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| Status |
Public on Feb 08, 2023 |
| Title |
Hepatocytes demarcated by EphB2 contribute to the progression of non-alcoholic steatohepatitis |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Current therapeutic strategies for treating non-alcoholic steatohepatitis (NASH) have failed to alleviate liver fibrosis, which is a devastating feature leading to hepatic dysfunction. Here, we integrated single-nucleus transcriptomics and epigenomics to characterize all major liver cell types during NASH development in mice and humans. The bifurcation of hepatocyte trajectory with NASH progression was conserved between mouse and human. At the non-alcoholic fatty liver (NAFL) stage, hepatocytes exhibited metabolic adaptation, whereas at the NASH stage, a subset of hepatocytes was enriched for the signatures of cell adhesion and migration, which was mainly demarcated by receptor tyrosine kinase EphB2. EphB2, acting as a downstream effector of Notch signaling in hepatocytes, was sufficient to induce cell-autonomously inflammation. Knockdown of Ephb2 in hepatocytes ameliorated inflammation and fibrosis in NASH. Thus, EphB2 expressing hepatocytes contribute to NASH progression and may serve as a potential therapeutic target.
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| Overall design |
Using unbiased genomic approaches including snRNA-seq and snATAC-seq on livers from mice fed a NASH promoting diet (modified ALIOS diet) for 3 months or 9 months, we comprehensively profiled transcriptomic and epigenomic changes of all major liver cell types during NASH progression. We identified receptor tyrosine kinase Ephb2 was specifically expressed in NASH hepatocytes. We confirmed this finding by performing snRNA-seq in human NASH livers. To determine the function of Ephb2, we performed bulk RNA-seq of the livers with forced expression of Ephb2 in hepatocytes.
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| Contributor(s) |
Xiao Y, Lazar MA |
| Citation(s) |
36753562 |
| |
| Submission date |
Nov 26, 2021 |
| Last update date |
Apr 25, 2023 |
| Contact name |
Yang Xiao |
| E-mail(s) |
[email protected]
|
| Phone |
8323604597
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| Organization name |
UNIVERSITY OF PENNSYLVANIA
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| Street address |
12-193 Smilow Translational Research Center, 3400 Civic Center Boulevard
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| City |
Philadelphia |
| State/province |
PA |
| ZIP/Postal code |
19104 |
| Country |
USA |
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| Platforms (2) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (21)
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| Relations |
| BioProject |
PRJNA783863 |
| SRA |
SRP348024 |
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