Methodological aspects of MRI of transplanted superparamagnetic iron oxide-labeled mesenchymal stem cells in live rat brain

Abstract

In vivo tracking of transplanted mesenchymal stem cells (MSCs) migration and homing is vital for understanding the mechanisms of beneficial effects of MSCs transplantation in animal models of diseases and in clinical trials. Transplanted cells can be labeled with superparamagnetic iron oxide (SPIO) particles and visualized in vivo using a number of iron sensitive MRI techniques. However, the applicability of those techniques for SPIO-labeled MSCs tracking in live brain has not been sufficiently investigated. The goal of this study was to estimate the efficiency of various MRI techniques of SPIO-labeled cell tracing in the brain. To achieve that goal, the precision and specificity of T2WI, T2*WI and SWI (Susceptibility-Weighted Imaging) techniques of SPIO-labeled MSCs tracing in vitro and in live rat brain were for the first time compared in the same experiment. We have shown that SWI presents the most sensitive pulse sequence for SPIO-labeled MSCs MR visualization. After intracerebral administration due to limitations caused by local micro-hemorrhages the visualization threshold was 102 cells, while after intra-arterial transplantation SWI permitted detection of several cells or even single cells. There is just one publication claiming detection of individual SPIO-labeled MSCs in live brain, while the other state much lower sensitivity, describe detection of different cell types or high resolution tracing of MSCs in other tissues. This study confirms the possibility of single cell tracing in live brain and outlines the necessary conditions. SWI is a method convenient for the detection of single SPIO labeled MSCs and small groups of SPIO labeled MSCs in brain tissue and can be appropriate for monitoring migration and homing of transplanted cells in basic and translational neuroscience.

<p>Efficient Labeling Of Mesenchymal Stem Cells For High Sensitivity Long-Term MRI Monitoring In Live Mice Brains</p>

“…On the other side, the non-labeled cells did not show hypointense regions similar to those observed with the labeled cells; however, there were minor magnetic field distortions along the needle and injection sites, similar to the findings of Namestnikova et al 38 and Brisset et al 39 We observed "blooming effect" which decreased with time in images acquired using T 2 * FLASH sequence for higher number of labeled cells, denoted by spread of the hypointense regions due to disturbance of the magnetic field of a region bigger than that occupied by the cells by iron nanoparticles. 38 Although the T 2 * FLASH sequence was sensitive enough to detect 2000 labeled cells, it did not show clear anatomical structures of the brain. Whereas, the T 2 MSME sequence was not as sensitive as the T 2 * FLASH sequence in detecting small numbers of labeled cells; it showed more clear anatomical structures of the brain and more realistic sizes of the transplanted cells regions.…”

“…We found that the decay in signal is correlated to the number of labeled cells, and that the scan parameters were sensitive enough to visualize about 175 labeled cells. There are published studies that reported different limits of sensitivity of detection for lower number of cells; 19,38 however, we cannot compare their findings to ours due to any of the following factors: different magnetic field strength of MRI scanners, varying MRI sequence protocols, distinct cell types, different nanoparticle formulations, and postprocessing of images. For in vivo live imaging of mice brains, we did not use the same scan sequence protocols we used for phantoms due to long scan times which were not suitable for live animals.…”

Human bone marrow mesenchymal stem cell-derived extracellular vesicles attenuate neuroinflammation evoked by focal brain injury in rats

“…To prove the donor origin of cells observed in MRI, additional methods, i.e., bioluminescence or immunohistochemically, are used. Namestnikova et al performed the co-localization studies of iron nanoparticles conjugated with fluorescence magnetic polymers MC03F and membrane marker PKH26 [21]. Walczak et al employed the marker of proliferating cells BrdU to show MSCs infused intra-arterially in the donor tissues [20].…”

Cell therapy for ischemic stroke. Stem cell types and results of pre-clinical trials

“…Этот эффект может быть обусловлен преимущественной миграцией МСК в нейрогенные зоны мозга и непосредственным взаимодействием с нейральными прогениторами реципиента, но может быть опосредован и воздействием секретируемых пересаженными МСК факторами [37]. Для понимания механизма действия трансплантированных клеток необходима разработка максимально надежных и чувствительных методов изучения их миграции и хоуминга как при жизни, так и на гистологических срезах, что в настоящее время достижимо с помощью магнитно-резонансной томографии и конфокальной микроскопии [48].…”

“…Однако ряд авторов [68,69] сообщили о риске развития эмболических инсультов при таком способе введения СК. Тем не менее другие исследователи [48,[70][71][72] считают, что эмболических осложнений можно избежать при подборе оптимальной дозы, скорости и условий введения СК. Доза и скорость введения являются важными пара-метрами для всех способов введения СК.…”