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Magnetic Resonance Imaging Detects Differences in Migration Between Primary and Immortalized Neural Stem Cells

Posted Sep 30, 2008 Updated Apr 7, 2023
By Sergey Magnitsky PhD , Raquel M. Walton VMD PhD , John H. Wolfe VMD PhD , Harish Poptani PhD
17 min read

Rationale and Objectives

The study was performed to evaluate the effect of magnetic resonance imaging (MRI) contrast agent (super paramagnetic iron oxide [SPIO]) on differentiation and migration of primary murine neural stem cells (NSCs) in comparison to a neural stem cell line (C17.2). Because detection of labeled cells depends on the concentration of SPIO particles per imaging voxel, the study was performed at various concentrations of SPIO particles to determine the concentration that could be used for in vivo detection of small clusters of grafted cells.

Materials and Methods

Murine primary NSCs or C17.2 cells were labeled with different concentrations of SPIO particles (0, 25, 100, and 250 μg Fe/mL) and in vitro assays were performed to assess cell differentiation. In vivo MRI was performed 7 weeks after neonatal transplantation of labeled cells to evaluate the difference in migration capability of the two cell populations.

Results

Both the primary NSCs and the C17.2 cells differentiated to similar number of neurons (Map2ab-positive cells). Similar patterns of engraftment of C17.2 cells were seen in transplanted mice regardless of the SPIO concentration used. In vivo MRI detection of grafted primary and C17.2 cells was only possible when cells were incubated with 100 μg/mL or higher concentration of SPIO. Extensive migration of C17.2 cells throughout the brain was observed, whereas the migration of the primary NSCs was more restricted.

Conclusions

Engraftment of primary NSCs can be detected noninvasively by in vivo MRI, and the presence of SPIO particles do not affect the viability, differentiation, or engraftment pattern of the donor cells.

Stem cells have the ability to differentiate into specific cell types. They have been used in several preclinical models of disease ( ) and are being used in Phase I–III clinical trials ( ). Neural stem cells (NSCs) can differentiate into neuronal or glial cells and express trophic factors to rescue dysfunctional brain tissue ( ). These properties of NSCs provide an opportunity to use them as delivery vehicles for therapeutic molecules into specific regions or into the entire brain ( ). Stem cell lines are generally used for investigation of basic properties of stem cells. One of the commonly used NSC lines, known as C17.2, was originally derived from neonatal mouse cerebellum and immortalized by the introduction of a v-myc oncogene ( ). When transplanted into the developing brain, this cell line consistently results in robust and stable engraftment throughout the brain. Because this line does not usually lead to formation of tumors, it has been extensively used in transplantation biology studies, including treatment of mouse models of lysosomal storage diseases ( ). However, use of neural stem cell lines for treatment of diseases in humans is potentially problematic because of their immortalized nature. An earlier study suggested that the biology of C17.2 cells differs significantly from primary neural stem cells ( ); therefore, it is important to assess the transplantation and migration properties of primary stem cells in experimental models.

Stem cell engraftment is generally determined postmortem by histologic, immunologic, or fluorescence assays. However, to evaluate the efficacy of stem cell migration and survival over time, it is necessary to use noninvasive techniques. Magnetic resonance imaging (MRI) methods have been applied to monitor implanted stem cells by loading the cells with iron oxide particles as a contrast agent ( ). The particles exhibit strong magnetic moments when placed in a magnetic field and create a hypointense (dark) signal on MRI. Based on their size, these agents can be broadly classified into three categories; ultra-small paramagnetic iron oxide particles (USPIO, 10–30 nm), super paramagnetic iron oxide particles (SPIO, 30–150 nm) and micrometer-sized paramagnetic iron oxide particles (0.5–2 μm). The SPIO particles are more commonly used ( ) because they are commercially available and have been used in the clinic for the detection of liver tumors ( ) and have recently been shown to be efficient in the detection of implanted cells in humans ( ).

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Methods

Experimental Animals

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Isolation of Mouse Neural Precursor Cells

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Primary Mouse Neural Precursor Cell Culture

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Cell Culture of C17.2 Cells

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Labeling of Cells with Iron Oxide Particles

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Differentiation Assay of NSCs

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Intracranial Cell Implantation

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MRI Experiments

In vivo imaging

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Ex vivo imaging

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Image analysis

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Histology

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Prussian blue staining for detection of iron

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β-galactosidase staining

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GUSB staining

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CD11b staining

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Results

Iron Uptake of Cells

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Figure 1, Prussian blue ( rows a and b ) and Map2ab staining ( rows c and d ) of neural stem cells (NSCs) labeled with different concentrations of SPIO particles. The results from C17.2 cells are shown in rows a and c , whereas that from primary NSCs are shown in rows b and d . A magnification factor of 40× is used for the Map2ab sections. In comparison to the C17.2 cells, the primary cells exhibited limited uptake of SPIO particles. The presence of neuronal differentiation is depicted in green ( rows c and d ).

