Abstract
BackgroundGraves’ ophthalmopathy (GO) is a complication of Graves’ disease (GD), in which orbital connective tissues become inflamed and increase in volume and orbital fibroblasts within the orbital fat and extraocular muscles differentiate into adipocytes in vitro when stimulated by hormones, several cytokines, and growth factors including TSH, IGF-1, IL-1, interferon γ, and platelet-derived growth factor. Human placental mesenchymal stem cells (hPMSCs) have immunomodulatory effects in disease pathogenesis. Although a number of studies have reported that hPMSCs can elicit therapeutic effects, these are not sufficient. Therefore, we constructed a GO animal model in order to find out the hPMSCs recovery effect.MethodsWe investigated their anti-adipogenic effects in in vitro cultures of orbital fibroblasts established from GO patients. Primary orbital fibroblasts were exposed to differentiation medium for 10 days. After being co-cultured with hPMSCs, the characteristics of orbital fibroblast were determined by Oil Red O stain and real-time PCR. Then, we explored the in vivo regulatory effects of hPMSCs in an experimental mouse model of GO. We developed the GO mouse model using immunization by leg muscle electroporation of pTriEx1.1Neo-hTSHR A-subunit plasmid. Human PMSC injection was performed into the left orbit. We also analyzed the effects of hPMSCs in the GO animal model.ResultWe found that hPMSCs inhibited a lipid accumulation and activated factors, such as ADIPONECTIN, PPARγ, C/EBPα, and TGFβ2 genes in adipogenesis-induced primary orbital fibroblasts from GO patients. Moreover, hPMSCs were highly effective at ameliorating adipogenesis in the orbital tissue of the model.ConclusionThese data indicate that hPMSCs recover pathogenic activation of orbital fibroblasts in animals undergoing experimental GO and confirm the feasibility of applying hPMSCs as a novel treatment for GO patients.
Highlights
Graves’ ophthalmopathy (GO) is a complication of Graves’ disease (GD), in which orbital connective tissues become inflamed and increase in volume and orbital fibroblasts within the orbital fat and extraocular muscles differentiate into adipocytes in vitro when stimulated by hormones, several cytokines, and growth factors including TSH, IGF-1, IL-1, interferon γ, and platelet-derived growth factor
We investigated the immunomodulatory effects of Human placental mesenchymal stem cells (hPMSCs) in the case of GO using both in vitro tests with orbital fibroblast (OF) cultures and in vivo tests and compared our results with those of conventional steroid treatments in an experimental mouse model of GO [20, 21]
In a TSH-binding inhibitory immunoglobulin (TBII) assay using an anti-TSH receptor (TRAb) ELISA, the GO models exhibited > 78% inhibition of labeled TSH binding activity compared to the control group (Fig. 1b)
Summary
Graves’ ophthalmopathy (GO) is a complication of Graves’ disease (GD), in which orbital connective tissues become inflamed and increase in volume and orbital fibroblasts within the orbital fat and extraocular muscles differentiate into adipocytes in vitro when stimulated by hormones, several cytokines, and growth factors including TSH, IGF-1, IL-1, interferon γ, and platelet-derived growth factor. Human placental mesenchymal stem cells (hPMSCs) have immunomodulatory effects in disease pathogenesis. The total amount of corticoid use is restricted for the systemic adverse effects, including hyperglycemia, hypertension, and immune system compromise, and the eye symptoms usually recur when the steroid treatment is tapered or withdrawn [4,5,6]. Radiation therapy is another popular modality for the treatment of GO and is considered to treat the patients who are resistant to or cannot tolerate the side effects of corticoids. A number of advanced therapies have been introduced, most of which have studied about immunomodulatory effects; these include rituximab (RTX), tocilizumab (TCZ), the humanized anti-interleukin-6 receptor monoclonal antibody, teprotumumab, IGF-1 receptor-blocking antibodies, and TNF-α inhibitors [9, 10]
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