Elsevier

NeuroImage

Volume 28, Issue 3, 15 November 2005, Pages 698-707
NeuroImage

Investigation of neural progenitor cell induced angiogenesis after embolic stroke in rat using MRI

https://doi.org/10.1016/j.neuroimage.2005.06.063Get rights and content

Abstract

Using MRI, we investigated dynamic changes of brain angiogenesis after neural progenitor cell transplantation in the living adult rat subjected to embolic stroke. Neural progenitor cells isolated from the subventricular zone (SVZ) of the adult rat were labeled by superparamagnetic particles and intracisternally transplanted into the adult rat 48 h after stroke (n = 8). Before and after the transplantation, an array of MRI parameters were measured, including high resolution 3D MRI and quantitative T1, T1sat (T1 in the presence of an off-resonance irradiation of the macromolecules of brain), T2, the inverse of the apparent forward transfer rate for magnetization transfer (kinv), cerebral blood flow (CBF), cerebral blood volume (CBV), and blood-to-brain transfer constant (Ki) of Gd-DTPA. The von Willerbrand factor (vWF) immunoreactive images of coronal sections obtained at 6 weeks after cell transplantation were used to analyze vWF immunoreactive vessels. MRI measurements revealed that grafted neural progenitor cells selectively migrated towards the ischemic boundary regions. In the ischemic boundary regions, angiogenesis confirmed by an increase in vascular density and the appearance of large thin wall mother vessels 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 of Ki with a peak at 2 to 3 weeks after cell therapy. Relative T1, T1sat, T2, and kinv decreased in the ischemic boundary regions with angiogenesis compared to that in the non-angiogenic ischemic region (T1, P < 0.01 at 6 weeks; T1sat, P < 0.05 at 2 to 6 weeks; T2, P < 0.05 at 3 to 6 weeks; kinv P < 0.05 at 6 weeks). Of these methods, Ki appear to be the most useful MR measurements which identify and predict the location and area of angiogenesis. CBF, CBV, T1sat, T1, T2, and kinv provide complementary information to characterize ischemic tissue with and without angiogenesis. Our data suggest that select MRI parameters can identify the cerebral tissue destined to undergo angiogenesis after treatment of embolic stroke with cell therapy.

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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