Student/Ph.D CHA University south korea, Kyonggi-do, Republic of Korea
Abstract: Thyroid eye disease (TED) is an autoimmune condition affecting the orbit and extraocular muscles (EOM) that may lead to orbital disfigurement, double vision, and even vision loss. The main processes involved in TED are inflammation, glycosaminoglycan accumulation, adipogenesis, and myofibrogenesis in the EOM tissue. These changes lead to the pathological characteristics of TED: orbital tissue expansion, remodeling, and fibrosis. While the clinical symptoms of myopathy in TED are diverse and difficult to treat, much of the research has focused on fat tissue, leading to a lack of understanding regarding myopathy. Human mesenchymal stem cells (hMSCs), which are important mediators of therapeutic effects in anti-inflammation and regenerative medicine. Human MSCs were injected into the left orbit of TED animal models, and their effects on EOM volume and fibrosis were compared between TED and hMSCs-treated TED using tissue staining. Additionally, single-cell RNA sequencing was performed on the EOM of TED animal models. As a result, the groups treated with hMSCs showed a reduction in EOM volume and fibrosis. In the TED EOM, treatment with hMSCs resulted in a decreased proportion of Type II myofibers, which was found to be mediated by the regulatory effects of Six1 and Eya1 on myofiber differentiation. Myofiber differentiation involves a synergistic regulatory relationship between Six1 and Eya1 during the transformation of adult myofibers. Balanced expressions of the Six1 and Eya1 co-factors in Type II myofibers can induce their transition to Type I myofibers. Furthermore, subclustering analysis of fibroblasts identified five major signaling pathways involved in the pathogenesis of TED. Examination of receptor-ligand (R-L) interactions within these pathways revealed that hMSC treatment led to a reduction in R-L activity, resulting in a decreased expression of TED-associated signaling pathways. This study explored the use of hMSCs as a therapeutic agent for TED myopathy and identified genes that modulate both TED myopathy and myofibrosis. By identifying the target genes modulated by hMSCs, this research provides a potential role of hMSCs as a treatment for TED myopathy.
Funding Source: This research was supported by grants from the National Research Foundation of Korea (NRF): 2021R1A2C2010523 and RS20233938.
