Fibroblasts represent a dynamic population of cells, exhibiting functional heterogeneity within and among tissues. Fibroblast heterogeneity also results from phenotypic differences and may arise from activation or differentiation processes taking place in the cells. We previously reported that human fibroblasts were heterogeneous with respect to surface Thy-1 expression and that separation into Thy-1 ؉ and Thy-1 ؊ subsets resulted in functionally distinct subpopulations, leading to the concept of fibroblast subset specialization. In this report we investigated whether Thy-1 ؉ and/or Thy-1 ؊ fibroblasts were capable of differentiating into myofibroblasts or lipofibroblasts. Fibroblast subsets were used from human myometrium and orbit to test this hypothesis. Only Thy-1 ؉ human myometrial and orbital fibroblasts were capable of myofibroblast differentiation after treatment with TGF or platelet concentrate supernatant, assessed by ␣ smooth muscle actin expression. Interestingly, only Thy-1 ؊ , but not Thy-1 ؉ subsets differentiated to lipofibroblasts, as determined by the accumulation of cytoplasmic lipid droplets after treatment with 15-deoxy-⌬ 12 , 14 -PGJ 2 or ciglitazone. We propose that fibroblast Thy-1 display predetermines lineage to a contractile or lipid-like phenotype in the human myometrium and orbit. This additional distinction between Thy-1 ؉ and Thy-1
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.
An emerging concept is that fibroblasts are not homogeneous, but rather consist of subsets, capable of producing regulatory mediators that control regional inflammatory responses. Fibroblasts are key effector cells in Graves' ophthalmopathy, responsible for the connective tissue remodeling, and are a rich source of inflammatory mediators. The purpose of this research was to characterize subsets of the fibroblasts in the human orbit. The strategy used was to define fibroblast subpopulations based on surface expression of the Thy‐1 antigen. Fibroblast strains derived from human orbital connective tissue exhibit heterogeneous Thy‐1 expression. We show, for the first time, separation of orbital fibroblasts into functionally distinct Thy‐1+ and Thy‐1‐ subsets using magnetic beading techniques. Both subsets produced the pro‐inflammatory cytokine interleukin‐6 (IL‐6) after stimulation with IL‐1β or the CD40 pathway, whereas Thy‐1+ fibroblasts produced higher levels of prostaglandin endoperoxide H synthase‐2 (PGHS‐2) and prostaglandin E2 (PGE2). Thy‐1‐ fibroblasts produced more IL‐8 than Thy‐1+ fibroblasts, and when treated with interferon γ (IFN‐γ) up‐regulated MHC class II expression more robustly. Furthermore, CD40 was expressed in a bimodal distribution within each fibroblast subset. These observations suggest that fibroblast subsets in the human orbit play distinct roles in the regulation of immune and inflammatory responses crucial in the initiation and development of thyroid‐associatedophthalmopathy.
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