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Polymeric meshes induce zonal regulation of matrix metalloproteinase-2 gene expression by macrophages and fibroblasts

Petra Lynen Jansen^*,1, Mona Kever, Raphael Rosch, Ellen Krott, Marc Jansen, Alexandra Alfonso-Jaume, Steven Dooley, Uwe Klinge, David H. Lovett^|| and Peter R. Mertens^¶

^* Interdisciplinary Center for Clinical Research BIOMAT, Aachen, Germany;

Department of Surgery, University Hospital, RWTH Aachen, Germany;

Department of Medicine, Williams Middleton Memorial, University of Wisconsin, Madison, Wisconsin, USA;

Department of Medicine II, University Hospital, Mannheim, Germany;

^|| Department of Medicine, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, California, USA; and

^¶ Department of Nephrology and Clinical Immunology, University Hospital, Aachen, Germany

¹Correspondence: Interdisciplinary Center for Clinical Research BIOMAT, University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany. E-mail: plynen{at}ukaachen.de

Matrix metalloproteinase-2 (MMP-2) is a key regulator in wound healing that orchestrates tissue remodeling. In the present study the spatial and temporal distribution of MMP-2 gene transcription, protein synthesis, and enzymatic activity were analyzed following polymeric mesh (polyglactin, polypropylene) implantation in transgenic reporter mice harboring MMP-2 regulatory sequences –1686/+423 or –1241/+423. Polymers induced MMP-2 promoter activity in macrophages within the foreign body granuloma via sequences –1686/+423 with concomitantly up-regulated protein synthesis and enzymatic activity. Macrophages distant from mesh filaments exhibited low MMP-2 expression levels. Fibroblasts surrounding mesh material displayed strong MMP-2 gene transcription independent of the included promoter sequences, whereas fibroblasts without close contact to mesh material had low MMP-2 synthesis rates due to silencing activity of sequences –1686/–1241. In vitro studies support a cellular crosstalk concept, as macrophages trans-repressed MMP-2 gene transcription in fibroblasts. The zonal and cell-specific regulation of MMP-2 gene transcription illuminates an intimate cellular crosstalk in foreign body reaction that may provide a new approach for mesh modification.—Jansen, P. L., Kever, M., Rosch, R., Krott, E., Jansen, M., Alfonso-Jaume, A., Dooley, S., Klinge, U., Lovett, D. H., Mertens, P. R. Polymeric meshes induce zonal regulation of matrix metalloproteinase-2 gene expression by macrophages and fibroblasts.

Key Words: polymers • wound healing • cell-specific gene regulation • transgene