The in vivo monitoring of cell survival and migration will be essential to the translation of cell-based therapies from the laboratory to clinical studies. The pre-labeling of cells with magnetic resonance imaging (MRI) contrast agents renders them visible in vivo for serial cellular imaging. However, little is known about the impact of the presence of these metal particles inside transplanted cells. The use of the bimodal contrast agent GRID made it possible to demonstrate by means of fluorescent microscopy and inductively coupled plasma mass spectrometry (ICP-MS) that, after 16 h of incubation (without the use of a transfection agent), neural stem cells (NSCs) were saturated and no longer incorporated particles. With this maximal uptake, no significant effect on cell viability was observed. However, a significant decrease in proliferation was evident in cells that underwent 24 h of labeling. A significant increase in reactive oxygen species was observed for all GRID labeling, with a very significant increase with 24 h of labeling. GRID labeling did not affect cell motility in comparison with PKH26-labeled NSCs in a glioma-based migration assay and also allowed differentiation into all major cell types of the brain. GRID-labeled cells induced a signal change of 47% on T(2) measurements and allows a detection of cell clusters of approximately 220 cells/microl. Further in vivo testing will be required to ensure that cell labeling with gadolinium-based MRI contrast agents does not impair their ability to repair.

Tumour angiogenesis is a tightly regulated process involving cross-talk between tumour cells and the host tissue. The underlying mechanisms that regulate such interactions remain largely unknown. NG2 is a transmembrane proteoglycan whose presence on transformed cells has been demonstrated to increase proliferation in vitro and angiogenesis in vivo. To study the effects of NG2 during tumour growth and progression, we engineered an NG2 positive human glioma cell line (U251-NG2) from parental NG2 negative cells (U251-WT) and implanted both cell types stereotactically into immunodeficient nude rat brains. The tumours were longitudinally monitored in vivo using multispectral MRI employing two differently sized contrast agents (Gd-DTPA-BMA and Gadomer) to assess vascular leakiness, vasogenic oedema, tumour volumes and necrosis. Comparisons of Gd-DTPA-BMA and Gadomer revealed differences in their spatial distribution in the U251-NG2 and U251-WT tumours. The U251-NG2 tumours exhibited a higher leakiness of the larger molecular weight Gadomer and displayed a stronger vasogenic oedema (69.9 +/- 15.2, P = 0.018, compared to the controls (10.7 +/- 7.7). Moreover, immunohistochemistry and electron microscopy revealed that the U251-NG2 tumours had a higher microvascular density (11.81 +/- 0.54; P = 0.0010) compared to controls (5.76 +/- 0.87), with vessels that displayed larger gaps between the endothelial cells. Thus, tumour cells can regulate both the function and structure of the host-derived tumour vasculature through NG2 expression, suggesting a role for NG2 in the cross-talk between tumour-host compartments.

Cellular multiparametric magnetic resonance imaging (MRI) provided an in vivo visualisation of neural stem cells' (NSCs) tropism for gliomas in the rat brain. NSCs were magnetically labelled in vitro with the bimodal gadolinium-based contrast agent, gadolinium rhodamine dextran (GRID), and injected into the contralateral hemisphere to the developing tumour. Contrast-to-noise measurements showed that GRID-labelled cells induced a signal attenuation on both T2-, T2(*)-weighted images, and a modest signal gain on T1-weighted images. Tumour development and progression were longitudinally monitored in vivo by serial MR scanning. Measurements of tumour volume and tumour progression over time in terms of tumour doubling time showed a tendency towards a reduced tumour growth in NSC-treated animals. MR findings of migration and infiltration of tumours by labelled NSCs were corroborated with immunohistopathology, where labelled cells were detected in the corpus callosum at the tumour border and dispersed in the solid tumour tissue. Immunohistopathology also revealed that macrophages invaded the tumour tissue and in some cases engulfed GRID-labelled stem cells. No significant difference in macrophage recruitment between NSC-treated and vehicle-treated animals were detected, indicating that magnetically labelled NSC do not increase macrophage invasion of tumour tissue. Our findings demonstrate that cellular multiparametric MRI provides a valuable tool for in vivo dynamic monitoring of tumour-directed neural stem cell migration as well as therapeutic efficacy.

The aim of the present study was to investigate differences in brain activation in a family with SLI as compared to intact individuals with normally developed language during processing of language stimuli. Functional magnetic resonance imaging (fMRI) was used to monitor changes in neuronal activation in temporal and frontal lobe areas in 5 Finnish family members with specific language impairment (SLI) and 6 individuals in an intact control group. Magnetic resonance (MR) image acquisitions were made while the participants listened to series of isolated vowel sounds, pseudowords, and real words. The stimuli were digitized single Finnish vowel sounds, 3-phoneme pseudowords, and 3- and 4-phoneme real words. MR scanning was made with a 1.5 T Siemens Vision Plus scanner, and the auditory stimuli were presented according to an event-related fMRI design. The results showed significant differences between the family with SLI and the intact control group with regard to brain activation in areas in the temporal and frontal lobes. Temporal lobe activation differences were most pronounced in the middle temporal gyrus bordering the superior temporal sulcus. The control participants also activated an area in the inferior frontal lobe in BA 44. It is concluded that individuals with SLI showed reduced activation in brain areas that are critical for speech processing and phonological awareness. The present functional brain imaging data fit well with other recent imaging data that also showed structural abnormalities in the same and neighboring areas.