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Robust Generation of Hepatocyte-like Cells from Human Embryonic Stem Cell Populations
Published on: October 26, 2011
Prediction of drug-induced immune-mediated hepatotoxicity using hepatocyte-like cells derived from human embryonic
Dong Eon Kim1, Mi-Jin Jang2, Young Ran Kim3
1Biomedical Science and Engineering Interdisciplinary Program, Daejeon, 34141, South Korea; Graduate School of Medical Science and Engineering, Biomedical Research Center, Daejeon, 34141, South Korea.
Abstract:
Drug-induced liver injury (DILI) is a leading cause of liver disease and a key safety factor during drug development. In addition to the initiation events of drug-specific hepatotoxicity, dysregulated immune responses have been proposed as major pathological events of DILI. Thus, there is a need for a reliable cell culture model with which to assess drug-induced immune reactions to predict hepatotoxicity for drug development. To this end, stem cell-derived hepatocytes have shown great potentials. Here we report that hepatocyte-like cells derived from human embryonic stem cells (hES-HLCs) can be used to evaluate drug-induced hepatotoxic immunological events. Treatment with acetaminophen significantly elevated the levels of inflammatory cytokines by hES-HLCs. Moreover, three human immune cell lines, Jurkat, THP-1, and NK92MI, were activated when cultured in conditioned medium obtained from acetaminophen-treated hES-HLCs. To further validate, we tested thiazolidinedione (TZD) class, antidiabetic drugs, including troglitazone withdrawn from the market because of severe idiosyncratic drug hepatotoxicity. We found that TZD drug treatment to hES-HLCs resulted in the production of pro-inflammatory cytokines and eventually associated immune cell activation. In summary, our study demonstrates for the first time the potential of hES-HLCs as an in vitro model system for assessment of drug-induced as well as immune-mediated hepatotoxicity.
Insights
Human embryonic stem cell-derived hepatocytes (hES-HLCs) offer a novel in vitro model for predicting drug-induced liver injury. This model effectively assesses drug-induced immune reactions and potential hepatotoxicity during drug development.
Area of Science:
- Hepatology
- Immunotoxicology
- Stem Cell Biology
Background:
- Drug-induced liver injury (DILI) is a significant cause of liver disease and a critical safety concern in pharmaceutical development.
- Immune responses play a crucial role in the pathology of DILI, necessitating models that can assess these reactions.
- Existing models often lack the capability to fully predict drug-induced immune-mediated hepatotoxicity.
Purpose of the Study:
- To establish and validate a human embryonic stem cell-derived hepatocyte (hES-HLC) model for assessing drug-induced hepatotoxicity.
- To evaluate the potential of hES-HLCs in predicting immune-mediated liver injury.
- To investigate the utility of hES-HLCs in early drug development for safety assessment.
Main Methods:
- Generation of hepatocyte-like cells from human embryonic stem cells (hES-HLCs).
- Treatment of hES-HLCs with known hepatotoxicants like acetaminophen and thiazolidinediones (TZDs).
- Analysis of inflammatory cytokine production by hES-HLCs and activation of co-cultured immune cell lines (Jurkat, THP-1, NK92MI).
Main Results:
- Acetaminophen treatment of hES-HLCs significantly increased inflammatory cytokine levels.
- Conditioned media from treated hES-HLCs activated human immune cell lines, indicating an immune response.
- TZD treatment, including troglitazone, induced pro-inflammatory cytokine production and subsequent immune cell activation in the hES-HLC model.
Conclusions:
- hES-HLCs serve as a robust in vitro model for evaluating drug-induced hepatotoxicity.
- This model demonstrates the capacity to assess immune-mediated liver injury, a critical aspect of DILI.
- The findings highlight the potential of hES-HLCs for predicting drug safety and mitigating hepatotoxicity risks in drug development.