Table 1

Net Iron Concentration per Cell as Measured by Inductively Coupled Plasma Mass Spectroscopy after Incubation of Cells with a Solution of Ferumoxide-poly- d -lysine

Iron Concentration per Cell (pg/cell) Iron Concentration in Incubation Medium (mg/mL) 0 25 100 250 C17.2 <0.15 10.6 ± 1.3 46.5 ± 27.5 152.9 ± 112 ⁎ Primary neural stem cells <0.15 5.5 ± 2.2 4.5 ± 2.1 8.3 ± 9.0 ⁎

Values are reported as mean ± standard deviation.

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Cell Differentiation in the Presence of SPIO Particles

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Table 2

Percentage of Map2ab (neuronal)-positive C17.2 and Murine Primary Stem Cells

% Map2ab Positive Iron Concentration in Incubation Medium (mg/mL) 0 25 100 250 C17.2 cells 9.08 ± 3.9 10.9 ± 4.7 11.6 ± 7.9 11.3 ± 5.3 Primary neural stem cells 5.4 ± 4.7 1.7 ± 1.9 6.3 ± 5.9 10.1 ± 6.0

C17.2 cells were differentiated for 5 days, whereas primary cells were differentiated for approximately 10 days. Values are reported as the average number of positive cells with respect to the total number of cells ± standard deviaiton (from five random fields and three separate experiments).

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Engraftment Pattern

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Figure 2, Engraftment ( top row, a ) and differentiation ( bottom row, b ) pattern of transplanted C17.2 cells in the presence of super paramagnetic iron oxide (SPIO) particles. Images in the top row are LacZ-stained sections of the cerebellar region after 7 weeks of cell transplantation in the neonatal brain. The images are depicted at a magnification of 5×. Presence of β-galactoside positive cells ( blue ) indicate no adverse effect on engraftment potency of cells labeled with SPIO particles. The images in the bottom row are Prussian blue–positive sections from similar regions of the brain as above. These images are shown at a magnification of 40×. Iron positive–transplanted C17.2 cells are depicted in blue . The insets show a larger magnification of some of these cells exhibiting processes and morphology similar to that of differentiating neuronal or astrocytic cells indicating that the presence of SPIO particles does not alter the differentiation capability of neural stem cells.

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MRI Detection of Labeled C17.2 Cells

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Figure 3, In vivo detection of super paramagnetic iron oxide–labeled neural stem cells (NSCs) after 7 weeks of transplantation in the neonatal mouse. Representative transverse sections from mice injected with C17.2 cells incubated with 25 (a) , 100 (b) , 250 μg Fe/mL (c) , and mice injected with primary mouse NSCs with 25 (d) , 100 (e) , 250 μg Fe/mL (f) . Labeled cells were not detectable at low iron concentration (25 μg/mL of Fe). Arrows indicate hypointense areas from the presence of cells labeled with high concentration of super paramagnetic iron oxide (100 and 250 μg Fe/mL).

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MRI Detection of Murine Primary Stem Cells

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Figure 4, Detection of transplanted mouse primary cells by in vivo magnetic resonance imaging (a) as confirmed by Prussian blue staining (b) and histochemical staining for detection of human β-glucuronidase (GUSB)-positive cells (c) . The murine primary neural stem cells (NSCs) were labeled with 100 μg Fe/mL of super paramagnetic iron oxide particles. (b, c) 10× magnification; (d, e) 40× magnification for the rectangular regions indicated in (b, c) . Arrows (d) indicate presence of iron-positive primary NSCs. The inset in (e) shows a GUSB-positive cell with processes similar to a neuronal cell indicating in vivo differentiation.

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Detection of Iron-positive Grafted Cells and Microglia

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Figure 5, Detection of iron-positive grafted neural stem cells and microglia cells from the cerebellar region of the brain after 7 weeks of neonatal transplantation of labeled C17.2 cells. Representative sections showing CD11b-negative and Prussian blue–positive cells (a, b) indicating presence of iron positive–transplanted cells; CD11b-positive and Prussian blue–negative cells (c) indicating presence of reactive microglia; and CD11b-positive, Prussian blue–positive cells (d) indicating the uptake of iron oxide particles by microglia. The horizontal bar (d) reflects a distance of 25 μm.

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Figure 6, Ex vivo magnetic resonance images of mouse brains transplanted with super paramagnetic iron oxide (100 μg Fe/mL) labeled neural stem cells (NSCs) and imaged 7 weeks after transplantation. Representative axial images from a three-dimensional (3D) data set are displayed for an animal injected with C17.2 cells (left) and murine primary NSCs (right) . The 3D reconstruction of the images is displayed in the central panel with the brain mask displayed in blue and iron-positive cells displayed in red . In comparison to the C17.2 cells, which exhibited extensive migration throughout the brain, the primary murine NSCs were primarily located near the ventricular region of the brain.

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Discussion

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Academic Radiology, Volume 15, Issue 10
Journals General Radiology
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