Human mesenchymal stem cells (MSCs) from bone marrow stroma can home to and repair injured tissue, but the rate of engraftment is generally low. Regulating migration-related signaling of MSCs may be a powerful strategy to enhance this process. To gain insight into the molecular mechanisms governing homing, we identified negative factors affecting MSC migration using an in vitro model of injured lung. Heat-labile factors in bovine pituitary extract, a component of serum-free epithelial medium, inhibited more than 97% of MSC migration. This was partly due to a dose-dependent response to macrophage migration inhibitory factor (MIF). Eighty-five ng/mL recombinant MIF, the concentration found in the epithelial medium, inhibited about 50% of MSC migration. Media conditioning by uninjured or bleomycin-injured bronchial epithelial cells partially attenuated this suppressive effect. Additionally, the anti-inflammatory agent ISO-1, a small-molecule MIF antagonist, further increased MSC migration by nearly fourfold in conditioned epithelial media. This is the first report of the effect of MIF and ISO-1 on MSC migration, and the data suggest that MIF and its antagonists may have therapeutic applications in controlling MSC homing during repair of injured lung and in other clinically relevant systems.
Get full access to this article
View all access options for this article.
References
1.
BarrilleauxB., PhinneyD.G., ProckopD.J., O'ConnorK.C.Review: ex vivo engineering of living tissues with adult stem cells. Tissue Eng, 12:3007. 2006.
2.
YoonS.J., ParkK.S., KimM.S., RheeJ.M., KhangG., LeeH.B.Repair of diaphyseal bone defects with calcitriol-loaded PLGA scaffolds and marrow stromal cells. Tissue Eng, 13:1125. 2007.
3.
AndoW., TateishiK., HartD.A., KatakaiD., TanakaY., NakataK., HashimotoJ., FujieH., ShinoK., YoshikawaH., NakamuraN.Cartilage repair using an in vitro generated scaffold-free tissue-engineered construct derived from porcine synovial mesenchymal stem cells. Biomaterials, 28:5462. 2007.
4.
ZhaoL.R., DuanW.M., ReyesM., KeeneC.D., VerfaillieC.M., LowW.C.Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp Neurol, 174:11. 2002.
5.
SasakiM., AbeR., FujitaY., AndoS., InokumaD., ShimizuH.Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J Immunol, 180:2581. 2008.
6.
GuptaN., SuX., PopovB., LeeJ.W., SerikovV., MatthayM.A.Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol, 179:1855. 2007.
7.
OrtizL.A., GambelliF., McBrideC., GauppD., BaddooM., KaminskiN., PhinneyD.G.Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci USA, 100:8407. 2003.
8.
AliottaJ.M., Sanchez-GuijoF.M., DoonerG.J., JohnsonK.W., DoonerM.S., GreerK.A., GreerD., PimentelJ., KolankiewiczL.M., PuenteN., FaradyanS., FerlandP., BearerE.L., PasseroM.A., AdediM., ColvinG.A., QuesenberryP.J.Alteration of marrow cell gene expression, protein production, and engraftment into lung by lung-derived microvesicles: a novel mechanism for phenotype modulation. Stem Cells, 25:2245. 2007.
9.
WangG., BunnellB.A., PainterR.G., QuinionesB.C., TomS., LansonN.A.Jr., SpeesJ.L., BertucciD., PeisterA., WeissD.J., ValentineV.G., ProckopD.J., KollsJ.K.Adult stem cells from bone marrow stroma differentiate into airway epithelial cells: potential therapy for cystic fibrosis. Proc Natl Acad Sci USA, 102:186. 2005.
10.
OrtizL.A., DutreilM., FattmanC., PandeyA.C., TorresG., GoK., PhinneyD.G.Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci USA, 104:11002. 2007.
11.
