Convergent Biochemical and Biomechanical Pathways in Tissue Remodeling: The Role of α₂β₁ Integrin and MMP Activity: A Dissertation

The extracellular matrix is a multi-functional environment that cells inhabit to form living tissue. To maintain the tissue, cells require constant telemetry with the matrix and respond to a variety of cues by remodeling matrix architecture. In this study the physical and biochemical manipulation of the matrix by resident cells is explored to better understand how these are used to remodel tissue. Cell-populated collagen hydrogels are used as a controllable in vitro tissue model. To directly measure mechanical forces involved with gel contraction, a culture force monitor was designed and built. Measuring dimensional changes together with contractile forces presents a method of separating mechanisms that influence tissue remodeling. Together, these techniques revealed a correlation between contractile force and gel deformation, suggesting a novel method for examining the material properties of the matrix. Limiting matrix metalloproteinase (MMP) activity altered the correlation as predicted, indicating a stiffer matrix. Contractile force was found to be regulated independent of MMP activity. In contrast, contractile force was found to be dependent on α2β1 integrin function. Collagen gel contraction correlated with both α2β1 function and MMP activity, and was significantly enhanced when combined. The results of this study indicate cells have the capacity to use multiple mechanisms for remodeling the extracellular matrix and may alternately use them together or independently to vary the rate of matrix contraction