Time-Dependent Extracellular Matrix Organization and Secretion from Vascular Endothelial Cells due to Macromolecular Cro
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Time-Dependent Extracellular Matrix Organization and Secretion from Vascular Endothelial Cells due to Macromolecular Crowding Frances D. Liu,1,2 Adam S. Zeiger,2,3 and Krystyn J. Van Vliet1,2,3 1
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 2 Biosystems & Micromechanics Interdisciplinary Research Group (BioSyM), Singapore-MIT Alliance in Research & Technology (SMART), Singapore 3 Department of Materials Science & Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 ABSTRACT
Interactions between biological cells and surrounding extracellular matrix (ECM) materials modulate many cell behaviors including adhesion and migration. One key example of this cellmatrix reciprocity is in the context of angiogenesis, the sprouting of new blood vessels from preexisting vasculature. Vascular endothelial cells (VECs) create and remodel the ECM during this process. In vivo, the surrounding fluid environment includes high concentrations of macromolecules, and is considered “crowded” in comparison to in vitro environments. Here, we quantified the amount and organization of collagen IV, a prominent ECM component of VECs, that was produced by these cells over four weeks in vitro in the presence or absence of macromolecular crowder (MMC) nanoparticles that approximated in vivo crowding. In the presence of MMCs, the amount and degree of alignment of collagen IV was greater. This ECM difference emerged within one week and was sustained for over four weeks. We explored the effect of initial cell density (cells/µm2) on this matrix production, to consider potential differences at a wound site versus an intact vessel. Moreover, we found the biophysical effect of MMCs to be unmodulated by secretions from an adjacent cell type in microvessels (pericytes). These results suggest that macromolecular crowding plays a direct role in remodeling the basement membrane, and that such crowding can be induced in vitro to more closely approximate the cell microenvironment. INTRODUCTION
Angiogenesis, the formation of new blood vessels extending from existing vasculature, is a complex process involving several potential cues at the molecular interfaces between cells and surrounding materials. Vascular endothelial cells (VECs) comprise the primary cell type that lines microvessel walls and secretes extracellular matrix (ECM) proteins [1], along with other vessel-associated cell types including pericytes (see Fig. 1). Although substantial previous work has explored biochemical and mechanical modulation of this process – including historical emphasis on therapies that modulate the type and amount of molecules the cells secrete or take up – there is increasing focus on direct manipulation of the cell-ECM microenvironment [2]. Here, we present and analyze a novel means to manipulate the organization of the VECs’ extracellular matrix via macromolecular crowding of the aqueous fluid surrounding these cells in vitro. This approach provides one way to promote self-assembly of a microvessel EC
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