SpeesJ.L., OlsonS.D., YlostaloJ., LynchP.J., SmithJ., PerryA., PeisterA., WangM.Y., ProckopD.J.Differentiation, cell fusion, and nuclear fusion during ex vivo repair of epithelium by human adult stem cells from bone marrow stroma. Proc Natl Acad Sci USA, 100:2397. 2003.
12.
RojasM., XuJ., WoodsC.R., MoraA.L., SpearsW., RomanJ., BrighamK.L.Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol, 33:145. 2005.
13.
OzakiY., NishimuraM., SekiyaK., SuehiroF., KanawaM., NikawaH., HamadaT., KatoY.Comprehensive analysis of chemotactic factors for bone marrow mesenchymal stem cells. Stem Cells Dev, 16:119. 2007.
14.
PonteA.L., MaraisE., GallayN., LangonneA., DelormeB., HeraultO., CharbordP., DomenechJ.The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem Cells, 25:1737. 2007.
EscribeseM.M., CondeE., Saenz-MoralesD., HordijkP.L., Garcia-BermejoM.L.Mononuclear cell extravasation in an inflammatory response is abrogated by all-trans-retinoic acid through inhibiting the acquisition of an appropriate migratory phenotype. J Pharmacol Exp Ther, 324:454. 2008.
17.
BernhagenJ., KrohnR., LueH., GregoryJ.L., ZerneckeA., KoenenR.R., DeworM., GeorgievI., SchoberA., LengL., KooistraT., Fingerle-RowsonG., GhezziP., KleemannR., McCollS.R., BucalaR., HickeyM.J., WeberC.MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med, 13:587. 2007.
18.
IshiiM., KoikeC., IgarashiA., YamanakaK., PanH., HigashiY., KawaguchiH., SugiyamaM., KamataN., IwataT., MatsubaraT., NakamuraK., KuriharaH., TsujiK., KatoY.Molecular markers distinguish bone marrow mesenchymal stem cells from fibroblasts. Biochem Biophys Res Commun, 332:297. 2005.
19.
RingeJ., StrassburgS., NeumannK., EndresM., NotterM., BurmesterG.R., KapsC., SittingerM.Towards in situ tissue repair: human mesenchymal stem cells express chemokine receptors CXCR1, CXCR2 and CCR2, and migrate upon stimulation with CXCL8 but not CCL2. J Cell Biochem, 101:135. 2007.
LengL., BucalaR.Insight into the biology of macrophage migration inhibitory factor (MIF) revealed by the cloning of its cell surface receptor. Cell Res, 16:162. 2006.
Al-AbedY., DabideenD., AljabariB., ValsterA., MessmerD., OchaniM., TanovicM., OchaniK., BacherM., NicolettiF., MetzC., PavlovV.A., MillerE.J., TraceyK.J.ISO-1 binding to the tautomerase active site of MIF inhibits its pro-inflammatory activity and increases survival in severe sepsis. J Biol Chem, 280:36541. 2005.
24.
KarpP.H., MoningerT.O., WeberS.P., NesselhaufT.S., LaunspachJ.L., ZabnerJ., WelshM.J.An in vitro model of differentiated human airway epithelia. Methods for establishing primary cultures. Methods Mol Biol, 188:115. 2002.
25.
SekiyaI., LarsonB.L., SmithJ.R., PochampallyR., CuiJ.G., ProckopD.J.Expansion of human adult stem cells from bone marrow stroma: conditions that maximize the yields of early progenitors and evaluate their quality. Stem Cells, 20:530. 2002.
26.
GrayT.E., GuzmanK., DavisC.W., AbdullahL.H., NettesheimP.Mucociliary differentiation of serially passaged normal human tracheobronchial epithelial cells. Am J Respir Cell Mol Biol, 14:104. 1996.
27.
HendrixM.J., SeftorE.A., SeftorR.E., FidlerI.J.A simple quantitative assay for studying the invasive potential of high and low human metastatic variants. Cancer Lett, 38:137. 1987.
