Accurate Prediction of Drug-Induced Liver Injury Using Stem Cell-Derived Populations

Szkolnicka, Dagmara; Farnworth, Sarah L.; Lucendo‐Villarin, Baltasar; Storck, Christopher; Zhou, Wenli; Iredale, John P.; Flint, Oliver; Hay, David C.

doi:10.5966/sctm.2013-0146

Cited by 103 publications

(107 citation statements)

References 23 publications

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“…To date, numerous studies in rodents have shown that predifferentiated ESC transplantation can reverse acute fulminant hepatic failure 6,50, 51, 52, 53, 54. In our study, we employed day‐3‐induced DE cells as a source of isolated cells for transplantation into injured liver.…”

Section: Resultsmentioning

confidence: 99%

Sustained Delivery Growth Factors with Polyethyleneimine‐Modified Nanoparticles Promote Embryonic Stem Cells Differentiation and Liver Regeneration

et al. 2016

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Stem‐cell‐derived hepatocyte transplantation is considered as a potential method for the therapy of acute and chronic liver failure. However, the low efficiency of differentiation into mature and functional hepatocytes remains a major challenge for clinical applications. By using polyethyleneimine‐modified silica nanoparticles, this study develops a system for sustained delivery of growth factors, leading to induce hepatocyte‐like cells (iHeps) from mouse embryonic stem cells (mESCs) and improve the expression of endoderm and hepatocyte‐specific genes and proteins significantly, thus producing a higher population of functional hepatocytes in vitro. When transplanted into liver‐injured mice after four weeks, mESC‐derived definitive endoderm cells treated with this delivery system show higher integration efficiency into the host liver, differentiated into iHeps in vivo and significantly restored the injured liver. Therefore, these findings reveal the multiple advantages of functionalized nanoparticles to serve as efficient delivery platforms to promote stem cell differentiation in the regenerative medicine.

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Section: Resultsmentioning

confidence: 99%

Sustained Delivery Growth Factors with Polyethyleneimine‐Modified Nanoparticles Promote Embryonic Stem Cells Differentiation and Liver Regeneration

et al. 2016

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“…For example, maintenance of hiPSC-derived hepatocytes for up to two weeks was reported, enabling repeated-dose chronic exposure to hepatotoxic compounds. 146,147 Studies on MPCC with hiPSC-derived human hepatocytes 148 indicate a similar sensitivity toward drug toxicity as observed in MPCC using PHH. 51 In addition, hepatocytes generated from pluripotent stem cells have been successfully applied in in vitro studies on infectious diseases like hepatitis B and C infection 149,150 or malaria pathogenesis.…”

mentioning

confidence: 99%

Cell sources forin vitrohuman liver cell culture models

Zeilinger

Freyer

Damm

et al. 2016

Exp Biol Med (Maywood)

186

160

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In vitro liver cell culture models are gaining increasing importance in pharmacological and toxicological research. The source of cells used is critical for the relevance and the predictive value of such models. Primary human hepatocytes (PHH) are currently considered to be the gold standard for hepatic in vitro culture models, since they directly reflect the specific metabolism and functionality of the human liver; however, the scarcity and difficult logistics of PHH have driven researchers to explore alternative cell sources, including liver cell lines and pluripotent stem cells. Liver cell lines generated from hepatomas or by genetic manipulation are widely used due to their good availability, but they are generally altered in certain metabolic functions. For the past few years, adult and pluripotent stem cells have been attracting increasing attention, due their ability to proliferate and to differentiate into hepatocyte-like cells in vitro. However, controlling the differentiation of these cells is still a challenge. This review gives an overview of the major human cell sources under investigation for in vitro liver cell culture models, including primary human liver cells, liver cell lines, and stem cells. The promises and challenges of different cell types are discussed with a focus on the complex 2D and 3D culture approaches under investigation for improving liver cell functionality in vitro. Finally, the specific application options of individual cell sources in pharmacological research or disease modeling are described.

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“…Protocols to differentiate human embryonic stem cells and human induced pluripotent stem cells into hepatocytes have improved immensely in recent years, and now hepatocyte cultures with high purity and many characteristics of functional hepatocytes can be obtained from hPSC (Brolen et al, 2010;Si-Tayeb et al, 2010;Touboul et al, 2010;Yildirimman et al, 2011;Hannan et al, 2013;Ulvestad et al, 2013;Szkolnicka et al, 2014). The fact that these cells can be derived in a robust and reproducible fashion from a well-characterized source makes them very attractive as a toxicity assessment model.…”

Section: Introductionmentioning

confidence: 99%

Long-Term Chronic Toxicity Testing Using Human Pluripotent Stem Cell–Derived Hepatocytes

et al. 2014

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Human pluripotent stem cells (hPSC) have the potential to become important tools for the establishment of new models for in vitro drug testing of, for example, toxicity and pharmacological effects. Late-stage attrition in the pharmaceutical industry is to a large extent caused by selection of drug candidates using nonpredictive preclinical models that are not clinically relevant. The current hepatic in vivo and in vitro models show clear limitations, especially for studies of chronic hepatotoxicity. For these reasons, we evaluated the potential of using hPSC-derived hepatocytes for long-term exposure to toxic drugs. The differentiated hepatocytes were incubated with hepatotoxic compounds for up to 14 days, using a repeated-dose approach. The hPSC-derived hepatocytes became more sensitive to the toxic compounds after extended exposures and, in addition to conventional cytotoxicity, evidence of phospholipidosis and steatosis was also observed in the cells. This is, to the best of our knowledge, the first report of a longterm toxicity study using hPSC-derived hepatocytes, and the observations support further development and validation of hPSCbased toxicity models for evaluating novel drugs, chemicals, and cosmetics.

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Accurate Prediction of Drug-Induced Liver Injury Using Stem Cell-Derived Populations

Cited by 103 publications

References 23 publications

Sustained Delivery Growth Factors with Polyethyleneimine‐Modified Nanoparticles Promote Embryonic Stem Cells Differentiation and Liver Regeneration

Sustained Delivery Growth Factors with Polyethyleneimine‐Modified Nanoparticles Promote Embryonic Stem Cells Differentiation and Liver Regeneration

Cell sources forin vitrohuman liver cell culture models

Long-Term Chronic Toxicity Testing Using Human Pluripotent Stem Cell–Derived Hepatocytes

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