A Human Liver Cell Atlas reveals Heterogeneity and Epithelial Progenitors
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ABSTRACT:
PROVIDER: PRJNA511895 | ENA |
REPOSITORIES: ENA
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Project description:The human liver is an essential multifunctional organ. The incidence of liver diseases is rising and there are limited treatment options. However, the cellular composition of the liver remains poorly understood. Here we performed single-cell RNA sequencing of about 10,000 cells from normal liver tissue from nine human donors to construct a human liver cell atlas. Our analysis identified previously unknown subtypes of endothelial cells, Kupffer cells, and hepatocytes, with transcriptome-wide zonation of some of these populations. We show that the EPCAM+ population is heterogeneous, comprising hepatocyte-biased and cholangiocyte populations as well as a TROP2int progenitor population with strong potential to form bipotent liver organoids. As a proof-of-principle, we used our atlas to unravel the phenotypic changes that occur in hepatocellular carcinoma cells and in human hepatocytes and liver endothelial cells engrafted into a mouse liver. Our human liver cell atlas provides a powerful resource to enable the discovery of previously unknown cell types in normal and diseased livers.
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Project description:We perfomed single-cell RNA-sequnecing of around 10,000 cells from normal human liver tissue to construct a human liver cell atlas. We reveal previously unknown subtypes in different cell type compartments. We also use our normal liver cell atlas to infer perturbed phenoytpes of cells from HCC samples, human cells engrafted into a mouse liver and liver organoids.
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Project description:We generated a high-resolution cellular atlas of the healthy human liver by profiling the transcriptome of more than 25,000 individual liver cells using droplet-based RNA-sequencing. Recently published datasets and in situ hybridization were integrated to confirm, validate and locate newly identified cell populations. We identified, annotated and characterized a total of 23 cell subpopulations that represent the degree of heterogeneity of parenchymal (i.e. hepatocytes and cholangiocytes) and non-parenchymal liver cells (i.e. endothelial cells, stellate cells, macrophages and lymphoid cells). We successfully classified human hepatocytes and liver sinusoidal endothelial cells along the porto-central axis and for the first time reveal the existence of functionally specialized pericentral GPC3+ and periportal HHIP+ DBH+ hepatic stellate cells in the healthy human liver. Our study provides a description of the different cell compartments that enter into the composition of a healthy human liver and currently constitutes the biggest single-cell RNA sequencing dataset available on human healthy hepatocytes and hepatic stellate cells. We identified subsets of hepatic stellate cells characterized by distinct localization and physiological functions.
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Project description:The human cerebral cortex depends for its normal development and size on a precisely controlled balance between self-renewal and differentiation of diverse neural progenitor cells. Specialized progenitors that are common in humans, but virtually absent in rodents, called â??outer radial gliaâ?? (ORG), have been suggested to be crucial to the evolutionary expansion of the human cortex. We combined cell type-specific sorting with transcriptome-wide RNA-sequencing to identify genes enriched in human ORG, including targets of the transcription factor Neurogenin, and previously uncharacterized, evolutionarily dynamic, long noncoding RNAs. Single-cell transcriptional profiling of human, ferret, and mouse progenitors showed that more human RGC co-express proneural Neurogenin targets than in ferret or mouse, suggesting greater self-renewal of neuronal lineage-committed progenitors in humans. Finally, we show that activating the Neurogenin pathway in ferret RGC promotes delamination and outward migration. Thus, we find that the abundance of human ORG is paralleled by increased transcriptional heterogeneity of cortical progenitors. Three biological replicates of human late mid-fetal cortex (18 to 19 weeks of gestation) were dissociated and immunolabeled. Apical and outer radial glial cells were purified by FACS and compared to an immunonegative population, predominantly neurons.
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