Dynamics of Endothelial Engagement and Filopodia Formation in Complex 3D Microscaffolds
Abstract
The understanding of endothelium–extracellular matrix interactions during the initiation
of new blood vessels is of great medical importance; however, the mechanobiological principles
governing endothelial protrusive behaviours in 3D microtopographies remain imperfectly understood. In blood capillaries submitted to angiogenic factors (such as vascular endothelial growth
factor, VEGF), endothelial cells can transiently transdifferentiate in filopodia-rich cells, named tip
cells, from which angiogenesis processes are locally initiated. This protrusive state based on filopodia
dynamics contrasts with the lamellipodia-based endothelial cell migration on 2D substrates. Using
two-photon polymerization, we generated 3D microstructures triggering endothelial phenotypes
evocative of tip cell behaviour. Hexagonal lattices on pillars (“open”), but not “closed” hexagonal
lattices, induced engagement from the endothelial monolayer with the generation of numerous
filopodia. The development of image analysis tools for filopodia tracking allowed to probe the
influence of the microtopography (pore size, regular vs. elongated structures, role of the pillars)
on orientations, engagement and filopodia dynamics, and to identify MLCK (myosin light-chain
kinase) as a key player for filopodia-based protrusive mode. Importantly, these events occurred
independently of VEGF treatment, suggesting that the observed phenotype was induced through
microtopography. These microstructures are proposed as a model research tool for understanding
endothelial cell behaviour in 3D fibrillary network
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