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Single cell RNA seq of hepatic and renal p16 positive cells

ABSTRACT: We performed the single cell RNA sequencing of mouse normal kidney, normal liver, and NASH-induced liver from p16-tdTomato mice. In order to enrich p16 positive cells, we independently sorted the non-separated cells (including both of p16 positive and negative cells) and p16 positive cells alone through tdTomato intensity by FACS. By obtaining 13,876 single cell transcripts, after the graph-based clustering and marker genes defined cell type classification, we identified the heterogeneity of in vivo p16-positive cells which dispersedly existed in renal cells and non-parenchymal hepatic cells. Differential expressing genes (DEGs) comparisons for each cell type were feasible to study the in vivo p16 dependent transcriptomic pattern change. Finally, we verified several cell type specific senescence-like phenotypes which were previously found on in vitro cellular senescence, and also identified the p16-related subpopulation which might involve in NASH progression and renal damage response.

ORGANISM(S): Mus musculus

PROVIDER: GSE155182 | GEO | 2020/09/16

REPOSITORIES: GEO

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Project description:Background: Senescent hepatocytes accumulate in parallel with fibrosis progression during NASH. The mechanisms that enable progressive expansion of nonreplicating cell populations and the significance of that process in determining NASH outcomes are unclear. Many types of senescing cells upregulate the THBD-PAR-1 signaling axis to remain viable. Vorapaxar, an FDA-approved PAR-1 inhibitor, blocks the activity of that pathway. We used vorapaxar to determine if and how THBD-PAR1 signaling promotes fibrosis progression in NASH. Methods: We evaluated the THBD-PAR1 pathway in liver biopsies from NAFLD patient cohorts with a spectrum of liver fibrosis. Chow fed mice were treated with viral vectors to over-express p16 specifically in hepatocytes and induce replicative senescence. Effects on the THBD-PAR-1 axis and regenerative capacity were assessed; the transcriptome of p16 over-expressing hepatocytes was characterized and we examined how conditioned medium from senescent but viable (dubbed ‘undead’) hepatocytes reprograms hepatic stellate cells. A genetically obese mouse model of NASH with little liver fibrosis, and a diet-induced mouse model of NASH with advanced fibrosis were treated with vorapaxar to determine effects on hepatocyte senescence and liver damage. Results: Inducing senescence up-regulates the THBD-PAR1 signaling axis in hepatocytes and induces their expression of fibrogenic factors, including hedgehog ligands. Hepatocyte THBD-PAR1 signaling increases in NAFLD and supports sustained hepatocyte senescence that limits effective liver regeneration and promotes maladaptive repair. Inhibiting PAR-1 signaling with vorapaxar interrupts this process, reduces the burden of ‘undead’ senescent cells, and safely improves NASH and fibrosis despite ongoing lipotoxic stress Conclusion: The THBD-PAR1 signaling axis is a novel therapeutic target for NASH because blocking this pathway prevents accumulation of senescing but viable hepatocytes that generate factors that promote maladaptive liver repair.