Elsevier

NeuroImage

Volume 32, Issue 3, September 2006, Pages 1080-1089
NeuroImage

MRI detects white matter reorganization after neural progenitor cell treatment of stroke

https://doi.org/10.1016/j.neuroimage.2006.05.025Get rights and content

Abstract

We evaluated the effects of neural progenitor cell treatment of stroke on white matter reorganization using MRI. Male Wistar rats (n = 26) were subjected to 3 h of middle cerebral artery occlusion and were treated with neural progenitor cells (n = 17) or without treatment (n = 9) and were sacrificed at 5–7 weeks thereafter. MRI measurements revealed that grafted neural progenitor cells selectively migrated towards the ischemic boundary regions. White matter reorganization, confirmed histologically, was coincident with increases of fractional anisotropy (FA, P < 0.01) after stroke in the ischemic recovery regions compared to that in the ischemic core region in both treated and control groups. Immunoreactive staining showed axonal projections emanating from neurons and extruding from the corpus callosum into the ipsilateral striatum bounding the lesion areas after stroke. Fiber tracking (FT) maps derived from diffusion tensor imaging revealed similar orientation patterns to the immunohistological results. Complementary measurements in stroke patients indicated that FT maps exhibit an overall orientation parallel to the lesion boundary. Our data demonstrate that FA and FT identify and characterize cerebral tissue undergoing white matter reorganization after stroke and treatment with neural progenitor cells.

Introduction

Cell-based therapies for the treatment of experimental stroke can significantly improve neurological outcome (Bang et al., 2005, Borlongan et al., 2004, Chen et al., 2003, Chopp and Li, 2002, Kondziolka et al., 2000, Savitz et al., 2004, Zhang et al., 2002b, Zhang et al., 2003a, Zhang et al., 2004). Neural progenitor cells (NPCs) derived from human fetal brain have also been employed to treat experimental stroke in rodents, with promising results (Borlongan et al., 2004, Jeong et al., 2003, Mizusawa, 2003, Park, 2000, Savitz et al., 2004). NPC treatment of stroke has demonstrated that cell-based treatments of stroke stimulate the secretion of growth factors and cytokines (Chen et al., 2002) which promote brain remodeling and recovery (Chopp and Li, 2002). Although the mechanism of cell-based treatment of stroke has been focused on angiogenesis and neurogenesis (Chen et al., 2003, Chopp and Li, 2002, Zhang et al., 2002b, Zhang et al., 2003a, Zhang et al., 2004), white matter reorganization may contribute to functional recovery after stroke (Li et al., 2005, Shen et al., 2006). Thus, restorative cell-based treatment of stroke alters brain structure and physiology. It is important for the application and development of neurorestorative therapeutic approaches to develop noninvasive methods to monitor the modifications of cerebral tissue which lead to improved outcome.

MRI can dynamically measure the migration and the location of injected or implanted cells employed to treat neurological diseases and stroke (Bulte et al., 1999, Hoehn et al., 2002, Jiang et al., 2005, Zhang et al., 2003a, Zhang et al., 2003b). However, little work has been performed on the assessment of tissue response to cell treatment (Jiang et al., 2005). In this study, for the first time, we measure the temporal profiles of a set of MR parameters in ischemic brain treated with NPCs. We demonstrate that MRI fractional anisotropy (FA) identifies and quantitatively characterizes tissue with white matter reorganization, and fiber tracking of axonal projection from fiber tracking (FT) algorithms of diffusion tensor imaging (DTI) detects the changes of axonal orientation in the ischemic boundary region after stroke. Longitudinal relaxation time (T1), transverse relaxation time (T2), and longitudinal relaxation time with an off-resonance irradiation (T1sat) are shown to provide complementary information to characterize the status of ischemic tissue.

Section snippets

Materials and methods

All experimental procedures have been approved by the Institutional Animal Care and Use Committee and Institutional Review Board of Henry Ford Hospital.

Quantitative characterization of MRI parameters of white matter reorganization

Measurements of FA, T1, T1sat, and T2 were performed on ischemic core and recovery ROIs. The relative changes of MR measurements in the ischemic core ROI (ischemic core/contralateral core) and recovery ROI (ischemic recovery/contralateral recovery) were calculated and used in the analysis. The relative ischemic damaged areas measured from T2 maps significantly decreased (P < 0.001) at 5 weeks (control group, 0.20 ± 0.04; treated group, 0.18 ± 0.04) compared to that at 24 h (control group,

Discussion

In this study, we found that MRI can detect white matter reorganization after stroke with and without NPC treatment. White matter reorganization after NPC treatment of stroke is also prominently located in the extended area of corpus callosum in striatum. FA differentiated white matter reorganized brain tissue from other ischemic damaged tissues. The novel finding is that MRI can be used to identify white matter reorganization in the host brain after stroke.

In the current study, we demonstrated

Acknowledgments

We thank Dr. Susumu Mori for providing the software DtiStadio to perform DTI data analysis, Qing Jiang Li, Polly Whitton, and Hemanthkumar Athiraman for data analysis, and Swayam Panda for data acquisitions. This work was supported by NIH grants RO1 NS48349, RO1 NS38292, RO1 NS43324, RO1 HL64766, PO1 NS23393, and PO1 NS42345.

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