Orbital Fibroblast Heterogeneity May Determine the Clinical Presentation of Thyroid-Associated Ophthalmopathy

Abstract

Thyroid-associated ophthalmopathy, a process in which the orbital tissues become inflamed and are remodeled, occurs with a variable presentation. In some patients, eye muscle enlargement predominates. In others, the connective/adipose tissue enlargement appears the more significant problem. Orbital fibroblasts exhibit heterogeneous phenotypes in culture. Here we report that fibroblasts derived from the connective/adipose tissue depot are distinct from those investing the extraocular muscles. Connective tissue fibroblasts represent a bimodal population of cells with regard to the surface display of the glycoprotein, Thy-1. Perimysial fibroblasts in contrast express Thy-1 uniformly. In that regard, they resemble those from the skin. When subjected to a newly defined set of culture conditions, adipocyte differentiation occurs in up to 43% of the cells. All adipocytes examined failed to display Thy-1. Fibroblasts derived from perimysium and dermis uniformly do not differentiate into adipocytes when incubated under identical culture conditions. Both Thy-1(+) and Thy-1(-) connective tissue fibroblasts express the adipogenic trigger, peroxisome proliferator activator gamma, suggesting that differences in the potential for differentiation may reside with phenotypic attributes downstream from this receptor/adipogenic transcription factor. These observations enhance our understanding of orbital adipogenesis and define previously unrecognized differences between fibroblasts from the extraocular muscle and connective tissue.

Mast Cells Induce Activation of Human Lung Fibroblasts in Vitro

“…This observation is similar to that seen with intestinal fibroblasts and is in contrast to our previous findings with foreskin fibroblasts and dermal fibroblasts [28]. Fibroblast heterogeneity in morphology, expression of surface markers such as CD40, ability to present antigen, expression of cytokines, and synthesis of collagen have been well documented [18][19][20]29]. Expression of the thymocyte-1 antigen (Thy-1) is frequently used to differentiate fibroblast subsets [18,19].…”

“…Fibroblast heterogeneity in morphology, expression of surface markers such as CD40, ability to present antigen, expression of cytokines, and synthesis of collagen have been well documented [18][19][20]29]. Expression of the thymocyte-1 antigen (Thy-1) is frequently used to differentiate fibroblast subsets [18,19]. This difference in fibroblast behavior supports the notion of fibroblast-phenotype heterogeneity and reiterates the necessity for caution in comparing fibroblasts from different tissues.…”

“…Although mast cell-fibroblast interactions have been studied previously for skin and intestinal fibroblasts, fibroblasts from different tissues and even within the same anatomical site may behave differently [18][19][20].…”

Interleukin-4 Induces 15-Lipoxygenase-1 Expression in Human Orbital Fibroblasts from Patients with Graves Disease

“…All experimental manipulations were conducted after a state of confluence had been reached. We have already characterized these cultures extensively (32). We found them to be essentially devoid of contamination with endothelial, epithelial, and smooth muscle cells.…”

Peroxisome Proliferator-activated Receptor γ Ligands Inhibit Transforming Growth Factor-β-induced, Hyaluronan-dependent, T Cell Adhesion to Orbital Fibroblasts

“…One of the key events initiating TED is considered to be excess synthesis of ECM by orbital fibroblasts (20). Hyaluronan (HA) is the major ECM glycosaminoglycan (GAG) in inflamed orbital tissue.…”