Cryptic laminin activity regulates matrix metalloproteinase expression during epithelial-to-mesenchymal transition – towards a strategy to target tissue fibrosis
|Starts:||12:00 16 Feb 2016|
|Ends:||13:00 16 Feb 2016|
|What is it:||Seminar|
|Organiser:||Faculty of Life Sciences|
|Who is it for:||University staff, Current University students|
The remodelling of the basement membrane (BM) – an integral part of the epithelial-to-mesenchymal transition (EMT) - involves constant modulation of integrin-BM protein interactions facilitated by the structural and conformational diversity of different BM proteins. During remodelling, cryptic sites can become biologically active by proteolytic processing through matrix metalloproteinases (MMPs) or by cell-induced mechanical strain. These cryptic sites mediate a variety of different biological activities which are still widely unexplored, especially in pathological phenotypes. The exploration of molecular mechanisms involved in the interplay of the BM and epithelial cells is critical to understand tissue remodelling as well as to grasp the complexity of EMT-related pathologies such as tissue fibrosis.
We have recently shown that a fragment of the b1-chain of laminin modulates the expression of MMP2 in human and mouse embryonic stem cells following the initiation of EMT (1). This 60kDa fragment is released by MMP2 processing and it exhibits specific binding sites for a3b1-integrin thereby triggering changes in EMT-related gene expression. This specific interaction causes a significant down-regulation of the expression and activity of MMP2. Given the similarities between EMT molecular pathways during development and tissue fibrosis, we hypothesized that similar inhibitory mechanisms could be switched on in epithelial cells undergoing TGFb-induced EMT. Here, we show that the fragment indeed modulates EMT gene expression in this setting. The interaction of the b1-fragment with mesothelial tissue of a mouse peritoneal membrane undergoing TGFb1-induced fibrosis, rescues tissue integrity by decreasing the amount of active MMP2 released by the tissue. Of importance, the fragment does not act on extracellular MMP2, but rather interferes with key EMT pathways. These results demonstrate the important role of cryptic basement membrane activities in the pathological differentiation of cells and suggests a feedback mechanism regulating MMP activities during matrix remodelling.
(1) Horejs C.-M., Serio A., Purvis A., Gormley A., Bertazzo S., Poliniewicz A., Wang A., DiMaggio P., Hohenester E., Stevens M.M., PNAS (2014), 111 (16) 5908-5913
Role: Project Leader
Organisation: Division of Biomaterials and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
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