In vivo monitoring of cellular transplants by magnetic resonance imaging and positron emission tomography

Modo, Michel; Roberts, Toby J; Sandhu, Jasdeep K; Williams, Steve CR

doi:10.1517/eobt.4.2.145.26331

Cited by 7 publications

(7 citation statements)

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“…Tracing the movement of cells repeatedly in living subjects will allow the non-invasive monitoring of cellbased therapy in clinical settings (27). The Gd-based bimodal contrast agent GRID allows the visualization of NSCs in vivo using MRI and in vitro using fluorescence microscopy (3,19).…”

Section: Discussionmentioning

confidence: 99%

The in vitro effects of a bimodal contrast agent on cellular functions and relaxometry

et al. 2006

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The in vivo monitoring of cell survival and migration will be essential to the translation of cell-based therapies from the laboratory to clinical studies. The pre-labeling of cells with magnetic resonance imaging (MRI) contrast agents renders them visible in vivo for serial cellular imaging. However, little is known about the impact of the presence of these metal particles inside transplanted cells. The use of the bimodal contrast agent GRID made it possible to demonstrate by means of fluorescent microscopy and inductively coupled plasma mass spectrometry (ICP-MS) that, after 16 h of incubation (without the use of a transfection agent), neural stem cells (NSCs) were saturated and no longer incorporated particles. With this maximal uptake, no significant effect on cell viability was observed. However, a significant decrease in proliferation was evident in cells that underwent 24 h of labeling. A significant increase in reactive oxygen species was observed for all GRID labeling, with a very significant increase with 24 h of labeling. GRID labeling did not affect cell motility in comparison with PKH26-labeled NSCs in a glioma-based migration assay and also allowed differentiation into all major cell types of the brain. GRID-labeled cells induced a signal change of 47% on T(2) measurements and allows a detection of cell clusters of approximately 220 cells/microl. Further in vivo testing will be required to ensure that cell labeling with gadolinium-based MRI contrast agents does not impair their ability to repair.

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Section: Discussionmentioning

confidence: 99%

The in vitro effects of a bimodal contrast agent on cellular functions and relaxometry

et al. 2006

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“…Despite contrary evidence from preclinical studies, there is some concern that transplantation of stem cells could further exacerbate tumor formation as there is mounting evidence that brain tumors are potentially caused by a single stem cell that did not differentiate [114]. The ability to monitor cell therapy in vivo is therefore desirable to potentially provide more control over the activity of stem cells [115]. One possibility is that stem cells will be engineered with a suicide gene [116] that could be activated if transplanted cells would not behave in a therapeutic manner.…”

Section: Monitoring Of Cell Therapy For Brain Tumors By Positron Emismentioning

confidence: 99%

Molecular Imaging of Brain Tumors: A Bridge Between Clinical and Molecular Medicine?

2007

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As the research on cellular changes has shed invaluable light on the pathophysiology and biochemistry of brain tumors, clinical and experimental use of molecular imaging methods is expanding and allows quantitative assessment. The term molecular imaging is defined as the in vivo characterization and measurement of biologic processes at the cellular and molecular level. Molecular imaging sets forth to probe the molecular abnormalities that are the basis of disease rather than to visualize the end effects of these molecular alterations and, therefore, provides different additional biochemical or molecular information about primary brain tumors compared to histological methods "classical" neuroradiological diagnostic studies. Common clinical indications for molecular imaging contain primary brain tumor diagnosis and identification of the metabolically most active brain tumor reactions (differentiation of viable tumor tissue from necrosis), prediction of treatment response by measurement of tumor perfusion, or ischemia. The interesting key question remains not only whether the magnitude of biochemical alterations demonstrated by molecular imaging reveals prognostic value with respect to survival, but also whether it identifies early disease and differentiates benign from malignant lesions. Moreover, an early identification of treatment success or failure by molecular imaging could significantly influence patient management by providing more objective decision criteria for evaluation of specific therapeutic strategies. Specially, as molecular imaging represents a novel technology for visualizing metabolism and signal transduction to gene expression, reporter gene assays are used to trace the location and temporal level of expression of therapeutic and endogenous genes. Molecular imaging probes and drugs are being developed to image the function of targets without disturbing them and in mass amounts to modify the target's function as a drug. Molecular imaging helps to close the gap between in vitro and in vivo integrative biology of disease.

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“…Several reports have demonstrated that iron-labeled NSCs can be tracked using magnetic resonance imaging (MRI) 13–15 but did not use MR evaluation for long periods of time (> 6 mo) and did not correlate NSC behavior with the dynamics of underlying pathology – critical for the actual translation of NSC-based therapeutics to patients7, 11, 16, 17. The ability to monitor NSCs for extended periods is particularly important in newborns because long-term implantation may pose unanticipated risks to the developing brain.…”

Section: Introductionmentioning

confidence: 99%

Long‐term magnetic resonance imaging of stem cells in neonatal ischemic injury

Obenaus

Dilmac

Tone

et al. 2010

Annals of Neurology

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Objective Quantitative magnetic resonance imaging (MRI) can serially and non-invasively assess the degree of injury in rat pup models of hypoxic ischemic injury (HII). It can also non-invasively monitor stem cell migration following iron oxide pre-labeling. Reports have shown that neural stem cells (NSCs) may help mediate neuroprotection or stimulate neuroreparative responses in adult and neonatal models of ischemic injury. We investigated the ability of high-field MRI to monitor and non-invasively quantify the migration, proliferation, and location of iron oxide-labeled NSCs over very long time periods (58 weeks) in real time while contemporaneously correlating this activity with the evolving severity and extent of neural damage. Methods Labeled clonal murine NSCs were implanted 3 days after unilateral HII in 10 day old rat pups into the contralateral striatum or ventricle. We developed methods for objectively quantifying key aspects of dynamic NSC behavior (e.g., viability; extent and speed of migration; degree of proliferation; extent of integration into host parenchyma). MRI images were validated with histological and immunohistochemical assessments. Results mNSCs rapidly migrated (100μm/day) to the lesion site. Chains of migrating NSCs were observed in the corpus callosum. In pups subjected to HII, though not in intact control animals, we observed a 273% increase in the MR-derived volume of mNSCs 4 weeks after implantation (correlating with the known proliferative behavior of endogenous and exogenous NSCs) that slowly declined over the 58 week time course, with no adverse consequences. Large numbers of now quiescent mNSCs remained at the site of injury, many retaining their iron oxide label. Interpretation Our studies demonstrate that MRI can simultaneously monitor evolving neonatal cerebral injury as well as NSC migration and location. Most importantly, it can non-invasively monitor proliferation dynamically for prolonged time periods. To be able to pursue clinical trials in newborns using stem cell therapies, it is axiomatic that safety be insured through the long-term real time monitoring of cell fate and activity, particularly with regard to observing unanticipated risks to the developing brain. This study supports the feasibility of reliably using MRI for this purpose.

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In vivo monitoring of cellular transplants by magnetic resonance imaging and positron emission tomography

Cited by 7 publications

References 0 publications

The in vitro effects of a bimodal contrast agent on cellular functions and relaxometry

The in vitro effects of a bimodal contrast agent on cellular functions and relaxometry

Molecular Imaging of Brain Tumors: A Bridge Between Clinical and Molecular Medicine?

Long‐term magnetic resonance imaging of stem cells in neonatal ischemic injury

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