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Series GSE45612 Query DataSets for GSE45612
Status Public on Sep 21, 2016
Title IL-15R-alpha controls hepatic stellate cell fibrogenic potential during murine chronic liver injury
Organism Mus musculus
Experiment type Expression profiling by array
Summary Gene-expression profiles of hepatic stellate cells isolated from IL15R-alpha knockout mouse
IL-15 and its high affinity receptor IL-15Rα are widely expressed in immune cells including dendritic cells and macrophages and non-immune cells such as hepatocytes, oval cells and hepatic stellate cells (HSC). IL-15 signaling has important functions in natural killers (NK), natural killers T (NKT) and cytotoxic T (CD8+T) cell homeostasis and also in liver regeneration. We hypothesized that IL-15 may have a protective role during liver fibrosis progression due to its role in NK cell homeostasis. We compared fibrosis progression in IL-15Rα knockout mice (IL-15RαKO) to wild type mice using two mechanistically distinct models, chronic carbon tetrachloride (CCl4) exposure and bile duct ligation (BDL). Enhanced fibrosis progression was observed in IL-15RαKO mice in both models. Furthermore, using congenic bone marrow transplantation (BMT), we demonstrated an unexpected role for IL-15 signaling in hepatic resident cells for the maintenance of liver NK and CD8+T cell populations. Using this approach, transplanting IL-15RKO hematopoietic cells results in NK defect that surprisingly is not reflected in a change of fibrosis progression. However, chimeric mice with defect of IL-15R on liver resident cells have similar NK defects and significant more fibrosis after CCL4 liver injury. This supports a direct protective, anti-fibrogenic role for IL-15R on one of the radioresistant liver cell populations (hepatocytes, HSC and sessile Kupffer cells). Microarray analysis of IL15RKO HSC suggests up-regulation of collagen transcripts and down-regulation of pathways involved in cell proliferation/survival. Finally, activated HSCs isolated from IL-15RKO mice show increased collagen secretion and as predicted, no changes in the growth curves. In summary, IL-15Rα signaling has an anti-fibrotic effect through both BM-derived and hepatic resident cells. These findings establish a rationale to explore IL-15 signaling in HSC as a potential therapeutic target in liver fibrogenesis.
Overall design Six week-old female IL-15RKO and wild type (WT) B6/129 mice were purchased from Jackson Laboratories (Bar Harbor, ME). All procedures were performed in accordance with the Institutional Animal Care and Use Committee Protocols of the Mount Sinai School of Medicine. Mouse HSCs were isolated from WT and IL-15RKO mice using an established method with modifications. Briefly, the mouse liver was perfused in situ with pronase and collagenase, followed by Percoll (GE) density gradient centrifugation. HSC cultures were maintained in Dulbecco's Modified Eagle Medium with 20% Fetal Bovine Serum. RNA was isolated from primary mouse hepatic stellate cell (Passage 0) with Triazol reagent (Invitrogen) followed by a cleanup procedure using QIAGEN RNeasy minicolumns according to manufacturer’s protocol. RNA samples were processed for hybridization on the MouseRef-8 v2.0 Expression Beadchip (Illumina) by the Genomics Core Facility of Mount Sinai School of Medicine. Raw data were taken from iScan Control Software (Illumina) and analyzed using Genomestudio Software (Illumina) with quantile normalization.
hepatic stellate cell, mouse, gene-expression microarray, Illumina, IL15R-alpha knockout
Contributor(s) Jiao J, Fiel MI, Rahmman AH, Miller J, Kojima K, Hoshida Y, de Paula T, Veter D, Sastre D, Lee KH, Merad M, Friedman SL, Aloman C
Citation(s) 27154062
Submission date Mar 28, 2013
Last update date Jun 14, 2018
Contact name Yujin Hoshida
Organization name University of Texas Southwestern Medical Center
Street address 5323 Harry Hines Blvd
City Dallas
State/province TX
ZIP/Postal code 75390
Country USA
Platforms (1)
GPL6885 Illumina MouseRef-8 v2.0 expression beadchip
Samples (8)
GSM1110762 IL15RaKO1
GSM1110763 IL15RaKO2
GSM1110764 IL15RaKO3
BioProject PRJNA195399

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE45612_RAW.tar 3.1 Mb (http)(custom) TAR
GSE45612_non-normalized.txt.gz 918.6 Kb (ftp)(http) TXT
Raw data are available on Series record
Processed data included within Sample table

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