Gene Expression Patterns of Quiescent and Activated Mouse Primary Hepatic Stellate Cell (HSC)
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE149508 | GEO | 2020/04/29
REPOSITORIES: GEO
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Project description:Liver fibrosis is characterized by the excessive formation and accumulation of matrix proteins as a result of wound healing in the liver. A main event during fibrogenesis is the activation of the liver resident quiescent hepatic stellate cell (qHSC). Recent studies suggest that reversion of the activated HSC (aHSC) phenotype into a quiescent-like phenotype could be a major cellular mechanism underlying fibrosis regression in the liver, thereby offering new therapeutic perspectives for the treatment of liver fibrosis. The goal of the present study is to identify experimental conditions that can revert the activated status of human HSCs and to map the molecular events associated with this phenotype reversion by gene expression profiling Transcriptomic profiling of primary human quiescent HSCs (qHSCs), in vitro activated HSCs (aHSCs) and in vitro reverted HSCs (rHSCs). The cell types come from different donors (This is detailed in the original manuscript.).
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Project description:Hepatic stellate cells (HSC) constitute the most important fibrogenic cell type during liver fibrosis. To analyse the different phenotypes of quiescent and activated cells, cells of 5 animals were transdifferentiated in a well established in vitro transdifferentiaition assay and compared to freshly seeded, quiescent HSC. Gene expression profiling of quiescent and in vitro activated HSC revealed well known and new marker genes upregulated upon HSC activation. ltbp1 (latent transforming growth factor beta binding protein 1) is a crucial factor controlling the secretion and bioactivation of TGFß1. Using the data comparing quiescent and activated HSC, we were able to qualify the subtle but reproducible differences in gene expression observed when comparing activated ltbp1-deficient and activted wt HSC. ltbp1-deficient HSC showed a less fibrogenic phenotype after 6 days of in vitro transdifferentiation compared to the wt counterparts. The microarray data was indepently confirmed in vivo using an experimental model for the induction of liver fibrosis (ligation of the common bile duct). ltbp1-/- mice, after 4 weeks of bile obstruction, showed markedly reduced signs of liver fibrosis. Keywords: gene expression profiling, analysyis of a fibrogenic cell type in the liver and the influence of ltbp1-k.o.
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Project description:Hepatic stellate cells (HSCs) are the major driving factor in liver fibrosis. Upon liver inflammation caused by alcohol abuse and/or a fatty liver, HSCs transform from a quiescent- into a proliferating, fibrotic phenotype. We study this transformation termed “activation”, using state of the art TIMS-TOF mass spectrometry proteomics, as well as phenotype analysis of the immortalized LX-2 HSC cell line. In our work we employ a simple, yet reliable model of HSC activation via an in-crease in growth media serum concentration (serum activation). Protein network analysis of ac-tivated LX 2 cells reveals an increase in the production of ribosomal proteins and proteins related to migration. Interestingly, we could also observe a decrease in the expression of lipogenic pro-teins and a loss of cytosolic lipid droplets during activation. Especially the downregulation of proteins associated with cholesterol biosynthesis might be a promising target for further study. This work provides an update on HSC activation characteristics using contemporary proteomic and bioinformatic analysis and presents an accessible model for HSC activation.
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