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Development of a novel, physiologically relevant cytotoxicity model: Application to the study of chemotherapeutic damage to mesenchymal stromal cells

May, Jennifer E.; Morse, H. Ruth; Xu, Jinsheng; Donaldson, Craig

Authors

Jennifer May Jennifer2.May@uwe.ac.uk
Senior Lecturer in Biomedical Science

Jinsheng Xu

Craig Donaldson



Abstract

There is an increasing need for development of physiologically relevant in-vitro models for testing toxicity, however determining toxic effects of agents which undergo extensive hepatic metabolism can be particularly challenging. If a source of such metabolic enzymes is inadequate within a model system, toxicity from prodrugs may be grossly underestimated. Conversely, the vast majority of agents are detoxified by the liver, consequently toxicity from such agents may be overestimated.In this study we describe the development of a novel in-vitro model, which could be adapted for any toxicology setting. The model utilises HepG2 liver spheroids as a source of metabolic enzymes, which have been shown to more closely resemble human liver than traditional monolayer cultures. A co-culture model has been developed enabling the effect of any metabolised agent on another cell type to be assessed. This has been optimised to enable the study of damaging effects of chemotherapy on mesenchymal stem cells (MSC), the supportive stem cells of the bone marrow. Several optimisation steps were undertaken, including determining optimal culture conditions, confirmation of hepatic P450 enzyme activity and ensuring physiologically relevant doses of chemotherapeutic agents were appropriate for use within the model. The developed model was subsequently validated using several chemotherapeutic agents, both prodrugs and active drugs, with resulting MSC damage closely resembling effects seen in patients following chemotherapy.Minimal modifications would enable this novel co-culture model to be utilised as a general toxicity model, contributing to the drive to reduce animal safety testing and enabling physiologically relevant in-vitro study. © 2012 Elsevier Inc.

Citation

May, J. E., Morse, H. R., Xu, J., & Donaldson, C. (2012). Development of a novel, physiologically relevant cytotoxicity model: Application to the study of chemotherapeutic damage to mesenchymal stromal cells. Toxicology and Applied Pharmacology, 263(3), 374-389. https://doi.org/10.1016/j.taap.2012.07.013

Journal Article Type Article
Publication Date Sep 15, 2012
Journal Toxicology and Applied Pharmacology
Print ISSN 0041-008X
Electronic ISSN 1096-0333
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 263
Issue 3
Pages 374-389
DOI https://doi.org/10.1016/j.taap.2012.07.013
Keywords toxicity testing, in vitro model, chemotherapy, HepG2 spheroids, mesenchymal stem cell
Public URL https://uwe-repository.worktribe.com/output/954577
Publisher URL http://dx.doi.org/10.1016/j.taap.2012.07.013
Additional Information Additional Information : Available online first 24 July 2012