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| Status |
Public on Sep 20, 2023 |
| Title |
IL-6 Trans-Signaling in a Humanized Mouse Model of Scleroderma |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Fibrosis is regulated by interactions between immune and mesenchymal cells. However, the capacity of cell types to modulate human fibrosis pathology is poorly understood due to lack of a fully humanized model system. MISTRG6 mice were engineered by homologous mouse/human gene replacement to develop an immune system like humans when engrafted with human hematopoietic stem cells (HSC) (1, 2). We utilized MISTRG6 mice to model scleroderma by transplantation of healthy or scleroderma skin from a patient with pansclerotic morphea to humanized mice engrafted with unmatched allogeneic HSC. We discovered that scleroderma skin grafts contained both skin and bone marrow derived human CD4 and CD8 T cells along with human endothelial cells and pericytes. Unlike healthy skin, fibroblasts in scleroderma skin were depleted and replaced by mouse fibroblasts. Furthermore, HSC engraftment alleviated multiple signatures of fibrosis, including expression of collagen and interferon genes, and proliferation and activation of human T cells. Fibrosis improvement correlated with reduced markers of T cell activation and expression of human IL-6 by mesenchymal cells. Mechanistic studies supported a model whereby IL-6 trans-signaling driven by CD4 T cell derived soluble IL-6 receptor complexed with fibroblast derived IL-6 promoted excess ECM gene expression. Thus, MISTRG6 mice transplanted with scleroderma skin demonstrated multiple fibrotic responses centered around human IL-6 signaling, which was improved by the presence of healthy bone marrow derived immune cells. Our results highlight the importance of IL-6 trans-signaling in pathogenesis of scleroderma and the ability of healthy bone marrow derived immune cells to mitigate disease.
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| Overall design |
we performed scRNA-Seq on 3 of the HSC-engrafted (+HSC) compared to 3 HSC unengrafted (-HSC) scleroderma skin grafts 4 weeks after transplantation onto MISTRG6 humanized mice.
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| Contributor(s) |
Odell I |
| Citation(s) |
37669366 |
| Submission date |
Aug 03, 2023 |
| Last update date |
Sep 21, 2023 |
| Contact name |
Ian Odell |
| E-mail(s) |
ian.odell@yale.edu
|
| Organization name |
Yale University
|
| Street address |
300 Cedar St. Tac-S570
|
| City |
New Haven |
| State/province |
CT |
| ZIP/Postal code |
06520 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL22245 |
Illumina HiSeq 2500 (Homo sapiens; Mus musculus) |
|
| Samples (6)
|
| GSM7679757 |
MISTRG6 scleroderma skin graft 1 [HSC-unengrafted] |
| GSM7679758 |
MISTRG6 scleroderma skin graft 2 [HSC-unengrafted] |
| GSM7679759 |
MISTRG6 scleroderma skin graft 3 [HSC-unengrafted] |
| GSM7679760 |
MISTRG6 scleroderma skin graft 4 [HSC-engrafted] |
| GSM7679761 |
MISTRG6 scleroderma skin graft 5 [HSC-engrafted] |
| GSM7679762 |
MISTRG6 scleroderma skin graft 6 [HSC-engrafted] |
|
| Relations |
| BioProject |
PRJNA1001914 |
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