Abstract
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.
Highlights
Matrix metalloproteinases (MMPs) contribute to the breakdown of tissue structures such as the basement membrane, promoting tissue fibrosis
Increased levels of matrix metalloproteinases (MMPs) that degrade the basement membrane have been detected in a variety of fibrotic tissues, and it has been demonstrated that processes related to the epithelialto-mesenchymal transition (EMT)[2,3] can contribute to the accumulation of a-smooth muscle actin (a-SMA) expressing myofibroblasts in certain fibrotic phenotypes[4,5,6,7], for example, in peritoneal, pulmonary, liver and kidney fibrosis, while fatemapping studies identified diverse sources of myofibroblasts depending on methodology, tissue type and experimental model[8,9,10]
In this work, we developed a biomaterial-based strategy to inhibit tissue fibrosis using a biomimetic approach, whereby we interface epithelial cells with high concentrations of a cryptic fragment of the laminin b1-chain exposed by the action of MMP2, to elicit a specific inhibition of MMP2 activity, the gene and protein expression of epithelial-to-mesenchymal transition (EMT)-related molecules and morphological changes associated with fibrosis
Summary
Matrix metalloproteinases (MMPs) contribute to the breakdown of tissue structures such as the basement membrane, promoting tissue fibrosis. Our strategy aims to interface a cryptic recombinant laminin fragment with epithelial tissue via localized biomaterial delivery to circumvent off-target effects associated with the use of soluble compounds. This is achieved by the immobilization of the fragment on a flexible electrospun poly(e-caprolactone) (PCL) membrane[35] via the deposition of a polydopamine (pDA) coating[36]. In its current form, the material intervention presented here is suited for short-term interventions for relatively small tissue areas, such as is required for the prevention of peritoneal adhesions following abdominal surgeries, including minimization of local effects following the insertion of catheters for peritoneal dialysis
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