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Bo Holmstead memorial lecture

 
Human skin stem cell-derived hepatic cells and their potential applications
Vera Rogiers
In vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel (VUB), Brussels, Belgium

Human skin-derived precursor cells (hSKP) are somatic, immune-privileged stem cells that reside in the dermis throughout life and harbour a high self-renewal and multipotent capacity. More specifically, it could be shown that besides their ectodermal and mesodermal differentiation potential, they can be directed towards the hepatic lineage.  Indeed, upon sequential exposure in vitro to hepatogenic growth factors and cytokines, hSKP are able to generate hepatic progenitor-like cells (hSKP-HPC). As such, they represent a convenient human cell source with a normal genotype (patented protocol EP1824965 B1). They express not only hepatic progenitor cell markers, but also some typical features of adult hepatocytes such as albumin production. They also express a number of key biotransformation enzymes, including CYP1B1, FMO1, GSTA4, GSTM3 and influx and efflux drug transporters such as ABCC4, ABCA1, SLC2A5. These properties give the cells a unique position among the actually existing in vitro models, which makes them suitable for pharmaceutical, toxicological and clinical applications. The predictive capacity of the hSKP-HPC for identifying hepatotoxic compounds was evaluated. Using a toxicogenomics approach, it was found that hSKP-HPC can predict hepatotoxicity equivalent to primary human hepatocytes. They even more closely reflect clinical samples from acute liver failure (ALF) and fatty liver patients in response to hepatotoxic compounds than primary human hepatocytes. The ability of hSKP-HPC to deliver in vitro prediction of hepatotoxicity for ALF (acetaminophen), phospholipidosis (amiodarone) and hepatic steatosis (sodium valproate) is especially relevant for drug discovery programs, where drug-induced liver injury (DILI) contributes to high attrition rates. Furthermore, hSKP-HPC’s sensitivity to hepatic steatosis underlies its relevance as a disease model for non-alcoholic fatty liver disease (NAFLD), which affects 20% of the adult population and which may evolve into severe, life threatening non-alcoholic steatohepatitis (NASH). Current pre-clinical investigations rely on animal or human in vitro models that do not accurately reflect clinical NAFLD. We have demonstrated that exposure to steatogenic compounds, including insulin, induces triglyceride accumulation in hSKP-HPC, a central feature of clinical NAFLD. Moreover, it could be shown that the key molecular mechanisms that underlie this effect can be modelled and modulated in hSKP-HPC, providing a valuable disease model for screening of novel anti-NAFLD molecules. Finally, hSKP themselves are key candidates for autologous and allogeneic cell-based therapy for the treatment of liver disease, given their immune privileged state. In a transgenic murine model of liver deficiency (uPA+/+/SCID), injected hSKP cells successfully engrafted, survived and repopulated the hepatic liver tissue and contributed to the increase in liver mass. Also, after oral administration of dianabol, an anabolic steroid, the in vitro generated hSKP-derived hepatocytes produced human-specific metabolites, detectable in the urine of the chimeric mice. This clearly demonstrates the in vivo biotransformation capacity of the hSKP-derived hepatocytes. Further developments are underway, among which the development of a hSKP-based NASH model suitable for toxicological screening and drug discovery.
Acknowledgements: a warm “thank you” to all the fine collaborators over the many years of research at the VUB.

 

 

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