suggest potential therapeutic mechanisms for GLP-1RA in MASLD, highlighting its direct effect on LSECs.