2017 07 LTRROur Mission

We aim to understand the mechanisms controling myofibroblast function and how they influence the development of fibrosis. We carry out functional analysis of the cell's contractile apparatus (actin stress fibers), of force transmission at sites of cell-extracellular matrix contacts (focal adhesions) and of the mechanical cross-talk between contractile stress fibers of contacting fibroblasts at sites of cell-cell adherens junctions. We develop novel strategies to counteract myofibroblast malfunction by targeting these instrumental structures of the contractile phenotype.

 

 

silconeOur Research

Myofibroblasts restore connective tissue integrity and contract the wound during tissue repair. Excessive myofibroblast activity is characteristic of the majority of fibrocontractive diseases. Following tissue injury, local fibroblasts and other mesenchymal cells, blood-circulating cells, epithelial and endothelial cells acquire smooth muscle features. Hallmark of this transition is the neo-expression of α-smooth muscle actin, generating high contractile activity in stress fibres. Of clinical relevance are the retractile phenomena caused by excessive myofibroblast activity characterizing the vast majority of fibrocontractive diseases. This includes fibrosis affecting vital organs, such as heart, liver, kidney and lung.

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Other fibrotic phenomena reduce life quality in scleroderma, hypertrophic scars (remarkably severe after large burn wounds), chronic asthma and Dupuytren's disease. Moreover, myofibroblasts at the tumor invasion front are activated by the transformed epithelium to stimulate tumor growth and invasion by promoting angiogenesis and tumor cell migration. In tissue engineering and regenerative medicine considerable effort is required to prevent myofibroblast formation, either arising from mesenchymal stem cells that are implanted to repair tissues or at the interface between the implant and the host connective tissue. But don't be fooled - the myofibroblast is not necessarily the 'bad guy' as it contributes to physiological wound healing and its absence has been associated with development of chronic wounds. In all these conditons, controlling the tissue activity of myofibroblasts will be beneficial for the outcome of the body repair process.

ElizabethOur Tools

At LTRR, we develop and use state of the art equipment for analyzing mechanical forces in vivo and in vitro and performing high sensitivity fluorescence microscopy. We specialize in analyzing and measuring forces on the level of subcellular structures (contact sites), of individual cells, of cell populations and ex vivo tissue samples.

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A variety of techniques are established in the laboratory to assess these different problems. This includes the use of micropatterned stiff and elastic culture substrates, laser trap technology, flow chamber assays, fibroblast-populated three-dimensional collagen gels and tissue myographs (isometric force measurements). Moreover, the group has a experience with and is partly equipped with systems to perform high-sensitivity fluorescence microscopy, latest laser scanning and spinning-disc confocal microscopy, and live videomicroscopy Software packages are available to analyze fluorescence intensity over time, to calculate force-displacement values, to track pathways of structures or cells and to quantify the dynamics of sub-cellular structures (lamellipodia, ruffles).