LeeW.K., AbouhamedM., ThevenodF.Caspase-dependent and -independent pathways for cadmium-induced apoptosis in cultured kidney proximal tubule cells. Am J Physiol Renal Physiol, 291:F823. 2006.
30.
CowgerN.L., O'ConnorK.C., HammondT.G., LacksD.J., NavarG.L.Characterization of bimodal cell death of insect cells in a rotating-wall vessel and shaker flask. Biotechnol Bioeng, 64:14. 1999.
31.
ColterD.C., SekiyaI., ProckopD.J.Identification of a subpopulation of rapidly self-renewing and multipotential adult stem cells in colonies of human marrow stromal cells. Proc Natl Acad Sci USA, 98:7841. 2001.
32.
DenkerA.E., HaasA.R., NicollS.B., TuanR.S.Chondrogenic differentiation of murine C3H10T1/2 multipotential mesenchymal cells: I. Stimulation by bone morphogenetic protein-2 in high-density micromass cultures. Differentiation, 64:67. 1999.
33.
SekiyaI., LarsonB.L., VuoristoJ.T., RegerR.L., ProckopD.J.Comparison of effect of BMP-2, -4, and -6 on in vitro cartilage formation of human adult stem cells from bone marrow stroma. Cell Tissue Res, 320:269. 2005.
34.
ClejanS., O'ConnorK.C., CowgerN.L., ChelesM.K., HaqueS., PrimaveraA.C.Effects of simulated microgravity on DU 145 human prostate carcinoma cells. Biotechnol Bioeng, 50:587. 1996.
35.
KrunkoskyT.M., FischerB.M., MartinL.D., JonesN., AkleyN.J., AdlerK.B.Effects of TNF-alpha on expression of ICAM-1 in human airway epithelial cells in vitro. Am J Respir Cell Mol Biol, 22:685. 2000.
36.
BancroftJ.D. and GambleM.Theory and Practice of Histological Techniques. Churchill, Livingstone, London:UK. 2002.
37.
TomchuckS.L., ZwezdarykK.J., CoffeltS.B., WatermanR.S., DankaE.S., ScandurroA.B.Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses. Stem Cells, 26:99. 2008.
38.
KentK.D. and BomserJ.A.Bovine pituitary extract provides remarkable protection against oxidative stress in human prostate epithelial cells. In Vitro Cell Dev Biol Anim, 39:388. 2003.
39.
SwopeM., SunH.W., BlakeP.R., LolisE.Direct link between cytokine activity and a catalytic site for macrophage migration inhibitory factor. EMBO J, 17:3534. 1998.
40.
LubetskyJ.B., DiosA., HanJ., AljabariB., RuzsicskaB., MitchellR., LolisE., Al-AbedY.The tautomerase active site of macrophage migration inhibitory factor is a potential target for discovery of novel anti-inflammatory agents. J Biol Chem, 277:24976. 2002.
41.
DenefC.Paracrinicity: the story of 30 years of cellular pituitary crosstalk. J Neuroendocrinol, 20:1. 2008.
42.
von OtteS., PalettaJ.R., BeckerS., KonigS., FobkerM., GrebR.R., KieselL., AssmannG., DiedrichK., NoferJ.R.Follicular fluid high density lipoprotein-associated sphingosine 1-phosphate is a novel mediator of ovarian angiogenesis. J Biol Chem, 281:5398. 2006.
43.
NoguchiY., OkamotoA., KasamaT., Imajoh-OhmiS., KaratsuT., NogawaH.Lysophosphatidic acid cooperates with EGF in inducing branching morphogenesis of embryonic mouse salivary epithelium. Dev Dyn, 235:403. 2006.
44.
NishinoT., BernhagenJ., ShiikiH., CalandraT., DohiK., BucalaR.Localization of macrophage migration inhibitory factor (MIF) to secretory granules within the corticotrophic and thyrotrophic cells of the pituitary gland. Mol Med, 1:781. 1995.
