Cell adhesion and extracellular matrix
As cell biologists, we have been exploring questions of wound healing in a model system for the corneal stroma. We view cell biology in a larger context that includes extracellular matrix and cell-cell interaction. Interactions of cells with matrix regulate cell differentiation, normal wound healing and cell migration in cancer. Cell-matrix interactions are complex: Cells synthesize and degrade the matrix in which they live and the matrix in turn presents the cells with growth factors and substrate, signals which regulate the cells. We have been exploring the dynamic equilibrium between cells and their extracellular matrix (ECM) in cultured cells derived from the cornea. In these studies we have recapitulated in culture, inter-conversions between activated fibroblasts and myofibroblasts found after wounding.
Our current working hypothesis is that the fibroblast to myofibroblast differentiation is reversible and that myofibroblast differentiation during wounding and healing is controlled by the interplay of three dominant factors: the loss of cell-cell contact, the presence of a growth factor (TGF-beta), and the alteration of cell-matrix interaction. We propose that the disconnection of one corneal fibroblast from another that occurs after wounding initiates a series of biochemical/molecular events that allow fibroblasts to respond to TGF- beta and to differentiate into myofibroblasts; the re-establishment of cell- cell contact attenuates the cellular response to TGF-beta; and integrin and matrix interaction initiate signals that are additional essential modulators of fibroblast differentiation and function and response to growth factors. We have recently discovered a novel form of Connective Tissue Growth Factor (CTGF, CCN2) generated in response to TGF-beta and are currently investigating its role in the myofibroblast differentiation and the fibrotic response.
Our model system of corneal cells provides a microcosm for testing hypotheses of reciprocal regulation by cells and matrix - an exciting area in cell biology currently.