Activation of CD74 inhibits migration of human mesenchymal stem cells.
Therapeutic administration of mesenchymal stem cells (MSCs) by systemic delivery utilizes the innate ability of the cells to home to damaged tissues, but it can be an inefficient process due to a limited knowledge of cellular cues that regulate migration and homing. Our lab recently discovered that a potent pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF), inhibits MSC migration. Because MIF may act on multiple cellular targets, an activating antibody (CD74Ab) was employed in this study to examine the effect of one MIF receptor, CD74 (major histocompatibility complex class II-associated invariant chain), on MSC motility. CD74 activation inhibits in a dose-dependent manner up to 90% of in vitro migration of MSCs at 40 mug/ml CD74Ab (p < 0.001), with consistent effects observed among three MSC donor preparations. A blocking peptide from the C-terminus of CD74 eliminates the effect of CD74Ab on MSCs. This suggests that MIF may act on MSCs, at least in part, through CD74. Late-passage MSCs exhibit less chemokinesis than those at passage 2. However, MSCs remain responsive to CD74 activation during ex vivo expansion: MSC migration is inhibited approximately 2-fold in the presence of 5 microg/ml CD74Ab at passage 9 vs. approximately 3-fold at passage 2 (p < 0.001). Consistent with this result, there were no significant differences in CD74 expression at all tested passages or after CD74Ab exposure. Targeting CD74 to regulate migration and homing potentially may be a useful strategy to improve the efficacy of a variety of MSC therapies, including those that require ex vivo expansion.
Barrilleaux
Bonnie L
BL
Department of Chemical and Biomolecular Engineering, Tulane University, Lindy Boggs Center Room 300, New Orleans, LA 70118, USA.
Fischer-Valuck
Benjamin W
BW
Gilliam
Jennifer K
JK
Phinney
Donald G
DG
O'Connor
Kim C
KC
D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D002454:Cell Differentiation; D002465:Cell Movement; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism
D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; C045084:invariant chain