A biomaterials approach to interface cryptic laminin information with epithelial tissue as a strategy to counteract TGFbeta1-induced fibrosis
Year: 2016
Type: article
Abstract: Event Abstract Back to Event A biomaterials approach to interface cryptic laminin information with epithelial tissue as a strategy to counteract TGFbeta1-induced fibrosis Jean-Philippe St-Pierre1, 2, 3*, Christine-Maria Horejs1, 2, 3, 4*, Juha R. Ojala4*, Alex J. Wang1, 2, 3*, Manuel M. Mazo1, 2, 3*, Amanda Y. You1, 2, 3*, Thomas Von Erlach1, 2, 3, Karl Tryggvason4, 5* and Molly M. Stevens1, 2, 3, 4 1 Imperial College London, Department of Materials, United Kingdom 2 Imperial College London, Department of Bioengineering, United Kingdom 3 Imperial College London, Institute of Biomedical Engineering, United Kingdom 4 Karolinska Institutet, Department of Medical Biochemistry and Biophysics, Sweden 5 Duke-NUS, Cardiovascular and Metabolism Disorders Program, Singapore Introduction: Targeting inflammation-induced epithelial-to-mesenchymal transition (EMT) has been proposed as a promising strategy for the treatment of tissue fibrosis. EMT is a critical step in fibrogenesis as it increases the pool of myofibroblasts that release elevated levels of matrix metalloproteinases (MMPs) and deposit excessive amounts of extracellular matrix. If left unchecked, this loss of epithelial tissue homeostasis can lead to impaired tissue function. Attempts to interfere with EMT have been plagued by the off-target effects of therapeutics[1]. Here, we propose a biomaterials-based strategy to interface a “cryptic” fragment of the laminin β1-chain with epithelial tissues and mitigate the effects of inflammation-induced EMT in a localized manner. This fragment is released by the action of MMP-2 on laminins and is thought to play a feedback control role on cells undergoing EMT[2]. Materials and Methods: Recombinantly produced laminin fragment was immobilized on electrospun poly(ε-caprolactone) (PCL) membranes via a polydopamine coating. The interaction of normal mouse mammary gland (NMuMG) epithelial cells undergoing transforming growth factor β1 (TGFβ1)-induced EMT changes with the bioactive membrane was characterized compared to that on non-functionalized membranes. The bioactive and non-functionalized membranes were also interfaced with mouse peritoneal tissue explants in the presence of TGFβ1. Metabolic activity, cell morphology, gene and protein expression, MMP-2 activity and immunohistological appearance of the tissues were evaluated. Results and Discussion: Electrospun PCL membranes functionalized with the laminin β1-chain were shown to abrogate the increase in MMP-2 gene expression and protein activity observed in NMuMG cells undergoing TGFβ1-induced EMT changes compared to non-functionalized membranes. This effect was accompanied by a significant decrease in the gene expression of the transcription factor slug known to be involved in the induction of EMT. Furthermore, the E- to N-cadherin switch and morphological changes associated with EMT were partially prevented by the presence of the laminin fragment. Of relevance to a potential therapeutic approach with this material, interfacing the bioactive membrane with peritoneal tissue explants in the presence of TGFβ1 rescued the integrity of the mesothelial tissue. This was attributed at least in part to the near complete inhibition of the pathological increase in MMP-2 activity. Conclusions: In this study, we demonstrate a promising biomaterials approach to the treatment of tissue fibrosis. Of note, the presentation of a “cryptic” fragment of the laminin β1-chain to epithelial cells prevents the phenotypic transition that leads to increased MMP-2 expression as a response to inflammation rather than inhibiting released MMP-2. The use of ECM information to specifically modulate cell phenotype via integrin signaling also ensures localization of the effect. The broad distribution of laminins in tissues suggests that this biomaterial could find applications in the treatment of fibrosis in a number of tissues. This work was supported in part by the Medical Research Council, the Engineering and Physical Sciences Research Council and the Biotechnology and Biological Sciences Research Council UK Regenerative Medicine Platform Hubs “Acellular Approaches for Therapeutic Delivery” (MR/K026682/1) and “A Hub for Engineering and Exploiting the Stem Cell Niche” (MR/K026666/1), the Medical Engineering Solutions in the Osteoarthritis Centre of Excellence, funded by the Wellcome Trust and the Engineering and Physical Sciences Research Council (088844) and the ERC Seventh Framework Programme Consolidator grant “Naturale CG” under grant agreement no. 616417.; We thank thank Prof. Erhard Hohenester for providing the cells and help with the production of the recombinant laminin fragment.; We also thank Dr. Mads Bergholt for his input in the analysis of the Raman spectroscopy data.; The authors consider that J.-P.S. and C.-M.H. contributed equally to the work presented in this abstract.References:[1] J. Rosenbloom, F.A. Mendoza and S.A. Jimenez, "Strategies for anti-fibrotic therapies", Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. Vol. 1832, Jul. 2013.[2] C.-M. Horejs, A. Serio, A. Purvis, A.J. Gormley, S. Bertazzo, A. Poliniewicz, A.J. Wang, P. DiMaggio, E. Hohenesterd and M.M. Stevens, "Biologically-active laminin-111 fragment that modulates the epithelial-to-mesenchymal transition in embryonic stem cells", PNAS. Vol. 111, Apr. 2014. Keywords: biofunctionalization, Cell modulation, bioactive interface, instructive microenvironment Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016. Presentation Type: Poster Topic: Fibrosis and biomaterials Citation: St-Pierre J, Horejs C, Ojala JR, Wang AJ, Mazo MM, You AY, Von Erlach T, Tryggvason K and Stevens MM (2016). A biomaterials approach to interface cryptic laminin information with epithelial tissue as a strategy to counteract TGFbeta1-induced fibrosis. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.01636 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Mar 2016; Published Online: 30 Mar 2016. * Correspondence: Dr. Jean-Philippe St-Pierre, Imperial College London, Department of Materials, London, United Kingdom, Email1 Dr. Christine-Maria Horejs, Imperial College London, Department of Materials, London, United Kingdom, [email protected] Dr. Juha R Ojala, Karolinska Institutet, Department of Medical Biochemistry and Biophysics, Stockholm, Sweden, [email protected] Dr. Alex J Wang, Imperial College London, Department of Materials, London, United Kingdom, [email protected] Dr. Manuel M Mazo, Imperial College London, Department of Materials, London, United Kingdom, [email protected] Dr. Amanda Y You, Imperial College London, Department of Materials, London, United Kingdom, [email protected] Dr. Karl Tryggvason, Karolinska Institutet, Department of Medical Biochemistry and Biophysics, Stockholm, Sweden, [email protected] Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Jean-Philippe St-Pierre Christine-Maria Horejs Juha R Ojala Alex J Wang Manuel M Mazo Amanda Y You Thomas Von Erlach Karl Tryggvason Molly M Stevens Google Jean-Philippe St-Pierre Christine-Maria Horejs Juha R Ojala Alex J Wang Manuel M Mazo Amanda Y You Thomas Von Erlach Karl Tryggvason Molly M Stevens Google Scholar Jean-Philippe St-Pierre Christine-Maria Horejs Juha R Ojala Alex J Wang Manuel M Mazo Amanda Y You Thomas Von Erlach Karl Tryggvason Molly M Stevens PubMed Jean-Philippe St-Pierre Christine-Maria Horejs Juha R Ojala Alex J Wang Manuel M Mazo Amanda Y You Thomas Von Erlach Karl Tryggvason Molly M Stevens Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W2315724530