{"id":95920,"date":"2016-10-06T17:09:18","date_gmt":"2016-10-06T15:09:18","guid":{"rendered":"http:\/\/ibecbarcelona.eu\/?post_type=tribe_events&amp;p=24823"},"modified":"2016-10-06T17:09:18","modified_gmt":"2016-10-06T15:09:18","slug":"ibec-seminar-targeting-fibroblast-durotaxis-as-anti-fibrotic-therapy-2","status":"publish","type":"tribe_events","link":"https:\/\/ibecbarcelona.eu\/es\/event\/ibec-seminar-targeting-fibroblast-durotaxis-as-anti-fibrotic-therapy-2\/","title":{"rendered":"IBEC Seminar: Targeting fibroblast durotaxis as anti-fibrotic therapy"},"content":{"rendered":"<h2>Targeting fibroblast durotaxis as anti-fibrotic therapy<\/h2>\n<address>Dr. David Lagares,\u00a0Harvard Medical School<\/address>\n<p class=\"p1\">Dysregulated wound repair process in response to chronic tissue injury can lead to the development of tissue fibrosis in most organs. Fibrosis is characterized by accumulation of collagens and other matrix proteins that result in the distortion of tissue architecture, and ultimately organ failure, in variety of human diseases including idiopathic pulmonary fibrosis (IPF). Tissue stiffening, traditionally thought to simply be a consequence of lung fibrosis, has been recently shown to be a contributing factor to its pathogenesis by inducing fibroblasts differentiation into activated myofibroblasts, the principal effector cells responsible matrix deposition.<\/p>\n<p class=\"p1\">The cellular and molecular mechanisms through which increased tissue rigidity drives disease progression remain to be fully elucidated. Using atomic force microscopy (AFM) to mechanically characterize the \u201ctopography\u201d, i.e. the spatial distribution, of alterations in matrix stiffness produced in mouse models of lung fibrosis, we consistently found that stiffness, rather than being uniformly elevated in lung fibrotic tissues from animals models, rises and falls in spatial gradients between \u201cpeaks\u201d and \u201cvalleys.\u201d We hypothesize that the stiffness \u201cpeaks\u201d represent areas in which the fibrotic process was initiated, or \u201cnucleated\u201d. Once fibrosis is nucleated, the stiffness gradients leading to these fibrotic peaks are amplified by fibroblast \u201cdurotaxis,\u201d \u2013 the directed migration of cells from regions of lower to higher stiffness, which occurs in the absence of chemoattractant gradients. Using hydrogels that recapitulate the stiffness gradients observed in animal fibrosis models, we demonstrated durotaxis of lung fibroblasts in time-lapse microscopy studies. In human studies with lung tissues from IPF patients, AFM revealed similar stiffness topography as we observed in mouse models, i.e. the presence of focal peaks surrounded by stiffness gradients. Of note, we have also found that primary lung fibroblasts from IPF patients exhibit greater durotactic responses to stiffness gradients than do control lung fibroblasts. In efforts to identify the molecular pathways involved in cell durotaxis, we have found that the increased durotaxis of IPF fibroblasts may be attributable, at least in part, to increased acetylation of their microtubules. Acetylation of \u03b1-tubulin is dependent on \u03b1-tubulin acetyltransferase (\u03b1TAT1) activity, which is upregulated in fibrotic fibroblasts compared with controls. siRNA-mediated \u03b1TAT1 downregulation in these fibrotic fibroblasts reduced their pro-durotactic phenotype without affecting fibroblast chemotaxis.<span class=\"Apple-converted-space\">\u00a0 <\/span>In vivo, \u03b1TAT-1-deficient mice were protected from bleomycin-induced lung fibrosis, as assessed qualitatively by histology and quantitatively by hydroxyproline levels. Together, we identified a novel mechanism through which gradients of matrix stiffness produced in the injured lung drives the progression of lung fibrosis, by recruiting additional fibroblasts to sites of injury and incipient fibrosis through durotaxis. We consequently hypothesize that inhibition of fibroblast durotaxis has the potential to be an entirely new therapeutic strategy for IPF and other fibrotic diseases.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Targeting fibroblast durotaxis as anti-fibrotic therapy<\/p>\n","protected":false},"author":4,"featured_media":0,"template":"","meta":{"_tribe_events_status":"","_tribe_events_status_reason":"","footnotes":""},"tags":[307,146,305],"tribe_events_cat":[105],"class_list":["post-95920","tribe_events","type-tribe_events","status-publish","hentry","tag-david-lagares","tag-ibec","tag-seminar","tribe_events_cat-ibec-seminar","cat_ibec-seminar"],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.3 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>IBEC Seminar: Targeting fibroblast durotaxis as anti-fibrotic therapy - Institute for Bioengineering of Catalonia<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/ibecbarcelona.eu\/event\/ibec-seminar-targeting-fibroblast-durotaxis-as-anti-fibrotic-therapy-2\/\" \/>\n<meta property=\"og:locale\" content=\"es_ES\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"IBEC Seminar: Targeting fibroblast durotaxis as anti-fibrotic therapy - 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