MiRNA expression in embryonic murine hepatocytes versus murine cholangiocytes at E18.5
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE100145 | GEO | 2018/12/20
REPOSITORIES: GEO
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Project description:Purpose: Cholestatic liver injury is associated with intrahepatic biliary fibrosis, which can progress to cirrhosis. Resident hepatic progenitor cells (HPCs) expressing Prominin-1 (Prom1/CD133) become activated and participate in the expansion of cholangiocytes known as the ductular reaction. Previously, we demonstrated that in biliary atresia, Prom1(+) HPCs are present within developing fibrosis and that null mutation of Prom1 significantly abrogates fibrogenesis. Here, we hypothesized that these activated Prom1-expressing HPCs promote fibrogenesis in cholestatic liver injury. Methods: Using Prom1CreERT2-nLacZ/+;Rosa26Lsl-GFP/+ mice, we traced the fate of Prom1-expressing HPCs in the growth of the neonatal and adult livers and in biliary fibrosis induced by bile duct ligation (BDL). Results: Prom1-expressing cell lineage labeling with Green Fluorescent Protein (GFP) on postnatal day 1 exhibited an expanded population as well as bipotent differentiation potential towards both hepatocytes and cholangiocytes at postnatal day 35. However, in the adult liver, they lost hepatocyte differentiation potential. Upon cholestatic liver injury, adult Prom1-expressing HPCs gave rise to both PROM1(+) and PROM1(-) cholangiocytes contributing to ductular reaction without hepatocyte or myofibroblast differentiation. RNA-sequencing analysis of GFP(+) Prom1-expressing HPC lineage revealed a persistent cholangiocyte phenotype and evidence of Transforming Growth Factor-b pathway activation. Conclusion: Our data indicate that Prom1-expressing HPCs promote biliary fibrosis by activation of myofibroblasts in cholestatic liver injury.
2020-06-30 | GSE144726 | GEO
Project description:Mallory-Denk bodies (MDBs) are misfolded protein aggregates that include hepatocytes present in liver diseases, and are considered a typical feature of chronic liver diseases. Cholangiocytes are an epithelial cell type constituting the hepatic parenchyma, and play a role in liver regeneration if hepatocyte regeneration is compromised. UbD, which is overexpressed in hepatocellular carcinoma (HCC) plays an important role in immune regulation and MDB pathogenesis. In this study, we conducted the first comprehensive study on cholangiocyte heterogeneity to demonstrate the pathogenesis of MDBs formation using single-nucleus RNA sequencing (snRNA-seq) from fractionations of normal and DDC-treated mouse livers. We found that cholangiocytes in the MDB-forming groups were significantly expanded, and the enrichment pathways of differentially expressed genes (DEGs) were markedly involved in metabolic processes, neurodegenerative diseases, autophagy, and ubiquitin-mediated proteolysis. We proposed a cellular-state landscape for cholangiocytes using uniform manifold approximation and projection (UMAP) analysis, which includes numerous cell subpopulations, referred to as Clusters0 through 7, with Cluster1 being the sole subpopulation made up entirely of DDC-treated cells. UbD was highly expressed in Cluster4 and colocalized with the cholangiocyte marker gene cytokeratin 19 (Krt19), implying that cholangiocytes function as facultative liver progenitor cells (LPCs) to supply damaged hepatocytes to promote MDBs formation. In summary, we revealed, for the first time, the heterogeneity of cholangiocytes and provided a novel viewpoint for understanding the mechanism of MDBs formation as well as chronic liver disease progression.
2023-06-15 | GSE228448 | GEO
Project description:To characterise liver cells from wt, untreated adult male mice. In particular we are interested on hepatocytes (HCs), hepatic stellate cells (HSCs), liver sinuisoidal endothelial cells (LSECs), Kupffer cells (KCs) and cholangiocytes (CHs).
2023-05-24 | GSE222597 | GEO
Project description:Background and aims: Signal transducer and activator of transcription 3 (Stat3) is the main mediator of interleukin-6 type cytokine signaling required for hepatocyte proliferation and hepatoprotection but its role in sclerosing cholangitis and other cholestatic liver diseases remains unresolved. Methods: We investigated the role of Stat3 in inflammation-induced cholestatic liver injury and used mice lacking the multidrug resistance gene 2 (mdr2-/-) as a model for SC. Results: We demonstrate that conditional inactivation of stat3 in hepatocytes and cholangiocytes (stat3 delta hc) of mdr2-/- mice strongly aggravated bile acid-induced liver injury and fibrosis. A similar phenotype was observed in mdr2-/- mice lacking IL-6 production. Biochemical and molecular characterization suggested that Stat3 exerts hepatoprotective functions in both, hepatocytes and cholangiocytes. Loss of Stat3 in cholangiocytes led to increased expression of TNFα which might reduce the barrier function of bile ducts. Loss of Stat3 in hepatocytes led to upregulation of bile acid biosynthesis genes and downregulation of hepatoprotective epidermal growth factor receptor and insulin-like growth factor 1 signaling pathways. Consistently, stat3deltahc mice were more sensitive to cholic acid-induced liver damage than control mice. Conclusions: Our data suggest that Stat3 prevents cholestasis and liver damage in sclerosing cholangitis via regulation of pivotal functions in hepatocytes and cholangiocytes. Affymetrix microarray analyses was performed to identify metabolic and molecular pathways in stat3Dhc mdr2-/- mice that lead to cholestasis and bile acid-induced liver injury. To avoid false positive results that are due to differential cellular composition, we defined the onset of fibrosis and expression of fibrogenic factors in stat3Dhc mdr2-/- mice.
