Mesenchymal stem cells (MSCs) have been shown to migrate toward tumors, but their distribution pattern in gliomas has not been completely portrayed. The primary purpose of the study was to assay the tropism capacity of MSCs to gliomas, to delineate the pattern of MSC distribution in gliomas after systemic injection, and to track the migration and incorporation of magnetically labeled MSCs using 1.5-T magnetic resonance (MR) imaging.
The MSCs from Fischer 344 rats were colabeled with superparamagnetic iron oxide nanoparticles (SPIO) and enhanced green fluorescent protein (EGFP). The tropism capacity of MSCs was quantitatively assayed in vitro using the Transwell system. To track the migration of MSCs in vivo, MR imaging was performed both 7 and 14 days after systemic administration of labeled MSCs. After MR imaging, the distribution patterns of MSCs in rats with gliomas were examined using Prussian blue and fluorescence staining.
The in vitro study showed that MSCs possessed significantly greater migratory capacity than fibroblast cells (p < 0.001) and that lysis of F98 glioma cells and cultured F98 cells showed a greater capacity to induce migration of cells than other stimuli (p < 0.05). Seven days after MSC transplantation, the SPIO–EGFP colabeled cells were distributed throughout the tumor, where a well-defined dark hypointense region was represented on gradient echo sequences. After 14 days, most of the colabeled MSCs were found at the border between the tumor and normal parenchyma, which was represented on gradient echo sequences as diluted amorphous dark areas at the edge of the tumors.
This study demonstrated that systemically transplanted MSCs migrate toward gliomas with high specificity in a temporal–spatial pattern, which can be tracked using MR imaging.
Abbreviations used in this paper: DMEM = Dulbecco modified Eagle medium; EDTA = ethylenediaminetetraacetic acid; EGFP = enhanced green fluorescent protein; FBS = fetal bovine serum; MR = magnetic resonance; MSC = mesenchymal stem cell; NSC = neural stem cell; PBS = phosphate-buffered saline; PFA = paraformaldehyde; SDF-1 = stromal cell-derived factor-1; SPIO = super-paramagnetic iron oxide nanoparticles.
ArbabASBashawLAMillerBRJordanEKLewisBKKalishH: Characterization of biophysical and metabolic properties of cells labeled with superparamagnetic iron oxide nanoparticles and transfection agent for cellular MR imaging. Radiology229:838–8462003
ArbabASPanditSDAndersonSAYocumGTBurMFrenkelV: Magnetic resonance imaging and confocal microscopy studies of magnetically labeled endothelial progenitor cells trafficking to sites of tumor angiogenesis. Stem Cells24:671–6782006
ArbabASYocumGTRadAMKhakooAYFellowesVReadEJ: Labeling of cells with ferumoxides-protamine sulfate complexes does not inhibit function or differentiation capacity of hematopoietic or mesenchymal stem cells. NMR Biomed18:553–5592005
BarberoSBonaviaRBajettoAPorcileCPiraniPRavettiJL: Stromal cell-derived factor 1alpha stimulates human glioblastoma cell growth through the activation of both extracellular signal-regulated kinases 1/2 and Akt. Cancer Res63:1969–19742003
BrownABYangWSchmidtNOCarrollRLeishearKKRainovNG: Intravascular delivery of neural stem cell lines to target intracranial and extracranial tumors of neural and non-neural origin. Hum Gene Ther14:1777–17852003
De PalmaMVenneriMAGalliRSergiLSPolitiLSSampaolesiM: Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell8:211–2262005
DwengerARosenthalFMacheinMWallerCSpyridonidisA: Transplanted bone marrow cells preferentially home to the vessels of in situ generated murine tumors rather than of normal organs. Stem Cells22:86–922004
EhteshamMKabosPGutierrezMAChungNHGriffithTSBlackKL: Induction of glioblastoma apoptosis using neural stem cell-mediated delivery of tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res62:7170–71742002
HeeschenCLehmannRHonoldJAssmusBAicherAWalterDH: Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease. Circulation109:1615–16222004
ImitolaJRaddassiKParkKIMuellerFJNietoMTengYD: Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1α/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci U S A101:18117–181222004
LeeJElkahlounAGMessinaSAFerrariNXiDSmithCL: Cellular and genetic characterization of human adult bone marrow-derived neural stem-like cells: a potential antiglioma cellular vector. Cancer Res63:8877–88892003
LefrancFBrotchiJKissR: Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. J Clin Oncol23:2411–24222005
MatuszewskiLPersigehlTWallASchwindtWTombachBFobkerM: Cell tagging with clinically approved iron oxides: feasibility and effect of lipofection, particle size, and surface coating on labeling efficiency. Radiology235:155–1612005
RempelSADudasSGeSGutierrezJA: Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin Cancer Res6:102–1112000
RuzinovaMBSchoerRAGeraldWEganJEPandolfiPPRafiiS: Effect of angiogenesis inhibition by Id loss and the contribution of bone-marrow-derived endothelial cells in spontaneous murine tumors. Cancer Cell4:277–2892003
SalmaggiAGelatiMPolloBMarrasCSilvaniABalestriniMR: CXCL12 expression is predictive of a shorter time to tumor progression in low-grade glioma: a single-institution study in 50 patients. J Neurooncol74:287–2932005
SordiVMalosioMLMarchesiFMercalliAMelziRGiordanoT: Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets. Blood106:419–4272005
WynnRFHartCACorradi-PeriniCO'NeillLEvansCAWraithJE: A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow. Blood104:2643–26452004