Hepatic stellate cell transcriptional dynamics in liver fibrosis

Chronic liver disease (CLD) is a global health burden accounting for an estimated 2 million deaths per year worldwide. CLD, caused by many etiologies including alcohol abuse, metabolic syndrome, and hepatitis B and C, can be broadly defined as a disease state of the liver marked by inflammation, fibrosis, and failure of liver regeneration processes over a prolonged period. Of these features, the extent of liver fibrosis is the primary prognostic determinant of CLD, irrespective of CLD etiology. At the cellular level, liver fibrosis (i.e., scarring of the liver) is caused by the expansion of myofibroblasts, a cell type barely present within the healthy liver. The primary cell type contributing to the myofibroblast pool is the hepatic stellate cell (HSC). In a healthy liver, the quiescent HSC is a retinol-storing pericyte-like cell that shows marked plasticity upon liver injury, after which it will differentiate (or activate) into a myofibroblast-like cell. Currently, no treatment options exist other than treating the underlying cause or transplanting livers in an end-stage disease state. Unfortunately, these options are often not feasible due to progressive liver disease, complex disease pathogenesis, or lack of organ donors. As such, there currently is an unmet need for the treatment of CLD.In order to tackle this unmet need, we adopted an HSC point-of-view approach. Using transcriptomics, we opted to understand the HSC activation process better by focusing on the transcriptional events that facilitate differentiation during the first moments of activation (called initiation). We hypothesized that these insights would allow us to identify new putative anti-fibrotic candidates to treat CLD. The results of this thesis show that, while initiation is historically defined asbeing limited to early events, initiation characteristics remain present throughout all stages of liver disease, from acute liver injury to end-stage liver disease. Thus, HSC initiation can be considered a previously unexplored entity for treating CLD.From the same data, we were able to identify GPR176, an orphan G-protein coupled receptor with enriched expression in HSCs, which is associated with the extent of HSC activation status and liver fibrosis. Furthermore, blocking of GPR176 expression reduced HSC activation and liver fibrosis. In conclusion, by analyzing HSC transcriptional dynamics, we were able to identify a new putative anti-fibrotic candidate. In the grand scheme of CLD, evidence provided in this thesis further broadens our understanding of HSC biology and might fuel new fundamental and translational research in pursuit of new CLD therapeutics.

Publication year:2022

Keywords:Chronic liver disease

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