title: Specific chemotaxis of magnetically labeled mesenchymal stem cells: implications for MRI of glioma.
abstract: OBJECTIVE
  Glioblastoma multiforme (GBM) is a lethal disease marked by infiltration of cancerous cells into the surrounding normal brain. The dire outcome of GBM patients stems in part from the limitations of current neuroimaging methods. Notably, early cancer detection methodologies are lacking, without the ability to identify aggressive, metastatic tumor cells. We propose a novel approach for tumor detection using magnetic resonance imaging (MRI) based on imaging specific tumor tropism of mesenchymal stem cells (MSCs) labeled with micron-sized iron oxide particles (MPIOs).
  
  
  METHODS
  MPIO labeled and unlabeled MSCs were compared for viability, multi-lineage differentiation, and migration, where both chemotactic and chemokinetic movement were assessed in the presence of serum-free medium, serum-containing medium, and glioma-conditioned medium. MRI was performed on agarose samples, consisting of MPIO-labeled single MSCs, to confirm the capability to detect single cells.
  
  
  RESULTS
  We determined that MPIO-labeled MSCs exhibit specific and significant chemotactic migration towards glioma-conditioned medium in vitro. Confocal fluorescence microscopy confirmed that MPIOs are internalized and do not impact important cell processes of MSCs. Lastly, MPIO-labeled MSCs appear as single distinct, dark spots on T(2)*-weighted MRI, supporting the robustness of this contrast agent for cell tracking.
  
  
  CONCLUSIONS
  This is the first study to show that MPIO-labeled MSCs exhibit specific tropism toward tumor-secreted factors in vitro. The potential for detecting single MPIO-labeled MSCs provides rationale for in vivo extension of this methodology to visualize GBM in animal models.
authors.affiliation: Department of Biomedical Engineering, Yale University, 300 Cedar Street, New Haven, CT 06510, USA.
authors.forename: Margaret F
authors.initials: MF
authors.lastname: Bennewitz
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Tang
authors.forename: Eleni A
authors.initials: EA
authors.lastname: Markakis
authors.forename: Erik M
authors.initials: EM
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D054443:Cell Migration Assays; D002633:Chemotaxis; D003911:Dextrans / Q000378:metabolism; D005260:Female; D005910:Glioma / Q000473:pathology*; D060328:Magnetic Phenomena; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D051381:Rats; D011916:Rats, Inbred F344; D013194:Staining and Labeling
chemical_list: D003911:Dextrans; D058185:Magnetite Nanoparticles; C065507:ferumoxides