The Role of Mechanical Stress in Regulating Integrin Recruitment to Latent TGF-β1
Fibrosis is characterized by excessive extracellular matrix (ECM) production and contraction of myofibroblasts that differentiate from fibroblasts under the action of pro-fibrotic cytokine TGF-β1 and mechanical stress. Myofibroblasts liberate active TGF-β1 by integrin-mediated pulling on the latency...
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| Language: | en_ca |
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2012
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| Online Access: | http://hdl.handle.net/1807/33280 |
| Summary: | Fibrosis is characterized by excessive extracellular matrix (ECM) production and contraction of myofibroblasts that differentiate from fibroblasts under the action of pro-fibrotic cytokine TGF-β1 and mechanical stress. Myofibroblasts liberate active TGF-β1 by integrin-mediated pulling on the latency-associated protein pro-peptide (LAP) which is stored together with the latent TGFβ1-binding protein-1 (LTBP-1) in the ECM. I hypothesized that the binding affinity/strength of LAP binding integrins, in particular of integrin αvβ3, is regulated by the mechanical stress arising from the contractile fibroblast cytoskeleton and the stiff ECM. To test this hypothesis, different methods were employed to investigate mechanically-regulated integrin αvβ3 recruitment to LAP in the physiological context of fibroblasts. The main findings of my thesis work are that (a) fibroblasts use αvβ3 integrin to bind to LAP; (b) αvβ3 integrin is capable of transmitting considerable cell force to LAP; and (c) mechanical stress increases the recruitment of αvβ3 integrin to LAP. |
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