2010-10-20 | E-GEOD-18759 | biostudies-arrayexpress
Project description:To understand the processes regulated by Smad4 in reactive cholangiocytes, Ctl and Smad4del mice were provided DDC diet for 2 weeks after which reactive cholangiocytes were isolated from digested injured mouse liver via FACS followed by RNA amplification and sequencing analysis. Gene set enrichment analysis of Smad4-perturbed reactive cholangiocytes implicates Smad4 in proliferative, metabolic, and inflammatory pathways.
2023-12-07 | GSE237678 | GEO
Project description:We reported the transcritpome in the healthy control liver of wild-type mice, liver bearing myrAKT-NICD driven ICC and livers bearing myrAKT-YAP driven Sox9 deleted HCC from liver-specific Sox9 knockout mice
2023-07-25 | GSE145900 | GEO
Project description:In this experiment, we want to assess the effect of a lentiviral miR-10a and miR-335 overexpression on the transcriptome of murine LSK (Lin-,Sca-1+,c-Kit+) cells. Primary LSK cells were transduced with lentiviral miRNA overexpression constructs (control: GFP overexpression) and sorted for transduced cells (GFP+) after five days of in vitro culture (Flt-3, TPO, IL-3, SCF containing media).
2018-06-01 | E-MTAB-6496 | biostudies-arrayexpress
Project description:The molecular identification of adult hepatic stem/progenitor cells has been hampered by the lack of truly specific markers. To isolate putative adult liver progenitor cells, we used cell surface-marking antibodies, including MIC1-1C3, to isolate subpopulations of liver cells from normal adult mice or those undergoing an oval cell response and tested their capacity to form bilineage colonies in vitro. Robust clonogenic activity was found to be restricted to a subset of biliary duct cells antigenically defined as CD45–/CD11b–/CD31–/MIC1-1C3+/CD133+/CD26–, at a frequency of one of 34 or one of 25 in normal or oval cell injury livers, respectively. Gene expression analyses revealed that Sox9 was expressed exclusively in this subpopulation of normal liver cells and was highly enriched relative to other cell fractions in injured livers. In vivo lineage tracing using Sox9creERT2-R26RYFP mice revealed that the cells that proliferate during progenitor-driven liver regeneration are progeny of Sox9-expressing precursors. A comprehensive array-based comparison of gene expression in progenitor-enriched and progenitor-depleted cells from both normal and DDC (3,5-diethoxycarbonyl-1,4-dihydrocollidine or diethyl1,4-dihydro-2,4,6-trimethyl- 3,5-pyridinedicarboxylate)-treated livers revealed new potential regulators of liver progenitors.
2011-05-07 | GSE29121 | GEO
Project description:The molecular identification of adult hepatic stem/progenitor cells has been hampered by the lack of truly specific markers. To isolate putative adult liver progenitor cells, we used cell surface-marking antibodies, including MIC1-1C3, to isolate subpopulations of liver cells from normal adult mice or those undergoing an oval cell response and tested their capacity to form bilineage colonies in vitro. Robust clonogenic activity was found to be restricted to a subset of biliary duct cells antigenically defined as CD45–/CD11b–/CD31–/MIC1-1C3+/CD133+/CD26–, at a frequency of one of 34 or one of 25 in normal or oval cell injury livers, respectively. Gene expression analyses revealed that Sox9 was expressed exclusively in this subpopulation of normal liver cells and was highly enriched relative to other cell fractions in injured livers. In vivo lineage tracing using Sox9creERT2-R26RYFP mice revealed that the cells that proliferate during progenitor-driven liver regeneration are progeny of Sox9-expressing precursors. A comprehensive array-based comparison of gene expression in progenitor-enriched and progenitor-depleted cells from both normal and DDC (3,5-diethoxycarbonyl-1,4-dihydrocollidine or diethyl1,4-dihydro-2,4,6-trimethyl- 3,5-pyridinedicarboxylate)-treated livers revealed new potential regulators of liver progenitors. Treated and untreated cells were sorted by cell surface markers then compared. M+/133+ untreated: 4 biological and 1 technical replicate - total of 5 M-/133- untreated: 2 biological and 1 technical replicate - total of 3 M+/133+ DDC-treated: 4 biological replicates - total of 4 M-/133- DDC-treated: 4 biological replicates - total of 4
2011-05-07 | E-GEOD-29121 | biostudies-arrayexpress
Project description:The transcription factor SOX9 can act as a pioneering factor in driving lineage dedifferentiation and tumor progression for breast cancer. To unbiasedly understand how committed luminal stem progenitor cells dedifferentiate into embryonic multipotent progenitor-like cells, we performed scRNA-seq in luminal cells FACS sorted from WT control mice and Sox9-GFP;C3-TAg mice at the age of 3.5 months when C3-TAg mice have developed extensive hyperplastic lesions but not yet malignant tumors.
2023-10-16 | GSE219109 | GEO