45.
Meyer-SieglerK.L., IczkowskiK.A., LengL., BucalaR., VeraP.L.Inhibition of macrophage migration inhibitory factor or its receptor (CD74) attenuates growth and invasion of DU-145 prostate cancer cells. J Immunol, 177:8730. 2006.
46.
OnoderaS., NishihiraJ., YamazakiM., IshibashiT., MinamiA.Increased expression of macrophage migration inhibitory factor during fracture healing in rats. Histochem Cell Biol, 121:209. 2004.
47.
OnoderaS., NishihiraJ., IwabuchiK., KoyamaY., YoshidaK., TanakaS., MinamiA.Macrophage migration inhibitory factor up-regulates matrix metalloproteinase-9 and -13 in rat osteoblasts. Relevance to intracellular signaling pathways. J Biol Chem, 277:7865. 2002.
48.
MerchantS., NadarajS., ChowdhuryD., ParnellV.A., SisonC., MillerE.J., OjamaaK.Macrophage migration inhibitory factor in pediatric patients undergoing surgery for congenital heart repair. Mol Med, 14:124. 2008.
49.
EmontsM., SweepF.C., GrebenchtchikovN., Geurts-MoespotA., KnaupM., ChansonA.L., ErardV., RennerP., HermansP.W., HazelzetJ.A., CalandraT.Association between high levels of blood macrophage migration inhibitory factor, inappropriate adrenal response, and early death in patients with severe sepsis. Clin Infect Dis, 44:1321. 2007.
LueH., ThieleM., FranzJ., DahlE., SpeckgensS., LengL., Fingerle-RowsonG., BucalaR., LuscherB., BernhagenJ.Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity. Oncogene, 26:5046. 2007.
55.
ChengK.F., Al-AbedY.Critical modifications of the ISO-1 scaffold improve its potent inhibition of macrophage migration inhibitory factor (MIF) tautomerase activity. Bioorg Med Chem Lett, 16:3376. 2006.
56.
QuintavallaJ., Uziel-FusiS., YinJ., BoehnleinE., PastorG., BlancuzziV., SinghH.N., KrausK.H., O'ByrneE., PellasT.C.Fluorescently labeled mesenchymal stem cells (MSCs) maintain multilineage potential and can be detected following implantation into articular cartilage defects. Biomaterials, 23:109. 2002.
57.
TaninoY., MakitaH., MiyamotoK., BetsuyakuT., OhtsukaY., NishihiraJ., NishimuraM.Role of macrophage migration inhibitory factor in bleomycin-induced lung injury and fibrosis in mice. Am J Physiol Lung Cell Mol Physiol, 283:L156. 2002.
58.
OnoderaS., OhshimaS., TohyamaH., YasudaK., NishihiraJ., IwakuraY., MatsudaI., MinamiA., KoyamaY.A novel DNA vaccine targeting macrophage migration inhibitory factor protects joints from inflammation and destruction in murine models of arthritis. Arthritis Rheum, 56:521. 2007.
59.
ZhengZ.H., LiX.Y., DingJ., JiaJ.F., ZhuP.Allogeneic mesenchymal stem cell and mesenchymal stem cell-differentiated chondrocyte suppress the responses of type II collagen-reactive T cells in rheumatoid arthritis. Rheumatology (Oxf ), 47:22. 2008.
60.
KucerovaL., AltanerovaV., MatuskovaM., TyciakovaS., AltanerC.Adipose tissue-derived human mesenchymal stem cells mediated prodrug cancer gene therapy. Cancer Res, 67:6304. 2007.
61.
RendonB.E., RogerT., TenengI., ZhaoM., Al-AbedY., CalandraT., MitchellR.A.Regulation of human lung adenocarcinoma cell migration and invasion by macrophage migration inhibitory factor. J Biol Chem, 282:29910. 2007.
