Modelling foetal exposure to maternal smoking using hepatoblasts from pluripotent stem cells

Area of Science:

• Hepatology
• Developmental Biology
• Toxicology

Background:

• The liver processes endogenous and exogenous compounds (xenobiotics).
• Maternal smoking during pregnancy poses risks to fetal development, with cigarette smoke containing numerous xenobiotics.
• Existing models for studying maternal smoking effects on fetal liver have limitations, including species differences and poor cell phenotype.

Purpose of the Study:

• To model the effects of cigarette smoke xenobiotics on human hepatocyte development using in vitro derived hepatoblasts.
• To investigate sex-specific molecular responses in fetal hepatocytes exposed to cigarette smoke components.

Main Methods:

• Utilized hepatoblasts derived from pluripotent stem cells to generate highly pure in vitro hepatocyte populations (>90%).
• Exposed these human hepatocytes to individual and cocktail mixtures of cigarette smoke derivatives.
• Analyzed ATP levels, metabolic activity, secretory function, cell depletion, and caspase activation.

Main Results:

• Individual cigarette smoke derivatives did not significantly deplete ATP levels.
• A cocktail of smoking derivatives reduced ATP production below 50% in a sex-dependent manner.
• Both male and female hepatocytes showed reduced metabolic and secretory activity; female hepatocytes exhibited less cell depletion but higher caspase activation.

Conclusions:

• Human hepatoblasts derived from stem cells provide a viable model for studying cigarette smoke effects on fetal liver development.
• Maternal smoking exposure induces sex-specific alterations in fetal hepatocyte function and cell death pathways.
• These findings highlight the differential impact of cigarette smoke on male and female fetal liver development.