Investigation of neural progenitor cell induced angiogenesis after embolic stroke in rat using MRI
Introduction
Cell-based therapies have shown promise for the treatment of neurological disease injury and stroke (Brownell et al., 1998, Bulte et al., 1999, Chen et al., 2003, Cicchetti et al., 2002, Hoehn et al., 2002, Zhang et al., 2003a, Zhang et al., 2003b). It is, however, important for the application of these therapeutic approaches to develop noninvasive methods to monitor the migration of cells and how the modification of the cerebral tissue by the injected cells leads to improved outcome.
Positron emission tomography (PET), single-photon emission computed tomography (SPECT) and MRI have been employed to dynamically monitor the movement and the location of injected or implanted cells employed to treat the brain with neurological diseases and stroke (Brownell et al., 1998, Bulte et al., 1999, Cicchetti et al., 2002, Hoehn et al., 2002, Zhang et al., 2003a, Zhang et al., 2003b). However, little work has been performed on the assessment of tissue response to the cell treatment. One of the major factors in the therapeutic response of brain to cell based treatment is the induction of angiogenesis (Chen et al., 2003). Angiogenesis catalyzes brain plasticity, including neurogenesis and synaptogenesis, all of which foster functional recovery from stroke (Chen et al., 2003, Zhang et al., 2003a, Zhang et al., 2003b). An outstanding question, however, is what is the anatomical relationship between the presence of exogenous cells and the induction of angiogenesis, and perhaps more importantly, are there MR indices that identify cerebral tissue destined for angiogenesis in response to treatment?
In this study, for the first time, we measure the temporal profiles of a set of MR parameters in ischemic brain treated with adult neural progenitor cells isolated from the subventricular zone (SVZ) of the brain. We demonstrate that exogenous cells are localized within or immediately adjacent to angiogenic ischemic tissue, that an MR parameter the blood brain transfer constant for gadolinium identifies tissue destined for angiogenesis, and that MR measurements of cerebral blood flow, cerebral blood volume, T1sat, T1, T2, and kinv provide complementary information to characterize ischemic tissue with and without angiogenesis.
Section snippets
Material and methods
All experimental procedures have been approved by the Institutional Animal Care and Use Committee of Henry Ford Hospital.
Histological studies
vWF immunoreactive staining was performed to detect angiogenic regions in the ischemic boundary zone (IBZ). Angiogenesis was found in six of eight neural progenitor cell treated animals. Four of these six animals showed angiogenesis in both cortex and striatum IBZ. The other two treated rats showed angiogenesis in the cortex or striatum IBZ, respectively. The angiogenic IBZ was primarily localized in the external capsule and parietal cortex area 1 regions (100% occurrence in either external
Discussion
In this study, we found that MRI can detect angiogenesis after neural progenitor cell treatment, and transplanted cells selectively migrate to the ischemic parenchyma, especially in the angiogenic related region in living rats. MRI parameters differentiated angiogenic tissue from non-angiogenic ischemic tissues. The novel finding is that MRI can be used to predict and identify cell induced brain angiogenesis in the host brain in living animals.
Preclinical studies in stroke indicate that
Acknowledgments
This work was supported by NIH grants RO1 NS48349, RO1 NS38292, RO1 NS43324, RO1 HL64766, RO1 HL70023, PO1 NS23393, and PO1 NS42345.
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