Single-nucleus RNA-seq2 reveals functional crosstalk between liver zonation and ploidy.

Funder: Cancer Research UKSingle-cell RNA-seq reveals the role of pathogenic cell populations in development and progression of chronic diseases. In order to expand our knowledge on cellular heterogeneity, we have developed a single-nucleus RNA-seq2 method tailored for the comprehensive analysis of the nuclear transcriptome from frozen tissues, allowing the dissection of all cell types present in the liver, regardless of cell size or cellular fragility. We use this approach to characterize the transcriptional profile of individual hepatocytes with different levels of ploidy, and have discovered that ploidy states are associated with different metabolic potential, and gene expression in tetraploid mononucleated hepatocytes is conditioned by their position within the hepatic lobule. Our work reveals a remarkable crosstalk between gene dosage and spatial distribution of hepatocytes

Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth

The overexpression of the protein tyrosine kinase, Focal adhesion kinase (FAK), in endothelial cells has implicated its requirement in angiogenesis and tumour growth, but how pericyte FAK regulates tumour angiogenesis is unknown. We show that pericyte FAK regulates tumour growth and angiogenesis in multiple mouse models of melanoma, lung carcinoma and pancreatic B-cell insulinoma and provide evidence that loss of pericyte FAK enhances Gas6-stimulated phosphorylation of the receptor tyrosine kinase, Axl with an upregulation of Cyr61, driving enhanced tumour growth. We further show that pericyte derived Cyr61 instructs tumour cells to elevate expression of the proangiogenic/protumourigenic transmembrane receptor Tissue Factor. Finally, in human melanoma we show that when 50% or more tumour blood vessels are pericyte-FAK negative, melanoma patients are stratified into those with increased tumour size, enhanced blood vessel density and metastasis. Overall our data uncover a previously unknown mechanism of tumour growth by pericytes that is controlled by pericyte FAK

Resolving the fibrotic niche of human liver cirrhosis at single-cell level.

Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2+CD9+ subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1+ and PLVAP+ endothelial cells that expand in cirrhosis, are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes. Multi-lineage modelling of ligand and receptor interactions between the scar-associated macrophages, endothelial cells and PDGFRα+ collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis.Includes Wellcome, BHF, MRC, BBSRC and NIHR

A tale of two countries: Comparing disability weights for gambling problems in New Zealand and Australia

Purpose: This study aimed to assess the impact of gambling problems on quality of life. Specifically, we generated disability weight estimates for gambling problems in New Zealand, and compared these results with (i) Australian figures (J Gambl Issues, 10.4309/jgi.v0i36.3978, 2017) and (ii) other health states (Lancet, 10.1016/S0140-6736(12)61680-8, 2013); such as anxiety and alcohol use disorders. Method: The 324 participants (48 experts and 276 general population members) evaluated a series of gambling harm vignettes. The participants rated the decrement to one’s quality of life using Visual Analogue Scale and Time Trade-Off protocols (Br Med Bull, 10.1093/bmb/ldq033, 2010). These evaluations enabled the calculation of disability weights for three categories of gamblers (low-risk, moderate-risk, and problem gamblers). Results: Disability weight estimates for low-risk, moderate-risk, and problem gamblers in NZ were consistently higher than the Australian weights: low (0.18 vs. 0.13), moderate (0.37 vs. 0.29), and problem (0.54 vs. 0.44). The quality of life impact for problem gambling in NZ (0.54) was comparable to that experienced in severe alcohol use disorder (0.55) (Lancet, 10.1016/S0140-6736(12)61680-8, 2013). Conclusions: This study represents one of the first attempts to assess gambling-related harm through a public health perspective. The results of this study are informative for policy-making, resource allocation, and service planning. These estimates now allow for the population-level impact of gambling in NZ to be calculated and tracked over time, which is essential for informing harm-minimisation initiatives. © 2018, Springer International Publishing AG, part of Springer Nature