Multiomic Analysis of the Hepatic Fibrotic Niche to Define New Therapeutic Targets for Liver Scarring

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Liver disease accounts for an estimated 2 million deaths per year globally. One feature of advanced liver disease is liver scarring (fibrosis), which is associated with poor clinical outcome. There are, at present, no effective anti-fibrotic therapies thus highlighting an important need to develop novel therapeutic strategies in this area. Recent work in the Ramachandran lab has used single-cell RNA sequencing (scRNA-seq) to identify a pathogenic subpopulation of cells in the liver which reside in a distinct spatial environment, named the fibrotic niche. Discovery of this fibrotic niche provides an opportunity to target the more diseased areas of tissue without perturbing non-diseased regions, and as such this precision-medicine based strategy may be used for patients with liver fibrosis. However, the cellular composition and cell-to-cell interactions within the fibrotic niche have not yet been assessed. To investigate this, spatial transcriptomics can be used to identify which transcripts are enriched within specific areas of scarring, subsequently allowing for a more targeted approach in terms of therapeutic strategies. Within this project, we will utilise spatial transcriptomics to determine the composition of the fibrotic niche within diseased human liver. We aim to integrate spatial transcriptomic and single-cell RNA sequencing data, such that we can interrogate the cell-cell interactions involved in the fibrotic process. Furthermore, we aim to investigate the niche in mouse models to determine any conserved pro-fibrogenic pathways between human and mouse, allowing us to identify potential therapeutic targets. Spatial transcriptomics approach will use the 10X genomics visium platform. Analysis of scRNA-seq data and spatial transcriptomic data will be done using a variety of packages in the R and Python languages including Seurat, Harmony, Giotto, BayesSpace and scanpy. Multiomic analysis of the niche will be performed to compare human and mouse liver fibrosis, such that conserved cell types and pathways can be defined. Molecules of interest will be manipulated using a combination of genetic approaches and in vivo mouse models and in vitro cell culture models.