Current status of human pluripotent stem cell based in vitro toxicity tests

Abstract

The present review assesses the current status of in vitro tests based on human pluripotent stem cell-derived toxicologically relevant target cells. The majority of the evaluated test systems are in the phase of test development. In particular the success rates of differentiation protocols and their reproducibility are varying depending on different culture conditions but also on the assessed marker panel and the functional evaluation of the cells. However, the amount of differentiated cells decreases in relation to their maturation status. No harmonization has been achieved yet about the required maturation status of the cellular models to be used for toxicological applications. Even with an established cellular model, the selection of appropriate readouts is challenging. Some areas of toxicity, such as developmental toxicity, suffer from insufficient knowledge on predictive biomarkers which leads to difficulties in the selection of the most appropriate endpoints. In this heterogeneous context the rapidly increasing knowledge about 'omics' technologies, might lead to an improvement of the current situation and allow the establishment of more predictive human in vitro toxicity tests.

Profiling of drugs and environmental chemicals for functional impairment of neural crest migration in a novel stem cell-based test battery

“…The currently available test systems have been characterized by the use of well-known positive control compounds, which mainly belong to the group of environmental toxicants (Klaric et al 2013; Vojnits et al 2012; Krug et al 2013a; Pallocca et al 2013; Laurenza et al 2013; Piersma et al 2013; Bal-Price et al 2012; Crofton et al 2011; Coecke et al 2007; Lein et al 2007; Kadereit et al 2012). Some others have used at most one to three drug-like compounds (Balmer et al 2012; Stiegler et al 2011; Kuegler et al 2012; Meganathan et al 2012; Jagtap et al 2011; Falsig et al 2004).…”

Fingerprinting of neurotoxic compounds using a mouse embryonic stem cell dual luminescence reporter assay

“…The results of valproic acid of the present study are in good agreement with previous studies performed in neuronal precursor cells derived from human embryonic stem cells (Waldmann et al 2014). In this study, three types of impacts related to different concentration ranges have been defined: (1) a range of tolerance, observed valproic acid concentrations up to 25 μM, suggesting the existence a threshold mechanisms (Dietrich et al 2013); (2) a deregulated/teratogenic effect was observed at concentrations between 150 and 550 μM of valproic acid, which was associated with developmental disturbances, impaired cell migration, and the down-regulation of neuronal pathways (Balmer et al 2012; Klaric et al 2013); (3) a cytotoxic concentration range at 800 and 1000 μM.…”

Comparison of gene expression regulation in mouse- and human embryonic stem cell assays during neural differentiation and in response to valproic acid exposure

“…This interest stems from the hypothesis that human hazard is probably best assessed in assays with human biological systems, which is one of the key messages from the NAS landmark report on toxicity testing in the 21st century [31]. In the past, primarily mESC were used for the stem cell test [32] which provided ground work for development of the EST [33].…”