Human placenta-derived mesenchymal stem cells ameliorate orbital adipogenesis in female mice models of Graves’ ophthalmopathy

摘要

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. 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. We 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. We 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. These 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.