Abstract
BackgroundGraves’ 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 (hPMSCsPRL-1) in an attempt to enhance the suppressive function of adipogenesis in GO animal models.MethodsIn order to investigate the anti-adipogenic effects, primary OFs were incubated with differentiation medium for 10 days. After co-culturing with hPMSCsPRL-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 hPMSCsPRL-1 in a GO mouse model that immunized by leg muscle electroporation of pTriEx1.1Neo-hTSHR A-subunit plasmid. Human PMSCsPRL-1 injection was performed in left orbit. We also analyzed the anti-adipogenic effects of hPMSCsPRL-1 in the GO model.ResultsWe found that hPMSCsPRL-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, hPMSCsPRL-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.ConclusionOur findings suggest that hPMSCsPRL-1 would restore inflammation and adipogenesis of GO model and demonstrate that they could be applied as a novel treatment for GO patients.
Highlights
Graves’ disease (GD) is an antibody-mediated autoimmune disease associated with thyroid-stimulating hormone receptor (TSHR) in the thyroid gland that causes hyperthyroidism [1]
All patients consented to the proper use for research. Human placental mesenchymal stem cells (hPMSCs) were cultured in α-modified minimal essential medium (α-MEM; HyClone, Logan, UT, USA) supplemented with 10% fetal bovine serum (FBS) (Gibco), 1% P/S (Gibco), 1 μg/mL heparin
We collected serum from the Graves’ ophthalmopathy (GO) model to evaluate for antibodies to TSHR
Summary
Graves’ disease (GD) is an antibody-mediated autoimmune disease associated with thyroid-stimulating hormone receptor (TSHR) in the thyroid gland that causes hyperthyroidism [1]. Graves’ ophthalmopathy (GO) is an autoimmune inflammatory disease in which TSHRstimulated antibodies and TSHR affect cells in surrounding tissues [2]. Human placental mesenchymal stem cells (hPMSCs) offer multilineage differentiation potential and especially strong immunomodulatory abilities for regenerative medicine applications [4]. 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), IL1, 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. We constructed PRL-1 overexpressed hPMSCs (hPMSCsPRL-1) in an attempt to enhance the suppressive function of adipogenesis in GO animal models
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