9-cis-Retinoic Acid Improves Disease Modelling in iPSC-Derived Liver Organoids

Area of Science:

• Biomedical Engineering
• Hepatology
• Stem Cell Biology

Background:

• Liver fibrosis is a significant global health concern requiring better in vitro models.
• Current induced pluripotent stem cell (iPSC)-based liver models often lack crucial in vivo functionalities.
• Three-dimensional (3D) organoid cultures are essential for mimicking the in vivo microenvironment.

Purpose of the Study:

• To develop and characterize advanced 3D liver organoids using iPSC-derived hepatocytes (iHepatocytes) and hepatic stellate cells (iHSCs).
• To investigate the role of the transcription factor RXRA and its ligand 9-cis-retinoic acid (9CRA) in liver fibrosis models.
• To enhance the fidelity of iPSC-based models for studying drug-induced liver injury and fibrosis.

Main Methods:

• Development of iPSC-derived hepatocyte and hepatic stellate cell organoids.
• Comparison of these organoids with HepaRG and primary HSC organoids.
• RNA sequencing analysis to identify key molecular players.
• Treatment with 9-cis-retinoic acid (9CRA) to assess its effects on cell function and fibrotic response.

Main Results:

• RNA sequencing identified RXRA as a potential regulator of hepatocyte differentiation and HSC quiescence.
• 9-cis-retinoic acid (9CRA) treatment promoted iHepatocyte metabolism and iHSC quiescence.
• In organoid models, 9CRA amplified fibrotic responses to TGF-β and acetaminophen.

Conclusions:

• RXRA and its ligand 9CRA play a role in regulating liver cell function and fibrotic processes.
• 9CRA can enhance the fibrotic response in iPSC-derived liver organoids.
• These findings suggest 9CRA can refine iPSC-based models for studying liver fibrosis and drug-induced liver injury.