We are interested in understanding the interplay of multiple liver cell types during the progression of liver disease, caused by dietary excesses (e.g., Non-Alcoholic Steatohepatitis; NASH), into fibrosis. In addition, we would like to have in vitro possibilities to validate novel drug targets and pre-clinical compounds, and to discover novel targets. To this end, we are building in vitro liver models by using human tissues to model healthy and diseased livers, and different technologies and approaches to find models that best represent the human liver. To validate our models, we are making use of all known in vivo and in vitro datasets to compare behaviors of multiple biomarkers and transcriptomes. Using this approach, we hope to speed up drug discovery and to use fewer animal models during drug development.
Specifically, we are creating models that encompass the three liver cell types most implicated in NASH and fibrosis: hepatocytes, hepatic stellate cells, and macrophages. Little is known about the signals that emanate from, and alter the behavior of, each cell type, so we have opportunities to utilize single-cell sequencing and metabolomics of single, double, and triple cell cultures to understand the effects that each cell is having on the other(s). These studies will allow us to create a comprehensive model of cell-cell interactions that will hopefully reveal more targets for potential intervention with drugs..