title: Human skin-derived stem cells as a novel cell source for in vitro hepatotoxicity screening of pharmaceuticals.
abstract: Human skin-derived precursors (hSKP) are postnatal stem cells with neural crest properties that reside in the dermis of human skin. These cells can be easily isolated from small (fore) skin segments and have the capacity to differentiate into multiple cell types. In this study, we show that upon exposure to hepatogenic growth factors and cytokines, hSKP acquire sufficient hepatic features that could make these cells suitable in vitro tools for hepatotoxicity screening of new chemical entities and already existing pharmaceutical compounds. Indeed, hepatic differentiated hSKP [hSKP-derived hepatic progenitor cells (hSKP-HPC)] express hepatic progenitor cell markers (EPCAM, NCAM2, PROM1) and adult hepatocyte markers (ALB), as well as key biotransformation enzymes (CYP1B1, FMO1, GSTA4, GSTM3) and influx and efflux drug transporters (ABCC4, ABCA1, SLC2A5). Using a toxicogenomics approach, we could demonstrate that hSKP-HPC respond to acetaminophen exposure in a comparable way to primary human hepatocytes in culture. The toxicological responses "liver damage", "liver proliferation", "liver necrosis" and "liver steatosis" were found to be significantly enriched in both in vitro models. Also genes associated with either cytotoxic responses or induction of apoptosis (BCL2L11, FOS, HMOX1, TIMP3, and AHR) were commonly upregulated and might represent future molecular biomarkers for hepatotoxicity. In conclusion, our data gives a first indication that hSKP-HPC might represent a suitable preclinical model for in vitro screening of hepatotoxicity. To the best of our knowledge, this is the first report in which human postnatal stem cells derived from skin are described as a potentially relevant cell source for in vitro hepatotoxicity testing of pharmaceutical compounds.
authors: 1 Department of Toxicology, Center for Pharmaceutical Research, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB) , Brussels, Belgium .
authors: Robim M
authors: RM
authors: Rodrigues
authors: Joery
authors: J
authors: De Kock
authors: Steven
authors: S
authors: Branson
authors: Mathieu
authors: M
authors: Vinken
authors: Kesavan
authors: K
authors: Meganathan
authors: Umesh
authors: U
authors: Chaudhari
authors: Agapios
authors: A
authors: Sachinidis
authors: Olivier
authors: O
authors: Govaere
authors: Tania
authors: T
authors: Roskams
authors: Veerle
authors: V
authors: De Boe
authors: Tamara
authors: T
authors: Vanhaecke
authors: Vera
authors: V
authors: Rogiers
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000293:injuries; D009432:Neural Crest / Q000166:cytology; D012867:Skin / Q000166:cytology*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*
chemical_list: D016207:Cytokines; D017228:Hepatocyte Growth Factor
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