Elucidating the contributions of cellular and microenvironment characteristics on cell adhesion processes in flow

Abstract

Circulating cell recruitment is critical to a variety of physiological and pathophysiological processes and occurs amidst the high shear environment of the vasculature via a multistep rolling to firm adhesion cascade. Cells initially engage the vascular endothelium through interactions between endothelial-presented selectins and their corresponding ligands presented by circulating cells. These interactions precede firm adhesion and arrest and eventually transmigration across the endothelium for tissue infiltration. Since many cell subtypes including leukocytes and metastatic cancer cells employ this mechanism to facilitate their escape the vasculature, understanding differences in cell-subtype adhesive behavior can inform the development of targeted therapeutics that interfere with metastatic cell transport, while leaving physiologically important immune cell recruitment mechanisms intact. As such, the overall objective of this work was to explore how selectin-mediated adhesion 1) is regulated by the biochemical and biophysical microenvironment of the vasculature and 2) varies among different cell subtypes and 3) with characteristics of circulating cells. Through the use of in vitro fluidic methodologies in conjunction with innovative single-cell analyses we have begun to elucidate key differences in the selectin-dependent adhesive behavior of metastatic versus leukocytic cells and identified potential molecular regulators of enhanced rolling adhesion behavior, which may serve as targets in the development of pharmacologic agents aimed at reducing selectin-mediated adhesion of clinically challenging cell subtypes.