Magnetic resonance imaging and cell-based neurorestorative therapy after brain injury

Abstract

Restorative cell-based therapies for experimental brain injury, such as stroke and traumatic brain injury, substantially improve functional outcome. We discuss and review state of the art magnetic resonance imaging methodologies and their applications related to cell-based treatment after brain injury. We focus on the potential of magnetic resonance imaging technique and its associated challenges to obtain useful new information related to cell migration, distribution, and quantitation, as well as vascular and neuronal remodeling in response to cell-based therapy after brain injury. The noninvasive nature of imaging might more readily help with translation of cell-based therapy from the laboratory to the clinic.

Keywords: MRI; angiogenesis; axonal remodeling; blood brain barrier permeability; cell labeling; cell therapy; cerebral blood flow; cerebral blood volume; diffusion tensor MRI; neuronal plasticity; stroke; traumatic brain injury; vascular remodeling.

Figure 1

Dynamic migration of transplanted cells in ischemic brain in a representative ischemic rat. MRI signals (dark areas) were not detected before transplantation of labeled subventricular zone cells (column N in A to C). In contrast, the same rat exhibited magnetic resonance imaging (MRI) signals at the fourth ventricle at the day of injection of superparamagnetic labeled cells into the cistern (A; 0 d, arrow). MRI signals moved forward along the fourth ventricle 1 and 2 days (B; 1 d and 2 d, arrows) and first reached the ipsilateral striatum nearby the ipsilateral lateral ventricle 2 days after transplantation (C; 2 d, arrow). MRI signals expanded from nearby the lateral ventricle to the distant lateral ventricle in the ipsilateral hemisphere 4 days after transplantation (C; 4 d, arrow), and MRI signal in the ipsilateral striatum increased from 2 to 4 days after transplantation (C; 5 d and 7 d). MRI signals were not detected in the contralateral hemisphere at any time points after transplantation (C; 0 d to 7 d). Panels A to C represent different levels of coronal sections from the posterior to anterior brain (A, bregma _13.3 mm; B, bregma _11.8 mm; and C, bregma_1.3 mm). N represents 1 day before transplantation, and 0 d to 7 d indicate days after transplantation from a representative rat. Prussian blue staining was used to identify superparamagnetic labeled cells on sagittal or coronal sections. This staining reacts with iron to produce blue color. Panel D is a schematic representation of a sagittal section from the ipsilateral hemisphere at lateral 1.40 mm. Panels E to G are microphotographic images of Prussian blue-stained sections from the same rat in which MRI images were presented above. Panel E is from the boxed area in the panel D. The arrow in the panel E indicates transplanted cells (blue) around the ischemic boundary. Higher magnification showed that these blue cells had round morphology (F and inset). A box and an arrowhead in panel E show transplanted cells at a distance from the ischemic boundary, and these cells exhibited bipolar morphology (G), indicating that these cells migrate. Panel H shows that MRI signals (arrows) from a representative rat localized to the boundary regions of the ischemic lesion and persisted for at least 5 weeks after transplantation. N represents 1 day before transplantation, and 1 W to 5 W indicate weeks after transplantation. Reprint from Ann Neurol, 2003;53:259-263, with permission.

Figure 2

The evolution of changes in MRI K_i and CBF after restorative cell treatment. The Ki maps revealed an increase in K_i in the subcortical region (yellow dotted circle) that maximized at 2 weeks (K_i, 2 weeks) and returned to normal 6 weeks after treatment. Panels A and B show the vWF immunoreactive images of coronal sections, which matched MRI sections from the same animal sacrificed at 6 weeks after treatment. The data show increased numbers of vWF immunoreactive vessels (left image in A, black line area; left image in the magnified vWF immunostained image B, arrows). The density of microscopic vessels was significantly higher in cell treated animals than in control animals, indicating that the cell therapy enhances vascular remodeling. CBF measurements revealed a small and gradual increase in the subcortical region (yellow dotted circle), where increased numbers of microvessels were confirmed by histology, starting at 3 weeks and with increased contrast at 6 weeks after treatment. By statistical analysis, vascular remodeling was coincident with increases of CBF and CBV (CBF, P < 0.01; CBV, P < 0.01) at 6 weeks after treatment, and coincident with transient increases (P < 0.05) of K_i with a peak at 2–3 weeks after cell therapy (Jiang et al., 2005). Bar in B: 100 μm. Reprint from Neuroimage, 2005;28:698-707, with permission. MRI: Magnetic resonance imaging; vWF: von Willebrand factor; CBF: cerebral blood flow; CBV: cerebral blood volume.

Figure 3

The evolution in T2 (A) and fractional anisotropy (B) maps after neural progenitor cell treatment and corresponding Bielshowsky silver and Luxol fast blue stained coronal section (C, D) from the same rat. The left image in D is a high magnification image from the box area in panel C and the corresponding contralateral area (right image in D). E is the axonal tracking image from ex vivo diffusion tensor imaging data of another rat which show that fiber tracks circumscribe the lesion boundary. The marker C in E represents ischemic core. The bar in D: 10 μm. Reprint from Neuroimage, 2006;32:1080-1089, with permission.