Human Pluripotent Stem Cell Applications in Drug Discovery and Toxicology – An overview

Potta, Shiva Prasad; Šarić, Tomo; Heke, Michael; HarinathBahudhanapati,; Hescheler, Jürgen

doi:10.5772/58485

Cited by 2 publications

(1 citation statement)

References 62 publications

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“…Modulation of these kinase pathways is often associated with off-target cardiotoxicity because the same kinases are also expressed by the heart cells [91]. Although animal studies play an important part in predicting the cardiotoxicity of drug candidates, differences in certain electrophysiological properties between animals and humans can often limit the translation of the results to the clinical setting [110,111]. Moreover, the detection of hERG inhibition in vitro relies heavily on mouse and human cardiac muscle cell lines [112] and non-cardiac cell lines, such as CHO or HEK293.…”

Section: Cytotoxicitymentioning

confidence: 99%

Translational Prospects and Challenges in Human Induced Pluripotent Stem Cell Research in Drug Discovery

Hashimoto

Czysz

2016

Cells

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Despite continuous efforts to improve the process of drug discovery and development, achieving success at the clinical stage remains challenging because of a persistent translational gap between the preclinical and clinical settings. Under these circumstances, the discovery of human induced pluripotent stem (iPS) cells has brought new hope to the drug discovery field because they enable scientists to humanize a variety of pharmacological and toxicological models in vitro. The availability of human iPS cell-derived cells, particularly as an alternative for difficult-to-access tissues and organs, is increasing steadily; however, their use in the field of translational medicine remains challenging. Biomarkers are an essential part of the translational effort to shift new discoveries from bench to bedside as they provide a measurable indicator with which to evaluate pharmacological and toxicological effects in both the preclinical and clinical settings. In general, during the preclinical stage of the drug development process, in vitro models that are established to recapitulate human diseases are validated by using a set of biomarkers; however, their translatability to a clinical setting remains problematic. This review provides an overview of current strategies for human iPS cell-based drug discovery from the perspective of translational research, and discusses the importance of early consideration of clinically relevant biomarkers.

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Section: Cytotoxicitymentioning

confidence: 99%

Translational Prospects and Challenges in Human Induced Pluripotent Stem Cell Research in Drug Discovery

Hashimoto

Czysz

2016

Cells

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Recent Advances for Enhancing Drug Metabolizing Functions of Hepatocyte-like Cells Derived from Human Pluripotent Stem Cells

Han

Kim

2015

Hanyang Med Rev

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Hepatocyte-like cells (HLCs) derived from human pluripotent stem cells are a promising cell source for drug screening and toxicity tests. Thus, various hepatic differentiating protocols have been developed, leading to a hepatic differentiation efficiency of approximately 90%. However, HLC drug metabolizing ability remains very low compared to human primary hepatocytes. In order to overcome this problem, several alternative methods, such as, co-culture, three-dimensional (3D) culture, bioreactor, nanochip-based, etc., have been developed, but optimization to produce fully functional HLCs is ongoing. Recently, our group reported that repeated exposure of HLCs to xenobiotics can improve the expression of hepatic metabolizing enzymes such as cytochrome P450s (CYPs) and glutathione S-transferases (GSTs). These data suggest that we should develop strategies for differentiating cells into mature HLCs by more closely mimicking in vivo fetal and postnatal liver development. Here, we review the current development of alternative methods for enhancing the drug metabolizing functions of HLCs derived from human embryonic stem cells, humaninduced pluripotent stem cells, and mesenchymal stem cells as used for drug screening and toxicity tests. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Human Pluripotent Stem Cell Applications in Drug Discovery and Toxicology – An overview

Cited by 2 publications

References 62 publications

Translational Prospects and Challenges in Human Induced Pluripotent Stem Cell Research in Drug Discovery

Translational Prospects and Challenges in Human Induced Pluripotent Stem Cell Research in Drug Discovery

Recent Advances for Enhancing Drug Metabolizing Functions of Hepatocyte-like Cells Derived from Human Pluripotent Stem Cells

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