21st Century Cell Culture for 21st Century Toxicology

Abstract

There is no good science in bad models. Cell culture is especially prone to artifacts. A number of novel cell culture technologies have become more broadly available in the 21st century, which allow overcoming limitations of traditional culture and are more physiologically relevant. These include the use of stem-cell derived human cells, cocultures of different cell types, scaffolds and extracellular matrices, perfusion platforms (such as microfluidics), 3D culture, organ-on-chip technologies, tissue architecture, and organ functionality. The physiological relevance of such models is further enhanced by the measurement of biomarkers (e.g., key events of pathways), organ specific functionality, and more comprehensive assessment cell responses by high-content methods. These approaches are still rarely combined to create microphysiological systems. The complexity of the combination of these technologies can generate results closer to the in vivo situation but increases the number of parameters to control, bringing some new challenges. In fact, we do not argue that all cell culture needs to be that sophisticated. The efforts taken are determined by the purpose of our experiments and tests. If only a very specific molecular target to cell response is of interest, a very simple model, which reflects this, might be much more suited to allow standardization and high-throughput. However, the less defined the end point of interest and cellular response are, the better we should approximate organ- or tissue-like culture conditions to make physiological responses more probable. Besides these technologic advances, important progress in the quality assurance and reporting on cell cultures as well as the validation of cellular test systems brings the utility of cell cultures to a new level. The advancement and broader implementation of Good Cell Culture Practice (GCCP) is key here. In toxicology, this is a major prerequisite for meaningful and reliable results, ultimately supporting risk assessment and product development decisions.

Rebooting the generally recognized as safe (GRAS) approach for food additive safety in the US

“…Currently, complementary guidance for in vitro tests is being developed: Good In Vitro Method Practices (GIVIMP) for the Development and Implementation of In Vitro Methods for Regulatory Use in Human Safety Assessment 16 . This corresponds closely with attempts to develop a revised Good Cell Culture Practice (Pamies and Hartung, 2017;Eskes et al, 2017;Pamies et al, 2018). Please consult these references for more details.…”

The need for strategic development of safety sciences

“…The respective approaches developed in the Human Toxome Project are currently being published (Fasani et al, 2016;Rosenberg et al, unpublished (Vrijheid et al, 2014), EXPOsOM-ICS 23 (Callaway, 2012;Vineis et al, 2016) (Stephens et al, 2016) and collaborating in EBTC, these approaches are gaining traction as a new paradigm of how to handle existing data in safety assessments. Noteworthy, EBT approaches cross-fertilize with the various quality assurance approaches: only evidence of high-quality sources can be used (requiring quality scoring (Samuel et al, 2016)) and this teaches the scientific community how to produce and report properly, as discussed recently for in vitro work (Pamies and Hartung, 2016). Taken together, these different approaches have in common that they use modern technologies for data generation, including high-throughput and high-content methods, that they rely much less on animal models but combine in vitro and in silico tools, aim for quality assurance in data generation / integration and often make use of exposure information.…”

A C‐terminal CXCL8 peptide based on chemokine–glycosaminoglycan interactions reduces neutrophil adhesion and migration during inflammation

“…It is also worth noting that chemokine peptides are usually associated with favourable properties such as low toxicity and low immunogenicity, which contributes to their increasing recognition as potential candidates for novel drugs. 85,86 Taken together, this approach shows the ability of CXCL8 (54-72) to bind GAG, and to significantly reduce chemokine-mediated neutrophil adhesion. In addition, the E70K CXCL8 peptide also showed a significant reduction in neutrophil transendothelial migration.…”

“…neutrophil chemoattractant CXCL1, or CXCL9; and on other GAGs, may unravel further functionality of synthetic peptides. It is also worth noting that chemokine peptides are usually associated with favourable properties such as low toxicity and low immunogenicity, which contributes to their increasing recognition as potential candidates for novel drugs …”