The purpose of this study was to label human monocytes with Gadofluorine M by simple incubation for subsequent cell depiction at 1.5 and 3 T. Gadofluorine M displays a high r(1) relaxivity and is spontaneously phagocytosed by macrophages. Human monocytes were incubated with Gadofluorine M-Cy at varying concentrations and incubation times and underwent MR imaging at 1.5 and 3 T at increasing time intervals after the labeling procedure. R1-relaxation rates and r1 relaxivities of the labeled cells and non-labeled controls were determined. Cellular contrast agent uptake was examined by fluorescence microscopy and quantified by ICP-AES. Efficient cell labeling was achieved after incubation of the cells with 25 mM Gd Gadofluorine M for 12 h, resulting in a maximal uptake of 0.3 fmol Gd/cell without impairment of cell viability. Fluorescence microscopy confirmed internalization of the fluorescent contrast agent by monocytes. The r1 relaxivity of the labeled cells was 137 mM(-1)s(-1) at 1.5 T and 80.46 mM(-1)s(-1) at 3 T. Imaging studies showed stable labeling for at least 7 days. Human monocytes can be effectively labeled for MR imaging with Gadofluorine M. Potential in vivo cell-tracking applications include targeting of inflammatory processes with Gadofluorine-labeled leukocytes or monitoring of stem cell therapies for the treatment of arthritis.
"Because of its good biocompatibility, relative noncytotoxicity, and nanostructure, mesoporous silica qualifies as an ideal biomaterial for stem cell labeling. The mesoporous structure can hold paramagnetic gadolinium (Gd) ions, allowing easy water access to Gd ions and a high degree of interaction between Gd ions and water protons, which contribute to increasing MR signals.16–20 Hsiao et al21 first reported on an efficient stem cell-tracking media made by Gd-loaded mesoporous silica nanoparticles that did not affect cell viability or differentiation; this laid the foundation for future visual stem cell therapies using T1-weighted MRI with a Gd-based positive contrast agent instead of superparamagnetic iron oxide (SPIO). "
[Show abstract][Hide abstract] ABSTRACT: We investigated the tracking potential of a magnetic resonance imaging (MRI) probe made of gadolinium-doped mesoporous silica MCM-41 (Gd(2)O(3)@MCM-41) nanoparticles for transplanted bone mesenchymal stem cells (MSCs) and neural stem cells (NSCs) in vivo. The nanoparticles, synthesized using a one-step synthetic method, possess hexagonal mesoporous structures with appropriate assembly of nanoscale Gd(2)O(3) clusters. They show little cytotoxicity against proliferation and have a lower effect on the inherent differentiation potential of these labeled stem cells. The tracking of labeled NSCs in murine brains was dynamically determined with a clinical 3T MRI system for at least 14 days. The migration of labeled NSCs identified by MRI corresponded to the results of immunofluorescence imaging. Our study confirms that Gd(2)O(3)@MCM-41 particles can serve as an ideal vector for long-term MRI tracking of MSCs and NSCs in vivo.
International Journal of Nanomedicine 01/2013; 8:119-27. DOI:10.2147/IJN.S38213 · 4.38 Impact Factor
"Our selection of investigated pulse sequences for depiction of GadofluorineM-Cy labeled MASI was based on practical considerations: T1-SE and T2* GE sequences have been previously applied for cell tracking studies ,  and 3D-SPGR and T2-FSE sequences are standard clinical sequences for cartilage imaging , , . Our data showed, that the T2* GE sequence provides the highest contrast between GadofluorineM-Cy-labeled cell implants and adjacent cartilage defects and is therefore best suited for detection of transplanted stem cells. "
[Show abstract][Hide abstract] ABSTRACT: The purpose of our study was to assess the chondrogenic potential and the MR signal effects of GadofluorineM-Cy labeled matrix associated stem cell implants (MASI) in pig knee specimen.
