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Status |
Public on Mar 02, 2017 |
Title |
Tricyclic Antidepressants Induce Inactivation of Hepatic Stellate Cell (HSC) Myofibroblasts |
Organism |
Homo sapiens |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
Hepatic stellate cells (HSCs) are the primary cell type responsible for liver fibrosis, the final common pathway leading to cirrhosis and liver failure for nearly every cause of chronic liver disease. Activation of HSCs in response to injury represents the key step in hepatic fibrogenesis, and is characterized by a phenotypic change from a non-fibrogenic, quiescent HSC to a fibrogenic HSC myofibroblast that secretes extracellular matrix proteins responsible for the fibrotic scar. We developed a small molecule screen to identify compounds that revert fibrotic human HSC myofibroblasts to an inactive phenotype through the quantification of lipid droplets with fluorescent microscopy. Conditions were optimized in a 384-well format using culture in Matrigel as a positive control. We screened 1600 compounds and identified 30 small molecules that induce reversion to an inactive phenotype. Among the hits, we identified five tricyclic antidepressants (TCAs) and showed that this class of drugs also repressed ACTA2 and COL1A1 while promoting PPAR-gamma expression. RNA sequencing analysis implicated extracellular matrix proteins and the sphingolipid pathway as a target of the TCAs.
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Overall design |
HSCs and HSCs stimulated with TGF-beta were treated with the TCA, nortriptyline or ethanol vehicle for 48 hours. RNA-seq was performed in duplicate for each condition
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Contributor(s) |
Chen JY, Zhou C, Pondick JV, Mullen AC |
Citation(s) |
28322247, 35617485 |
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Submission date |
Mar 02, 2016 |
Last update date |
Jun 01, 2022 |
Contact name |
Chan Zhou |
E-mail(s) |
zhou.chan@mgh.harvard.edu
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Phone |
7062543741
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Organization name |
Mass General Hospital, Harvard Medical School
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Department |
gastroenterology
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Lab |
Alan Mullen
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Street address |
55 Fruit Street
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City |
Boston |
State/province |
Massachusetts |
ZIP/Postal code |
02114 |
Country |
USA |
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Platforms (2) |
GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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Samples (12)
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GSM2079611 |
RNA-seq of Nortriptyline treated HSC rep 1 |
GSM2079612 |
RNA-seq of Nortriptyline treated HSC rep 2 |
GSM2079613 |
RNA-seq of Vehicle treated HSC rep 1 |
GSM2079614 |
RNA-seq of Vehicle treated HSC rep 2 |
GSM2079615 |
RNA-seq of Nortriptyline-TGFb treated HSC rep 1 |
GSM2079616 |
RNA-seq of Nortriptyline-TGFb treated HSC rep 2 |
GSM2079617 |
RNA-seq of Vehicle-TGFb treated HSC rep 1 |
GSM2079618 |
RNA-seq of Vehicle-TGFb treated HSC rep 2 |
GSM2470220 |
RNA-seq of Vehicle treated HSC rep1- ceramide control |
GSM2470221 |
RNA-seq of Vehicle treated HSC rep2 - ceramide control |
GSM2470222 |
RNA-seq of ceramide treated HSC rep1 |
GSM2470223 |
RNA-seq of ceramide treated HSC rep2 |
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Relations |
BioProject |
PRJNA314144 |
SRA |
SRP071088 |