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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Nov 01, 2023 |
| Title |
The Triptryium wilfordii derivative celastrol has anti-fibrotic effects in systemic sclerosis [Spatial Transcriptomics] |
| Organism |
Mus musculus |
| Experiment type |
Other
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| Summary |
Objectives: Scleroderma (systemic sclerosis, SSc), as a prototypic inflammation-driven fibrotic disease, possesses connective tissue lesions populated with persistently activated myofibroblasts maintained by an mechanotranductive/pro-adhesive signaling loop. Drugs targeting this pathway are therefore of likely therapeutic benefit. The mechanosensitive transcriptional co-activator, yes activated protein-1 (YAP1), is activated in SSc fibroblasts. The terpenoid celastrol has recently been identified as a YAP1 inhibitor: however, if celastrol can alleviate SSc fibrosis is unknown. Methods: Human dermal fibroblasts from healthy individuals and patients with diffuse cutaneous SSc were treated with or without transforming growth factor b1 (TGFb1) in the presence or absence of celastrol. C57BL6J mice were subjected to the inflammatory-driven bleomycin-induced model of skin SSc, in the presence or absence of celastrol. RNA expression was assessed using RNAseq, real-time polymerase chain reaction and spatial transcriptomic analyses. Protein expression was determined using Western blot and enzyme-linked immunosorbent assay. Fibrosis was monitored by hematoxylin and eosin and trichrome staining, and indirect immunofluorescence analysis. Results: In dermal fibroblasts, celastrol impaired the ability of TGFβ1 to induce an SSc-like pattern of gene expression, including the induction of cellular communication network factor 2 (CCN2), collagen I and TGFβ1 protein. Celastrol alleviated the persistent fibrotic phenotype of dermal fibroblasts cultured from lesions of SSc patients. In the bleomycin-induced model of SSc dermatopathology, celastrol inhibited fibrosis and blocked nuclear localization of YAP in myofibroblasts. Conclusion: Our data are consistent with the hypothesis that compounds, such as celastrol, that antagonize the YAP pathway may be potential treatments for SSc skin fibrosis.
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| Overall design |
To investigate the gene expression of the PBS, Bleomycin and Celastrol treated mouse skin tissue samples
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| Contributor(s) |
Chitturi P, Shi-wen X, Ahmed Abdi B, Nguyen J, Carter DE, Stratton RJ, Sinha S, Arora R, Leask A |
| Citation(s) |
37328193 |
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| Submission date |
Mar 06, 2023 |
| Last update date |
Jan 31, 2024 |
| Contact name |
Andrew Leask |
| E-mail(s) |
anl312@mail.usask.ca
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| Organization name |
University of Saskatchewan
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| Department |
College of Dentistry
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| Lab |
Leask Lab
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| Street address |
105 Wiggins
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| City |
Saskatoon |
| State/province |
Saskatchewan |
| ZIP/Postal code |
S7N5E4 |
| Country |
Canada |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (8)
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| This SubSeries is part of SuperSeries: |
| GSE226376 |
The Triptryium wilfordii derivative celastrol has anti-fibrotic effects in systemic sclerosis |
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| Relations |
| BioProject |
PRJNA941340 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE226760_Geo_Integrated_groups.R.gz |
4.3 Kb |
(ftp)(http) |
R |
| GSE226760_RAW.tar |
3.7 Gb |
(http)(custom) |
TAR (of CLOUPE, CSV, H5, JPG, JSON, MTX, PNG, TAR, TSV) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
| Processed data are available on Series record |
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