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

Holmgren, GustavHögskolan i Skövde,Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för klinisk kemi och transfusionsmedicin,Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine,Institutionen för biovetenskap,Forskningscentrum för Systembiologi,Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden,Bioinformatics (författare)

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 long-term toxicity study using hPSC-derived hepatocytes, and the observations support further development and validation of hPSC-based toxicity models for evaluating novel drugs, chemicals, and cosmetics.

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinsk bioteknologi Medicinsk bioteknologi hsv//swe
MEDICAL AND HEALTH SCIENCES Medical Biotechnology Medical Biotechnology hsv//eng
INDUCED LIVER-INJURY
DIRECT THROMBIN INHIBITOR
HUMAN HEPATOMA-CELL
IN-VITRO MODEL
HEPARG CELLS
DRUG-METABOLISM
CYTOCHROMES P450
HEPG2
CELLS
XIMELAGATRAN
HEPATOTOXICITY
Pharmacology & Pharmacy
Bioinformatik

Sjögren, Anna-Karin,1980Department of Discovery Safety, Drug Safety and Metabolism, AstraZeneca RandD, Mölndal, Sweden(Swepub:gu)xsannz (författare)
Barragan, I.Karolinska Institutet,Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (författare)
Sabirsh, A.Department of Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca RandD, Mölndal, Sweden (författare)
Synnergren, Jane,1967Högskolan i Skövde,Institutionen för biovetenskap,Forskningscentrum för Systembiologi,Bioinformatics(Swepub:his)synj (författare)
Bjorquist, P.NovaHep AB, Gothenburg, Sweden / Cellectis AB, Gothenburg, Sweden (författare)
Ingelman-Sundberg, M.Karolinska Institutet,Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (författare)
Andersson, B Tommy,1964Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden / Department of Drug Metabolism and Pharmacokinetics, AstraZeneca RandD, Mölndal, Sweden(Swepub:gu)xandbt (författare)
Edsbagge, Josefina,1973Cellectis AB, Gothenburg, Sweden (författare)
Sartipy, PeterHögskolan i Skövde,Institutionen för biovetenskap,Forskningscentrum för Systembiologi,Cellectis AB, Gothenburg, Sweden,Bioinformatics(Swepub:his)sarp (författare)
Göteborgs universitetInstitutionen för biomedicin, avdelningen för klinisk kemi och transfusionsmedicin (creator_code:org_t)

Ingår i:Drug Metabolism and Disposition: American Society for Pharmacology & Experimental Therapeutics (ASPET)42:9, s. 1401-14060090-95561521-009X

Av författaren/redakt...: Holmgren, Gustav; Sjögren, Anna-Ka ...; Barragan, I.; Sabirsh, A.; Synnergren, Jane ...; Bjorquist, P.; visa fler...; Ingelman-Sundber ...; Andersson, B Tom ...; Edsbagge, Josefi ...; Sartipy, Peter; visa färre...

Om ämnet

MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Medicinsk biotek ...; och Medicinsk biotek ...

Av lärosätet: Göteborgs universitet; Karolinska Institutet; Högskolan i Skövde

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