Thy-1 (CD90) mediates fibroblast adhesion and migration: Relevance to engineered cell migration

Fibroblasts are critical in the process of wound-healing. The normal wound-healing functions of fibroblasts, including migration into and proliferation within provisional matrices, as well as matrix deposition and resolution, are likely dysregulated in fibrotic disorders leading to loss of function of the involved organ system. The goal of biomedical engineering is to improve the quality of life through the development of medical technologies that restore lost functionality. For this purpose, fibroblasts, which hold potential in the design of tissue-engineered constructs for implantation, are an ideal target of study. Alterations in their normal functions lead to the premature loss of function of synthetic implants. Fibroblasts are heterogeneous throughout the body and thus react differently to various stimuli. Despite this fact, scientists and engineers often neglect this heterogeneity in the design of experiments and implants. Thy-1 surface expression represents the best-defined model of fibroblast heterogeneity; despite the early characterization of their morphological differences, the mechanism directing the different morphologies has yet to be identified. In these studies, the role of Thy-1 in directing fibroblast adhesion and migration is determined. By using a molecular biology approach, we developed a model system and determined that Thy-1 surface expression is sufficient to induce a reorganization of the cytoskeleton characterized by the formation of actin stress fibers and a redistribution of cellular adhesions. Thy-1-induced cytoskeletal changes were a result of the inhibition of src family kinase activity, which in turn resulted in a decrease in the phosphorylation of the rhoGAP p190 and a subsequent increase in the levels of active rho, ultimately resulting in a significant inhibition of cell migration. Thy-1 has an additional level of control over fibroblast-matrix interactions by acting in a manner to facilitate thrombospondin-1 signaling through SFKs and subsequent focal adhesion disassembly. These findings represent novel mechanisms of Thy-1 regulation of cell phenotype that constitute possible avenues toward the development of new therapeutics and demonstrate the importance of having a strong understanding of the biology being applied in the design of engineered medical devices by demonstrating a novel nuance determining cell phenotype that could impact the utility of the design.