Myofibroblast Social Networking
We aim to develop strategies that target transmembrane cell-cell junction proteins to therapeutically induce myofibroblast regression. We have shown that myofibroblasts form cell-to-cell contacts with specific molecular properties. We hypothesize that formation of homotypic junctions in the highly cellularized environment of contracted tissue induces myofibroblast regression and termination of contracture. This project also considers that the signal(s) mediated through cell-cell junctions will likely depend on the mechanical microenvironment.
Pulling on a Growth Factor Contributes to Fibrosis
TGF-β1 is the most potent pro-fibrotic growth factor known. Generally inhibiting TGF-β1 in clinical strategies is unsuccessful because TGF-?1 has many beneficial actions, such as reducing inflammation, regulating blood vessel growth and preventing tumour formation. It is our objective to stop myofibroblast activation by blocking mechanical activation of TGF-β1. We have discovered that myofibroblasts pull TGF-β1 out from stores in the extracellular matrix, literally like candy out of a wrapper. Liberated TGF-β1 stimulates more myofibroblasts. To prevent vicious cycle, we interfere with specific integrins that myofibroblasts use as a handle to pull on latent TGF-β1. We have already identified the integrins possibly activating TGF-β1 in lung, cardiac and dermal myofibroblasts and test how cell force and matrix stiffness control their efficacy to activating TGF-β1 using a variety of biomechanical assays. Using different animal models of fibrosis, we are testing the importance of our integrin candidates by turning them on and off with molecular biology and specific drugs.
We want to decipher the mechanisms of mesenchymal stromal cell (MSC) differentiation into myofibroblasts. MSCs are pluripotent cells with the potential to regenerate organs. Many of the therapeutic applications for MSCs imply their engraftment into fibrotic tissue, such as infarcted heart, fibrotic lung, wounded skin, fractured bone and cartilage. This hostile environment can force MSCs into a fibrogenic rather than regenerative character. The molecular mechanisms that determine success or failure of regenerative approaches are virtually unknown. We ask how the mature and stiff scar microenvironment drives MSC-to-myofibroblast differentiation and how can we control this harmful transition.
Getting the best out of myofibroblasts by controlling substrate mechanics
Ageing is accompanied by changes in the stiffness of the skin, partly caused by the decreased synthesizing activity of dermal fibroblasts. Little is known about the feedback between dermis compliance and fibroblast activity. We hypothesize this ageing effect is partly due to lower skin stiffness. With the use of novel compliant substrates, we are now able to mimic the mechanical conditions of old versus young skin in culture. Our in vitro studies has been supported by measuring skin stiffness of subjects with the atomic force microscope. In more general terms, we are developing a novel generation of rubber-based culture substrates that effectively prevent spontaneous myofibroblast activation in cell culture.