Dataset Information

PRL-1 overexpressed placenta-derived mesenchymal stem cells suppress adipogenesis in Graves' ophthalmopathy through SREBP2/HMGCR pathway.

ABSTRACT:

Background

Graves' ophthalmopathy (GO) is a disorder, in which orbital connective tissues get in inflammation and increase in volume. Stimulants such as thyroid-stimulating hormone (TSH), insulin-like growth factor 1(IGF-1), IL-1, interferon γ, and platelet-derived growth factor cause differentiation into adipocytes of orbital fibroblasts (OFs) in the orbital fat and extraocular muscles. Human placental mesenchymal stem cells (hPMSCs) are known to have immune modulation effects on disease pathogenesis. Some reports suggest that hPMSCs can elicit therapeutic effects, but to date, research on this has been insufficient. In this study, we constructed PRL-1 overexpressed hPMSCs (hPMSCs^PRL-1) in an attempt to enhance the suppressive function of adipogenesis in GO animal models.

Methods

In order to investigate the anti-adipogenic effects, primary OFs were incubated with differentiation medium for 10 days. After co-culturing with hPMSCs^PRL-1, the characteristics of the OFs were analyzed using Nile red stain and quantitative real-time polymerase chain reaction. We then examined the in vivo regulatory effectiveness of hPMSCs^PRL-1 in a GO mouse model that immunized by leg muscle electroporation of pTriEx1.1Neo-hTSHR A-subunit plasmid. Human PMSCs^PRL-1 injection was performed in left orbit. We also analyzed the anti-adipogenic effects of hPMSCs^PRL-1 in the GO model.

Results

We found that hPMSCs^PRL-1 inhibited adipogenic activation factors, specifically PPARγ, C/EBPα, FABP4, SREBP2, and HMGCR, by 75.1%, 50%, 79.6%, 81.8%, and 87%, respectively, compared with naïve hPMSCs in adipogenesis-induced primary OFs from GO. Moreover, hPMSCs^PRL-1 more effectively inhibited adipogenic factors ADIPONECTIN and HMGCR by 53.2% and 31.7%, respectively, than hPMSCs, compared with 15.8% and 29.8% using steroids in the orbital fat of the GO animal model.

Conclusion

Our findings suggest that hPMSCs^PRL-1 would restore inflammation and adipogenesis of GO model and demonstrate that they could be applied as a novel treatment for GO patients.

SUBMITTER: Park M

PROVIDER: S-EPMC8164285 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundA large gene region, called GD-1, was first described by this laboratory as linked to Graves' disease (GD) and included the gene for the thyroid-stimulating hormone receptor (TSHR). Recent studies have now suggested an association of TSHR intronic polymorphisms with GD. We have taken the opportunity to examine a population of well-characterized patients with autoimmune thyroid disease (AITD) typed for an additional thyroid susceptibility gene, the immunoregulatory gene for cytotoxic T-lymphocyte antigen 4 (CTLA-4), to examine its relationship with the susceptibility to GD endowed by TSHR gene polymorphisms.MethodsWe used TSHR-SNP-rs2268458, located in intron 1 of the TSHR gene, measured using standard PCR-RFLP procedures, as our marker for the TSHR gene association. We genotyped 200 patients with GD, 83 patients with Hashimoto's thyroiditis (HT), and 118 healthy controls (all female Caucasians).ResultsThe allele and genotype frequencies from GD patients, but not HT patients, were significantly different from controls. The frequency of the combined genotype (allele) CC + TC was significantly higher in GD patients versus controls, suggesting that the C-containing genotype increased the risk for GD in a dominant manner (p = 0.018, odds ratio [OR] = 1.8). When compared with CTLA-4 (A/G)(49) single-nucleotide polymorphism (SNP), we were unable to demonstrate additive risk in patients with established AITD. Further, subsetting the patients (n = 120) into those with clinically significant Graves' ophthalmopathy (GO) showed no association with the TSHR SNP.ConclusionsThese results demonstrated that the intronic TSHR-SNP-rs2268458 was associated with GD, but not with HT, thus indicating that the TSHR gene has the potential to increase susceptibility to GD. However, we were not able to demonstrate any additive risk with the CTLA-4 (A/G)(49) SNP, which is, therefore, an independent risk factor for AITD. This suggested that, within the limits of the study population, each of these two genes provided a small contribution to GD susceptibility and that neither was essential. In addition, there was no evidence for the TSHR gene association adding to the risk of developing GO. Direct functional analyses are now needed to help explain the mechanisms of this TSHR gene susceptibility to GD.

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