Zone dependent distinctive gene expression profile of the normal human liver tissue
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE83990 | GEO | 2018/02/16
REPOSITORIES: GEO
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Project description:Differential expression of genes and proteins, as well as physiological processes, along the hepatic acinus, known collectively as hepatic zonation, is a fundamental feature of hepatic physiology. However, the precise cellular location of only a relatively small proportion of the ~14,000 genes expressed in the liver is known. This is critical information for understanding hepatic physiology as well as for the accurate targeting of gene transfer vectors for gene therapy. We have employed laser capture microdissection (LCM) and unbiased transcriptomic analysis of the normal adult mouse liver to define gene expression in a very distinct population of cells in the acinus, the glutamine-synthetase sub-compartment of perivenous hepatocytes, encompassing a one- to two-layer of cells surrounding the centrilobular vein. We confirmed the location of a number of genes whose expression is known to be restricted to these cells by virtue of immunohistochemistry or in situ hybridization (Slc1a2, Glul, Rhbg). We also identified genes whose expression had not previously been reported to be enriched in these cells (e.g. Sp5, Vldlr, Lpl, Gabrb3, Rcan2). Transcription factor analysis of the differentially expressed genes suggested important roles, in these cells, for members of the polycomb group, Wt1 and Tbx3. Collectively, our findings highlight the utility of combined LCM and transcriptome analysis for the identification of novel functions of distinct subclasses of hepatocytes. We plan to extend this approach to the mapping of physiological function across hepatic acini of the human liver. Comparison of mRNA expression by two hepatic cell populations: the glutamine synthetase-subcompartment of the perivenous compartment and zones 1+2 of the hepatic acinus Cells were isolated by laser capture microdissection and mRNA extracted by standard protocol.
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Project description:Differential expression of genes and proteins, as well as physiological processes, along the hepatic acinus, known collectively as hepatic zonation, is a fundamental feature of hepatic physiology. However, the precise cellular location of only a relatively small proportion of the ~14,000 genes expressed in the liver is known. This is critical information for understanding hepatic physiology as well as for the accurate targeting of gene transfer vectors for gene therapy. We have employed laser capture microdissection (LCM) and unbiased transcriptomic analysis of the normal adult mouse liver to define gene expression in a very distinct population of cells in the acinus, the glutamine-synthetase sub-compartment of perivenous hepatocytes, encompassing a one- to two-layer of cells surrounding the centrilobular vein. We confirmed the location of a number of genes whose expression is known to be restricted to these cells by virtue of immunohistochemistry or in situ hybridization (Slc1a2, Glul, Rhbg). We also identified genes whose expression had not previously been reported to be enriched in these cells (e.g. Sp5, Vldlr, Lpl, Gabrb3, Rcan2). Transcription factor analysis of the differentially expressed genes suggested important roles, in these cells, for members of the polycomb group, Wt1 and Tbx3. Collectively, our findings highlight the utility of combined LCM and transcriptome analysis for the identification of novel functions of distinct subclasses of hepatocytes. We plan to extend this approach to the mapping of physiological function across hepatic acini of the human liver.
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Project description:The conclusive identity of Wnt proteins regulating liver zonation (LZ) and regeneration (LR) remains unclear despite an undisputed role of beta-catenin. Using single-cell analysis of liver cells from various species, a conserved Wnt2 and Wnt9b expression in endothelial cells (ECs) in zone 3 shown to be the major Wnt cell source, was identified. Conditional EC-elimination of Wnt2 and Wnt9b led to perturbation of LZ with not only loss of beta-catenin targets in zone 3, but also re-appearance of zone 1 genes in zone 3, unraveling dynamicity as revealed by single-cell spatial transcriptomics using Molecular Cartography. Defective LR observed in the knockouts phenocopied other models of defective hepatic Wnt signaling. Administration of a tetravalent antibody to activate Wnt signaling rescued LZ and LR in the knockouts. Molecular Cartography on the livers of the agonist-treated animal revealed changes in LZ. Administration of the agonist also promoted LR in acetaminophen overdose acute liver failure (ALF) fulfilling an unmet clinical need. Overall, we report an unequivocal role of EC-Wnt2 and Wnt9b in LZ and LR and show the role of Wnt activators as regenerative therapy for ALF.
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