title: Migratory response of mesenchymal stem cells to macrophage migration inhibitory factor and its antagonist as a function of colony-forming efficiency.
abstract: Human mesenchymal stem cells (MSCs) are capable of repairing pulmonary disorders, but their efficacy is limited by poor engraftment. A strategy is proposed to augment MSC migration to lung tissue by antagonizing macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine. Recombinant MIF (85 ng/ml) inhibited in vitro chemokinesis of multipotent MSCs by nearly 50 and 20% for donor preparations with colony-forming efficiencies of 22 +/- 4% and 66 +/- 3%, respectively (P < 0.05). The small-molecule MIF antagonist, (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1, 85 microg/ml), restored MSC migration for all donors to levels found in the absence of MIF. At this concentration, ISO-1 increased migration to conditioned medium from bronchial epithelial cell cultures by >or=3-fold for all donor MSC preparations (P < 0.05). Transcript levels for the MIF receptor, CD74, in MSCs were independent of colony-forming efficiency. These data suggest that MIF and its antagonists may be relevant to the control of MSC homing and efficacy of stem cell therapies in a variety of clinical scenarios.
authors.affiliation: Department of Chemical and Biomolecular Engineering, Tulane University, New Orleans, LA, 70118, USA.
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Fischer-Valuck
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Barrilleaux
authors.forename: Donald G
authors.initials: DG
authors.lastname: Phinney
authors.forename: Katie C
authors.initials: KC
authors.lastname: Russell
authors.forename: Darwin J
authors.initials: DJ
authors.lastname: Prockop
authors.forename: Kim C
authors.initials: KC
authors.lastname: O'Connor
mesh_terms: D050156:Adipogenesis / Q000187:drug effects; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D016130:Immunophenotyping; D007555:Isoxazoles / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D011994:Recombinant Proteins; C045084:invariant chain