Mimicking the extracellular matrix – a biomaterials approach to inhibit tissue fibrosis

Epithelial tissue is marked by the presence of a specialized, highly cross-linked, sheet-like extracellular matrix, the basement membrane. Tissue-invasive events, such as the epithelial-to-mesenchymal transition (EMT) - a key event in gastrulation, tissue fibrosis and cancer metastasis – are characterized by irreversible structural changes of the basement membrane through proteolytic processing by matrix metalloproteinases (MMPs). We have recently reported a previously unidentified laminin fragment that is released during EMT by MMP2 and that modulates key EMT-signalling pathways. Specifically, interaction of the laminin fragment with α3β1-integrin triggers the down-regulation of MMP2 expression, thereby constituting a cell-basement membrane-cell feedback mechanism. Inhibiting MMPs has been proposed as a strategy to prevent pathological cell migration and basement membrane breakdown in the course of EMT. Here, we explore this cell-matrix-cell feedback mechanism to target pathological EMT in the course of tissue fibrosis. We present an electrospun biomaterial that is functionalized with the recombinant laminin fragment and that can be directly interfaced with epithelial tissue to interfere with EMT pathways and inhibit MMP2 expression and activity in vitro and in vivo. We demonstrate how interaction of the functionalized synthetic membrane with peritoneal tissue inhibits mesothelial EMT in a mouse model of TGFβ-induced peritoneal fibrosis by decreasing active MMP2 levels, and propose a mechanism of how the laminin fragment acts downstream of α3β1-integrin in epithelial cells, after it is released from the basement membrane

A designer peptide as a template for growing Au nanoclusters

A peptide was designed to generate a sub-nanometric template that guides the growth of fluorescent gold nanoclusters. The peptide was endorsed with nucleating moieties and a three-dimensional structure that arrests the growth of ultrasmall nanoparticles. The nanoclusters are not cytotoxic and can be found in the cytosol of cells

Preventing tissue fibrosis by local biomaterials interfacing of specific cryptic extracellular matrix information

Matrix metalloproteinases (MMPs) contribute to the breakdown of tissue structures such as the basement membrane, promoting tissue fibrosis. Here we developed an electrospun membrane biofunctionalized with a fragment of the laminin β1-chain to modulate the expression of MMP2 in this context. We demonstrate that interfacing of the β1-fragment with the mesothelium of the peritoneal membrane via a biomaterial abrogates the release of active MMP2 in response to transforming growth factor β1 and rescues tissue integrity ex vivo and in vivo in a mouse model of peritoneal fibrosis. Importantly, our data demonstrate that the membrane inhibits MMP2 expression. Changes in the expression of epithelial-to-mesenchymal transition (EMT)-related molecules further point towards a contribution of the modulation of EMT. Biomaterial-based presentation of regulatory basement membrane signals directly addresses limitations of current therapeutic approaches by enabling a localized and specific method to counteract MMP2 release applicable to a broad range of therapeutic targets.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). M.M.S. also acknowledges the grant ‘State of the Art Biomaterials Development and Characterization of the Cell-Biomaterial Interface’ (MR/L012677/1) from the Medical Research Council. J.-P.S. and M.M.S. were also supported by the Medical Engineering Solutions in the Osteoarthritis Centre of Excellence, funded by the Wellcome Trust and the Engineering and Physical Sciences Research Council (EPSRC) (088844).Peer Reviewe

Preventing tissue fibrosis by local biomaterials interfacing of specific cryptic extracellular matrix information

Matrix metalloproteinases (MMPs) contribute to the breakdown of tissue structures such as the basement membrane, promoting tissue fibrosis. Here we developed an electrospun membrane biofunctionalized with a fragment of the laminin b1-chain to modulate the expression of MMP2 in this context. We demonstrate that interfacing of the b1-fragment with the mesothelium of the peritoneal membrane via a biomaterial abrogates the release of active MMP2 in response to transforming growth factor b1 and rescues tissue integrity ex vivo and in vivo in a mouse model of peritoneal fibrosis. Importantly, our data demonstrate that the membrane inhibits MMP2 expression. Changes in the expression of epithelial-to-mesenchymal transition (EMT)-related molecules further point towards a contribution of the modulation of EMT. Biomaterial-based presentation of regulatory basement membrane signals directly addresses limitations of current therapeutic approaches by enabling a localized and specific method to counteract MMP2 release applicable to a broad range of therapeutic targets

Cell-geometry-dependent changes in plasma membrane order direct stem cell signalling and fate

Cell size and shape affect cellular processes such as cell survival, growth and differentiation1,2,3,4, thus establishing cell geometry as a fundamental regulator of cell physiology. The contributions of the cytoskeleton, specifically actomyosin tension, to these effects have been described, but the exact biophysical mechanisms that translate changes in cell geometry to changes in cell behaviour remain mostly unresolved. Using a variety of innovative materials techniques, we demonstrate that the nanostructure and lipid assembly within the cell plasma membrane are regulated by cell geometry in a ligand-independent manner. These biophysical changes trigger signalling events involving the serine/threonine kinase Akt/protein kinase B (PKB) that direct cell-geometry-dependent mesenchymal stem cell differentiation. Our study defines a central regulatory role by plasma membrane ordered lipid raft microdomains in modulating stem cell differentiation with potential translational applications