High-content assays for hepatotoxicity using induced pluripotent stem cell-derived cells

Area of Science:

• Toxicology
• Stem Cell Biology
• Drug Development

Background:

• Predictive in vitro assays are crucial for early toxicity evaluation to improve drug development and reduce clinical attrition.
• High-content imaging-based assays offer efficient tools for safety and efficacy testing.

Purpose of the Study:

• To develop and validate automated, multiparameter high-content screening assays for hepatotoxicity assessment.
• To utilize induced pluripotent stem cell (iPSC)-derived hepatocytes for a robust in vitro toxicity model.

Main Methods:

• Employed iPSC-derived hepatocytes with tissue-like phenotypes for unlimited availability and individual comparisons.
• Developed automated screening methods to assess multiple phenotypic markers including cell viability, nuclear shape, cell area, mitochondrial membrane potential, phospholipid accumulation, cytoskeleton integrity, and apoptosis.
• Assayed compounds with known toxic mechanisms and a diverse library of 240 hepatotoxicity compounds.

Main Results:

• Demonstrated the feasibility of high-content automated screening using iPSC-derived hepatocytes.
• Acquired multiparameter readouts providing insights into general and mechanism-specific hepatotoxicity.
• Successfully evaluated a diverse library of compounds for their toxicological profiles.

Conclusions:

• High-content automated screening assays utilizing iPSC-derived hepatocytes are effective for drug safety assessment.
• These assays provide valuable information on mechanisms of toxicity, aiding in early drug evaluation.
• The developed methods facilitate the safety assessment of both drugs and chemicals, improving drug development efficiency.