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Published on: August 23, 2019
CD34+ Orbital Fibroblasts Contribute to the Pathogenesis of Thyroid Eye Disease via miR-182-5p
Baiguang Yu1,2,3,4, Yi Wang1,2,3,4, Jun Jin1,2,3,4
1Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, and Center for Basic Medical Research and Innovation in Visual System Diseases of Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China.
Context:
CD34+ orbital fibroblasts (OFs) play a pathogenic role in thyroid eye disease (TED). Several micro (mi)RNAs have been shown to promote TED progression.
Objective:
This study aims to explore the regulatory effects of miRNAs on CD34+ OFs and to find potential therapeutic targets.
Methods:
In this case-control study, orbital connective tissues (OCTs) and OFs were obtained from 25 TED patients and 24 healthy donors. MiRNA-seq was performed to examine differential expression of miRNAs in OCTs, and miR-182-5p was selected for subsequent experiments. MiR-182-5p was detected both in CD34+ and CD34- OFs. The upstream regulators of miR-182-5p were studied. Downstream targets of miR-182-5p were analyzed. The functionality of miR-182-5p in CD34+ OFs was evaluated.
Results:
MiR-182-5p was highly expressed in TED OCTs and their derived CD34+ OFs. TED OCTs displayed increased expression of interleukin (IL)-6, IL-17A, CD34, and phosphorylated STAT3 at Ser727 and Tyr705. Activation of IL-6/STAT3 signaling promoted the expression of miR-182-5p in CD34+ OFs. MiR-182-5p enhanced wound repair ability, proliferation, and RANTES expression while inhibiting apoptosis in CD34+ OFs. CD34+ OFs transfected with miR-182-5p were susceptible to TGF-β-initiated myofibroblast differentiation. Luciferase reporter and pull-down assays revealed Smad7 as the downstream target of miR-182-5p, which modulated the proliferation, migration, fibrosis, and apoptosis of CD34+ OFs.
Conclusion:
The IL-6/STAT3/miR-182-5p pathway led to activation of CD34+ OFs. MiR-182-5p promoted the proliferation, migration, fibrosis, and anti-apoptosis of CD34+ OFs via targeting Smad7. Our findings suggest that miR-182-5p may potentially serve as a therapeutic target for TED.
Insights
MicroRNA-182-5p (miR-182-5p) promotes thyroid eye disease (TED) by activating CD34+ orbital fibroblasts. Targeting miR-182-5p and its downstream effects on Smad7 offers a potential therapeutic strategy for TED.
Area of Science:
- Ophthalmology
- Molecular Biology
- Immunology
Background:
- CD34+ orbital fibroblasts (OFs) are implicated in the pathogenesis of thyroid eye disease (TED).
- Specific microRNAs (miRNAs) are known to exacerbate TED progression.
Purpose of the Study:
- To investigate the regulatory role of miRNAs in CD34+ OFs.
- To identify potential therapeutic targets for TED.
Main Methods:
- A case-control study involving orbital connective tissues (OCTs) and OFs from TED patients and healthy donors.
- MiRNA sequencing (miRNA-seq) to identify differentially expressed miRNAs, focusing on miR-182-5p.
- Analysis of upstream regulators, downstream targets, and functional impact of miR-182-5p in CD34+ OFs.
Main Results:
- miR-182-5p was significantly upregulated in TED OCTs and CD34+ OFs.
- The IL-6/STAT3 signaling pathway was found to promote miR-182-5p expression in CD34+ OFs.
- miR-182-5p enhanced CD34+ OF proliferation, migration, and fibrosis while inhibiting apoptosis, partly through targeting Smad7.
Conclusions:
- The IL-6/STAT3/miR-182-5p pathway activates CD34+ OFs in TED.
- miR-182-5p promotes key pathogenic features of CD34+ OFs by targeting Smad7.
- miR-182-5p represents a promising therapeutic target for thyroid eye disease.
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