Trends in Molecular Medicine
OpinionRoad Map for Development of Stem Cell-Based Alternative Test Methods
Section snippets
Preclinical Safety Evaluation: Animal Studies versus Human In Vitro Systems
Much effort has been invested into the development of human in vitro systems 1, 2, 3, 4. The question of whether these alternative systems are preferred over animal experiments for safety evaluation of drugs and chemicals has been discussed intensively in the past decade 5, 6. This debate is not new – as early as the 11th century, the Persian physician, Avicenna, noted that medicine may affect the human body differently from the animal body [7]. The thalidomide disaster represents a well-known
Cultured Hepatocytes
Today, in vitro systems can successfully identify compounds that would fail during further preclinical and clinical development. For example, if a concentration of 200 μM of a drug candidate is required to achieve a therapeutic effect but this concentration is already cytotoxic to cultured hepatocytes, the probability of hepatotoxicity during clinical development is high. Therefore, preclinical in vitro tests can help to avoid animal experiments with compounds that would fail because of toxicity
Application of Stem-Cell-Based In Vitro Test Systems: Analysis of Developmental Processes and Mature Cell Types
An attractive long-term perspective is the generation of all types of mature human cells, or even tissues and organs, for the development of therapeutics and toxicity testing. Artificially generated induced pluripotent stem cells (iPSCs) are of special interest in this regard due to their donor specificity and autologous transplantation potential, while the use of embryonic stem cells (ESCs) is limited by ethical considerations, law, and availability of freshly isolated cells that do not have a
Road Map for Stem-Cell-Based In Vitro Toxicity Test System Development
Progress in the field of stem-cell-based in vitro systems depends on basic knowledge and technology in developmental biology and stem cell research. As discussed for hepatocytes, this may be a demanding long-term task. For the existing and future cell systems, the following road map (Figure 3) will be useful.
Concluding Remarks
Recently, in vitro test systems with hiPSCs have been established for safety evaluation of drugs and chemicals as an alternative to animal experiments. One application is to identify developmental toxicants by analysing the influence of test compounds on differentiating stem cells in vitro, which can be quantified by statistical concepts, such as the developmental potency (Dp) that gives the fraction of all developmental genes that are affected by a compound and the developmental index (Di)
Acknowledgements
This work has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 681002 (EU-ToxRisk), from TransQST (No. 116030), StemCellNet (BMBF, 01EK1604A), LiSyM (BMBF, 031Loo45), LivSysTransfer (BMBF, 0101-31Q0517), SteatoTox (031L0114B) and SysDT-Trans (031L0117C).
Glossary
- Anticonvulsants
- drugs used for treatment of epilepsy (antiepileptic drugs).
- Feeder cells
- supportive growth-arrested somatic cells (e.g., mouse fibroblasts) for culturing and proliferation of mouse and human embryonic and induced pluripotent stem cells.
- Hepatocyte-like cells (HLCs)
- HLCs are immature human hepatocytes and are normally generated from hiPSCs.
- Xenobiotic metabolising enzyme (XME)
- enzymes of the liver that detoxify and eliminate xenobiotics. Xenobiotics are chemical substances found in an
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2022, Toxicology in VitroCitation Excerpt :This in vitro-in vivo extrapolation plot showed a good separation between hepatotoxic and non-hepatotoxic compounds, which demonstrates that it is theoretically possible to extrapolate blood concentrations from test compound concentrations in the culture medium. Previously, the in vitro data for in vitro-in vivo extrapolation was obtained from cytotoxicity assays with cultivated human hepatocytes, which still represent the gold standard among alternative methods for hepatotoxicity testing because of their in vivo like metabolism (Albrecht et al., 2019; Gu et al., 2018; Hewitt et al., 2007; Sachinidis et al., 2019). Concentration-response curves obtained from cytotoxicity tests allow for the precise determination of the concentration where cytotoxicity of a specific compound begins.
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