Development of a human skin stem cell-derived in vitro model for the investigation of drug-induced steatosis and its mode of action. (FWOTM797)

Primary human hepatocytes represent the gold standard in vitro model for toxicity testing of pharmaceutical compounds. These cells reflect the in vivo situation most appropriately, but their availability is problematic due to the shortage of human organs. On the contrary, human stem cells, which have the ability to differentiate towards multiple cell types, including liver cells, represent a virtually inexhaustible cell source. Stem cells derived from human skin are multipotent, which means that they can differentiate towards hepatic cells following a protocol that mimics the liver development in vivo. Preliminary results have shown that the obtained cells respond in a similar way as human hepatocytes when exposed to compounds known to induce liver damage. However, their metabolic competence is not yet fully developed. The first part of this research proposal aims at developing a strategy for enhancing the metabolic capacity of the hepatic cells generated from human skin. These cells will be modified by transfection of mRNA corresponding to genes that play a key role in the expression and activation of biotransformation enzymes. In the second part of the project, a set of reference hepatosteatotic compounds and appropriate controls will be investigated using the obtained metabolically enhanced hepatic cells. High content microscopy and “omics” techniques will be employed to investigate the mode of action of the steatotic substances at the molecular level.

Keywords:pharmaceutical science

Disciplines:Pharmacology not elsewhere classified