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Prediction of hepatotoxicity for drugs using human pluripotent stem cell-derived hepatocytes

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Abstract

Drug-induced liver toxicity is a main reason for withdrawals of new drugs in late clinical phases and post-launch of the drugs. Thus, hepatotoxicity screening of drug candidates in pre-clinical stage is important for reducing drug attrition rates during the clinical development process. Here, we show commercially available hepatocytes that could be used for early toxicity evaluation of drug candidates. From our hepatic differentiation technology, we obtained highly pure (≥98%) hepatocytes from human embryonic stem cells (hESCs) having mature phenotypes and similar gene expression profiles with those of primary human tissues. Furthermore, we optimized 96-well culture condition of hESC-derived hepatocytes suitable for toxicity tests in vitro. To this end, we demonstrated the efficacy of our optimized hepatocyte model for predicting hepatotoxicity against the Chinese herbal medicines and showed that toxicity patterns from our hepatocyte model was similar to those of human primary cultured hepatocytes. We conclude that toxicity test using our hepatocyte model could be a good alternative cell source for pre-clinical study to predict potential hepatotoxicity in drug discovery industries.

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Abbreviations

AFP:

α-fetoprotein

ALB:

Albumin

ASGPR1:

Asialoglycoprotein receptor 1

FACS:

Fluoresecence-activated cell sorting

HCS:

High-content screening

hESCs:

Human embryonic stem cells

HNF4α:

Hepatocyte nuclear factor 4 α

hPH:

Human primary hepatocytes

ICG:

Indocyanine green

LDL:

Low-density lipoprotein

mPH:

Mouse primary hepatocytes

MRP2:

Multidrug resistance-associated protein 2

NTCP:

Sodium taurocholate cotransporting polypeptide

PAS:

Periodic acid-Schiff

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Acknowledgments

This work was supported by the Technological Innovation R&D program (C0399282) funded by the Small and Medium Business Administration (SMBA, Korea).

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Correspondence to Xiao-Bo Sun, Jong-Hoon Kim or Dong-Hun Woo.

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The hepatic differentiation method is protected by unpublished patent (KOR/1020160129064), and this intellectual property rights belong to NEXEL Co., Ltd.

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Kim, J.H., Wang, M., Lee, J. et al. Prediction of hepatotoxicity for drugs using human pluripotent stem cell-derived hepatocytes. Cell Biol Toxicol 34, 51–64 (2018). https://doi.org/10.1007/s10565-017-9392-y

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  • DOI: https://doi.org/10.1007/s10565-017-9392-y

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