Regulating in Vitro Motility of Human Mesenchymal Stem Cells with Macrophage Migration Inhibitory Factor (MIF) and a Small-Molecule MIF Antagonist

Human mesenchymal stem cells (MSCs) from bone marrow possess a remarkable capacity to home to and regenerate damaged tissue, but the molecular mechanisms governing their migration and homing are not well defined. The present study reveals that a potent pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF), regulates in vitro chemokinesis of MSCs in a dose-dependent manner, inhibiting approximately 50% of migration at 100 ng/ml recombinant MIF. The small-molecule MIF antagonist (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1, 500 μg/μg rMIF) restores MSC migration to levels found in the absence of MIF. ISO-1 (85 μg/ml) increases migration to conditioned medium containing MIF from bronchial epithelial cells by ≥ 3-fold for a variety of donor MSC preparations (p < 0.05). Regulation of MIF signaling may be an effective method to control the innate homing response of MSCs and improve the efficacy of MSC therapies for injured lung and other damaged tissues.