Embryonic stem cells and the next generation of developmental toxicity testing

ABSTRACT

Introduction: The advent of stem cell technology has seen the establishment of embryonic stem cells (ESCs) as molecular model systems and screening tools. Although ESCs are nowadays widely used in research, regulatory implementation for developmental toxicity testing is pending.

Areas Covered: This review evaluates the performance of current ESC, including human (h)ESC testing systems, trying to elucidate their potential for developmental toxicity testing. It shall discuss defining parameters and mechanisms, their relevance and contemplate what can realistically be expected. Crucially this includes the question of how to ascertain the quality of currently employed cell lines and tests based thereon. Finally, the use of hESCs will raise ethical concerns which should be addressed early on.

Expert Opinion: While the suitability of (h)ESCs as tools for research and development goes undisputed, any routine use for developmental toxicity testing currently still seems premature. The reasons for this comprise inherent biological deficiencies as well as cell line quality and system validation. Overcoming these issues will require collaboration of scientists, test developers and regulators. Also, validation needs to be made worthwhile for academia. Finally we have to continuously rethink existing strategies, making room for improved testing and innovative approaches.

KEYWORDS:

• Embryonic stem cells (ESCs)
• induced pluripotent stem cells (iPSCs)
• developmental toxicity testing
• embryonic stem cell test (EST)

Article highlights

• (h)ESCs recapitulate early aspects of human development and can be used to assess the effects of teratogens.

• Aspects missing in in vitro developmental toxicity testing comprise fetal-maternal interactions, late-onset effects and predisposition to diseases.

• Ethical concerns related to hESCs (and hiPSCs) have to be dealt with prior to assay development and evaluation.

• The validation of hESC-based test systems has to be reconsidered and much effort is needed to set a new ‘gold standard’.

• There is a need to increase efforts for in vivo to in vitro extrapolation.

• From the regulatory point of view, we also need to consider an assay proofing the harmlessness of tested substances.

This box summarizes key points contained in the article.

Declaration of interest

The authors have received intramural financial support by the German Federal Institute for Risk Assessment, Berlin, Germany. The authors have no other 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 apart from those disclosed.

Additional information

Funding

This paper was not funded