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:Endothelial cell heterogeneity shapes the unique attributes of organ-specific blood vessels; however, how intra-organ vascular cell diversity is established remains unsolved. Liver vascular network is patterned by sinusoidal and hepatocyte co-zonation, however how intra-liver vessels acquire their hierarchical specialized functions is unknown. Here, we resolve the heterogeneity of hepatic vascular cells during development through functional and single-cell RNA sequencing. We show that acquisition of sinusoidal endothelial cell identity is initiated during early development and is completed postnatally, originating from a pool of undifferentiated vascular progenitors at E12. Notably, we identify the peri-natal induction of the transcription factor c-Maf as a critical switch for sinusoidal identity determination. Endothelium-restricted deletion of c-Maf disrupts liver sinusoidal development, aberrantly expands postnatal liver hematopoiesis, promotes excessive postnatal sinusoidal proliferation, and aggravates liver pro-fibrotic sensitivity to chemical insult. Notably, c-Maf overexpression in generic differentiated endothelial cells switches on a liver sinusoidal transcriptional zonation program that maintains hepatocyte function. Therefore, c-Maf represents an inducible intra-organotypic and niche-responsive molecular determinant of sinusoidal cell identity and lays the foundation for designing strategies to initiate vasculature-driven liver repair.
2022-04-02 | GSE174209 | GEO
Project description:Endothelial cell heterogeneity shapes the unique attributes of organ-specific blood vessels; however, how intra-organ vascular cell diversity is established remains unsolved. Liver vascular network is patterned by sinusoidal and hepatocyte co-zonation, however how intra-liver vessels acquire their hierarchical specialized functions is unknown. Here, we resolve the heterogeneity of hepatic vascular cells during development through functional and single-cell RNA sequencing. We show that acquisition of sinusoidal endothelial cell identity is initiated during early development and is completed postnatally, originating from a pool of undifferentiated vascular progenitors at E12. Notably, we identify the peri-natal induction of the transcription factor c-Maf as a critical switch for sinusoidal identity determination. Endothelium-restricted deletion of c-Maf disrupts liver sinusoidal development, aberrantly expands postnatal liver hematopoiesis, promotes excessive postnatal sinusoidal proliferation, and aggravates liver pro-fibrotic sensitivity to chemical insult. Notably, c-Maf overexpression in generic differentiated endothelial cells switches on a liver sinusoidal transcriptional zonation program that maintains hepatocyte function. Therefore, c-Maf represents an inducible intra-organotypic and niche-responsive molecular determinant of sinusoidal cell identity and lays the foundation for designing strategies to initiate vasculature-driven liver repair.
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Project description:Zone 1 and zone 3 areas were captured from mouse liver sections by laser capture microdissection Total RNA was isolated and gene expression profiles were determined using microarrays
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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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