Application of human pluripotent stem cells and pluripotent stem cell-derived cellular models for assessing drug toxicity

ABSTRACT

Introduction: Human pluripotent stem cells (hPSCs) are capable of differentiating into all types of cells in the body and so provide suitable toxicology screening systems even for hard-to-obtain human tissues. Since hPSCs can also be generated from differentiated cells and current gene editing technologies allow targeted genome modifications, hPSCs can be applied for drug toxicity screening both in normal and disease-specific models. Targeted hPSC differentiation is still a challenge but cardiac, neuronal or liver cells, and complex cellular models are already available for practical applications.

Areas covered: The authors review new gene-editing and cell-biology technologies to generate sensitive toxicity screening systems based on hPSCs. Then the authors present the use of undifferentiated hPSCs for examining embryonic toxicity and discuss drug screening possibilities in hPSC-derived models. The authors focus on the application of human cardiomyocytes, hepatocytes, and neural cultures in toxicity testing, and discuss the recent possibilities for drug screening in a ‘body-on-a-chip’ model system.

Expert opinion: hPSCs and their genetically engineered derivatives provide new possibilities to investigate drug toxicity in human tissues. The key issues in this regard are still the selection and generation of proper model systems, and the interpretation of the results in understanding in vivo drug effects.

KEYWORDS:

• Human pluripotent stem cells (hPSCs)
• stem cell-derived cellular models
• directed hPSC differentiation
• model cells for toxicity screening
• cardiomyocytes
• hepatocytes
• neural cell cultures
• body-on-a-chip

Article highlights

• New methodology for high capacity drug screening based on hPSCs include the generation of reporter hPSC lines, hPSC-derived models and multiparametric methodologies for toxicity screening.

• Application of hPSC-based models for embryonic toxicity is an emerging area of toxicity testing.

• hPSC-derived cardiac, hepatic and neural cellular models represent fetal phenotypes yet seem to be applicable in toxicity testing.

• hPSC-derived 3D models and ‘body-on-a-chip’ are developed for assessing drug toxicity in complex models.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This study has been supported by the National Brain Research Program (NAP) of Hungary [2017-1.2.1-NKP-2017-00002], by the Momentum Program of the Hungarian Academy of Sciences [LP2012-025] and by the National Research, Development and Innovation Office grant numbers [OTKA- K115375 and OTKA-K 128369].