Human mesenchymal stem cells (hMSCs) were labeled with the micelle-based contrast agent GadofluorineM-Cy. Ferucarbotran-labeled hMSCs, non-labeled hMSCs and scaffold only served as controls. Chondrogenic differentiation was induced and gene expression and histologic evaluation were performed. The proportions of spindle-shaped vs. round cells of chondrogenic pellets were compared between experimental groups using the Fisher's exact test. Labeled and unlabeled hMSCs and chondrocytes in scaffolds were implanted into cartilage defects of porcine femoral condyles and underwent MR imaging with T1- and T2-weighted SE and GE sequences. Contrast-to-noise ratios (CNR) between implants and adjacent cartilage were determined and analyzed for significant differences between different experimental groups using the Kruskal-Wallis test. Significance was assigned for p<0.017, considering a Bonferroni correction for multiple comparisons.
Collagen type II gene expression levels were not significantly different between different groups (p>0.017). However, hMSC differentiation into chondrocytes was superior for unlabeled and GadofluorineM-Cy-labeled cells compared with Ferucarbotran-labeled cells, as evidenced by a significantly higher proportion of spindle cells in chondrogenic pellets (p<0.05). GadofluorineM-Cy-labeled hMSCs and chondrocytes showed a positive signal effect on T1-weighted images and a negative signal effect on T2-weighted images while Ferucarbotran-labeled cells provided a negative signal effect on all sequences. CNR data for both GadofluorineM-Cy-labeled and Ferucarbotran-labeled hMSCs were significantly different compared to unlabeled control cells on T1-weighted SE and T2*-weighted MR images (p<0.017).
hMSCs can be labeled by simple incubation with GadofluorineM-Cy. The labeled cells provide significant MR signal effects and less impaired chondrogenesis compared to Ferucarbotran-labeled hMSCs. Thus, GadoflurineM-Cy might represent an alternative MR cell marker to Ferucarbotran, which is not distributed any more in Europe or North America.
PLoS ONE 12/2012; 7(12):e49971. DOI:10.1371/journal.pone.0049971 · 3.23 Impact Factor
"Meding et al. demonstrated, that Gf binds to serum albumin and components of the extracellular matrix such as collagens, proteoglycans, fibronectin and tenascin , explaining a possible mechanism of Gf accumulation in atherosclerotic plaques [12,28]. Furthermore, Gf is taken up by macrophages in vivo and in vitro [13,29] and thus could highlight spots of immune activity in autoimmune neuritis, EAE and peripheral nerve degeneration [8,9,13,30]. Recently, Gf was also applied to detect disease progression in an animal model of muscular dystrophy . "
[Show abstract][Hide abstract] ABSTRACT: Circumventricular organs (CVO) are cerebral areas with incomplete endothelial blood-brain barrier (BBB) and therefore regarded as "gates to the brain". During inflammation, they may exert an active role in determining immune cell recruitment into the brain.
In a longitudinal study we investigated in vivo alterations of CVO during neuroinflammation, applying Gadofluorine M- (Gf) enhanced magnetic resonance imaging (MRI) in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. SJL/J mice were monitored by Gadopentate dimeglumine- (Gd-DTPA) and Gf-enhanced MRI after adoptive transfer of proteolipid-protein-specific T cells. Mean Gf intensity ratios were calculated individually for different CVO and correlated to the clinical disease course. Subsequently, the tissue distribution of fluorescence-labeled Gf as well as the extent of cellular inflammation was assessed in corresponding histological slices.
We could show that the Gf signal intensity of the choroid plexus, the subfornicular organ and the area postrema increased significantly during experimental autoimmune encephalomyelitis, correlating with (1) disease severity and (2) the delay of disease onset after immunization. For the choroid plexus, the extent of Gf enhancement served as a diagnostic criterion to distinguish between diseased and healthy control mice with a sensitivity of 89% and a specificity of 80%. Furthermore, Gf improved the detection of lesions, being particularly sensitive to optic neuritis. In correlated histological slices, Gf initially accumulated in the extracellular matrix surrounding inflammatory foci and was subsequently incorporated by macrophages/microglia.
Gf-enhanced MRI provides a novel highly sensitive technique to study cerebral BBB alterations. We demonstrate for the first time in vivo the involvement of CVO during the development of neuroinflammation.
Journal of Neuroinflammation 10/2010; 7(1):70. DOI:10.1186/1742-2094-7-70 · 5.41 Impact Factor
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