Gregory G Burrows1, Richard T Maziarz2, Karen Hunady3, Nicholas Lehman3, Amy Raber3, Robert J Deans4, Wouter Van't Hof4. 1. Center for Hematologic Malignancies, Division of Hematology & Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA; Department of Neurology, Oregon Health & Science University, Portland, Oregon, USA; Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, Oregon, USA. Electronic address: ggb@ohsu.edu. 2. Department of Neurology, Oregon Health & Science University, Portland, Oregon, USA. 3. Athersys Inc., Regenerative Medicine Program, Cleveland, Ohio, USA. 4. Athersys Inc., Regenerative Medicine Program, Cleveland, Ohio, USA; National Center for Regenerative Medicine, Cleveland, Ohio, USA.
Abstract
BACKGROUND AIMS: 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 for eventual leukocyte extravasation into sites of inflammation. These key events are mediated by interactions between glycosylated ligands expressed on leukocytes and selectins expressed on activated endothelium. Cell surface expression of selectin ligands on leukocytes is regulated by the rate-limiting enzyme fucosyltransferase VII (Fut7), and in its absence extravasation of leukocytes is severely inhibited. Multipotent adult progenitor cells (MAPCs) are an adherent cell population isolated from adult bone marrow. Intravenous administration of MAPCs provided functional improvement in multiple pre-clinical models of injury or disease, but the mechanisms by which these outcomes were achieved remain poorly understood. METHODS: In vitro cell analysis studies including fluorescence-activated cell sorting, messenger RNA analysis, T-cell proliferation assays and endothelial cell binding assays were performed. RESULTS: The in vitro cell analysis studies characterized the ability of MAPCs to secrete factors that transcriptionally attenuate expression of Fut7 in T cells, blocking the terminal fucosylation event in the biosynthesis of selectin ligands and reducing T-cell binding to endothelial cells. CONCLUSIONS: This study presents the first example of a distinct regulatory mechanism involving transcriptional down-regulation of Fut7 by MAPCs that could modulate the trafficking behavior of T cells in vivo.
BACKGROUND AIMS: 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 for eventual leukocyte extravasation into sites of inflammation. These key events are mediated by interactions between glycosylated ligands expressed on leukocytes and selectins expressed on activated endothelium. Cell surface expression of selectin ligands on leukocytes is regulated by the rate-limiting enzyme fucosyltransferase VII (Fut7), and in its absence extravasation of leukocytes is severely inhibited. Multipotent adult progenitor cells (MAPCs) are an adherent cell population isolated from adult bone marrow. Intravenous administration of MAPCs provided functional improvement in multiple pre-clinical models of injury or disease, but the mechanisms by which these outcomes were achieved remain poorly understood. METHODS: In vitro cell analysis studies including fluorescence-activated cell sorting, messenger RNA analysis, T-cell proliferation assays and endothelial cell binding assays were performed. RESULTS: The in vitro cell analysis studies characterized the ability of MAPCs to secrete factors that transcriptionally attenuate expression of Fut7 in T cells, blocking the terminal fucosylation event in the biosynthesis of selectin ligands and reducing T-cell binding to endothelial cells. CONCLUSIONS: This study presents the first example of a distinct regulatory mechanism involving transcriptional down-regulation of Fut7 by MAPCs that could modulate the trafficking behavior of T cells in vivo.
Authors: Gregory G Burrows; Wouter Van't Hof; Ashok P Reddy; Phillip A Wilmarth; Larry L David; Amy Raber; Annelies Bogaerts; Lien Timmerman; Jef Pinxteren; Valerie D Roobrouck; Robert J Deans; Richard T Maziarz Journal: Stem Cells Transl Med Date: 2015-10-22 Impact factor: 6.940
Authors: Ekaterina Minskaia; Barbara C Saraiva; Maria M V Soares; Rita I Azevedo; Ruy M Ribeiro; Saumya D Kumar; Ana I S Vieira; João F Lacerda Journal: Front Immunol Date: 2018-11-05 Impact factor: 7.561