Rapport final
Development of a human skin stem cell-derived in vitro model to study non-alcoholic steatohepatitis - Marcelino Rodrigues Robim
Non-alcoholic steatohepatitis (NASH) is a chronic liver disease characterized by hepatic steatosis, inflammation and pericellular fibrosis for which no drugs are available. The lack of trustful in vitro and in vivo preclinical models jeopardizes the development of efficacious therapies. This project focused on the development of accurate in vitro systems that mimic important NASH characteristics and could be used as a tool for screening of potential new anti-NASH molecules. Human skin-derived precursors (hSKP), which are multipotent stem cells, can be differentiated towards cells with hepatic properties (hSKP-HPC). We found that these cells acquire typical NASH features upon triggering with key factors that play a role during NASH progression in patients. We first showed that this hSKP-HPC-based ‘NASH model’ was effective in identifying anti-steatotic and anti-inflammatory characteristics of elafibranor, which is a PPAR-alpha and PPAR-delta agonist under investigation as anti-NASH drug. Subsequently, we investigated whether the same methodology could be applied to other, commonly-used hepatic cell systems (i.e. primary human hepatocytes, HepG2, HepaRG and LX2) and if these systems could be used to classify the anti-NASH potency of multiple PPAR-agonists under different stages in the drug development process. We found that PPAR agonists (bezafibrate, elafibranor, fenofibrate, lanifibranor, pemafibrate, pioglitazone, rosiglitazone, and saroglitazar) differently attenuated lipid accumulation, inflammatory chemokine secretion, and pro-fibrotic gene expression. Based on a battery of the most performant models, an in vitro scoring system was developed to grade the anti-NASH potencies of the different compounds. These data corroborated available clinical data and showed the relevance of in vitro preclinical investigation of anti-NASH compounds.