Fibrous connective tissue provides mechanical support and frameworks for the other tissues of the body. Type 1 collagen is the major protein component of fibrous connective tissue. Fibroblasts are the cell type primarily responsible for collagen biosynthesis and remodeling. As a result of mechanical remodeling, collagen and other components of fibrous connective tissue stretch, slip, and undergo stable reorganization. Such remodeling has been implicated in diverse aspects of normal physiology and pathology including wound repair, fibrosis, scar formation, tumorigenesis, and aging. Matrix remodeling also is an important design feature in tissue engineering. Underlying our research is the premise that we can use 3D collagen matrices to analyze and dissect the structural, functional and mechanical features of fibroblast-matrix interactions in a tissue-like environment. Understanding these features should facilitate discovery of interventions to promote wound repair and enhance development of the field of tissue engineering. Indeed, the general usefulness of 3D matrix models to accelerate a wide range of translational research work increasingly has been recognized. In the current proposal, we plan to analyze human fibroblast migration and collagen flow in nested collagen matrices and in fibrin matrices. We also will analyze human fibroblast migration and clustering on collagen matrices as a function of the growth factor environment and determine if myofibroblasts are migratory cells given appropriate growth factor stimulation. In other studies, the role of cell-cell adherens junctions in cell clustering and cell migration will be assessed. Work on the growth factor environment will focus especially on sphingosine-1-phosphate (S1P), which potentially plays a dual regulatory role -- negative for fibroblast migration and positive for contraction. We will analyze the receptors important for S1P function and analyze the presence of S1P and other promigratory/procontractile factors in acute human wound fluid. Finally, we will test if discoidin domain receptor 2, a cell surface tyrosine kinase receptor that binds collagen, plays a specific role in fibroblast-collagen matrix interactions.
Remodeling of fibrous connective tissue by fibroblasts has been implicated in diverse aspects of normal physiology and pathology including wound repair, fibrosis, scar formation, tumorigenesis, and aging. Matrix remodeling also is an important design feature in tissue engineering. Underlying our research is the premise that we can use 3D collagen matrices containing human fibroblasts to analyze and dissect the structural, functional and mechanical features of connective tissue remodeling in a tissue-like environment. Understanding these features should facilitate discovery of interventions to promote wound repair and enhance development of the field of tissue engineering. Indeed, the general usefulness of 3D matrix models to accelerate a wide range of translational research work increasingly has been recognized.
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