Human multipotent adult progenitor cells modulate leukocyte extravasation by transcriptional regulation of fucosyltransferase VII (P5142)

Abstract

Abstract The targeted recruitment of leukocytes to sites of inflammation is a crucial event in normal host defense against pathogens, and attachment to and rolling on activated endothelial cells is a prerequisite first step required for eventual leukocyte extravasation into sites of inflammation. These first key events are mediated by interactions between sialylated ligands expressed on leukocytes and selectins expressed on activated endothelium. Cell surface expression of sialylated ligands on leukocytes is regulated by the rate-limiting enzyme fucosyltransferase VII (Fut7), and in its absence extravasation of leukocytes is severely inhibited. Intravenous administration of multipotent adult progenitor cells (MAPC), an adherent cell isolated from adult bone marrow, provides functional improvement in multiple preclinical models of injury or disease, but the mechanism(s) by which these outcomes are achieved remain poorly understood. In this manuscript, in vitro data are presented that characterize the ability of MAPC to secrete factor(s) that transcriptionally attenuate expression of Fut7 in T cells, thereby blocking sialylation of leukocyte cell surface-expressed selectin ligands and reducing T cell binding to endothelial cells. This represents the first example of a distinct regulatory mechanism involving transcriptional down-regulation of Fut7 by MAPC that could modulate the trafficking behavior of T cells in vivo.