Human hepatocytes derived from pluripotent stem cells: a promising cell model for drug hepatotoxicity screening.
Drug-induced liver injury (DILI) is a frequent cause of failure in both clinical and post-approval stages of drug development, and poses a key challenge to the pharmaceutical industry. Current animal models offer poor prediction of human DILI. Although several human cell-based models have been proposed for the detection of human DILI, human primary hepatocytes remain the gold standard for preclinical toxicological screening. However, their use is hindered by their limited availability, variability and phenotypic instability. In contrast, pluripotent stem cells, which include embryonic and induced pluripotent stem cells (iPSCs), proliferate extensively in vitro and can be differentiated into hepatocytes by the addition of soluble factors. This provides a stable source of hepatocytes for multiple applications, including early preclinical hepatotoxicity screening. In addition, iPSCs also have the potential to establish genotype-specific cells from different individuals, which would increase the predictivity of toxicity assays allowing more successful clinical trials. Therefore, the generation of human hepatocyte-like cells derived from pluripotent stem cells seems to be promising for overcoming limitations of hepatocyte preparations, and it is expected to have a substantial repercussion in preclinical hepatotoxicity risk assessment in early drug development stages.
Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe de Valencia, Torre A, 6ª Planta, Avenida Fernando Abril Martorell 106, 46026, Valencia, Spain.|CIBERehd, FIS, 08036, Barcelona, Spain.
María José
MJ
Gómez-Lechón
Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe de Valencia, Torre A, 6ª Planta, Avenida Fernando Abril Martorell 106, 46026, Valencia, Spain. laiatolosa@hotmail.com.
Laia
L
Tolosa
D000826:Animal Testing Alternatives; D000818:Animals; D001681:Biological Assay; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D018570:Risk Assessment; D018675:Toxicity Tests / Q000379:methods*
Embryonic stem cells; Hepatocyte-like cells; Hepatotoxicity; Induced pluripotent stem cells; Pluripotent stem cells; Screening