Het volgen van cellen met behulp van MRI
Informatie over het onderzoek naar het volgen van cellen met behulp van MRI
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Principal Investigator for Radiology: Monique R Bernsen, PhD
In vivo cell tracking is of crucial importance for the development and validation of (stem-) cell-based therapies. For clinical translation, MRI is currently considered the modality of choice. MRI offers excellent resolution capabilities and high penetration depth, through which detailed anatomical structures, tissue physiology and tissue metabolism can be visualized without the burden of ionizing radiation.
By incorporation of paramagnetic probes into the cells of interest, cells can be visualized and tracked by MRI. The most commonly used particles for this purpose are iron-oxide nanoparticles. Iron-oxide nanoparticles have superparamagnetic properties causing susceptibility artifacts, resulting in a decrease in signal intensity. Iron-oxide labeled cells can be visualized in T2/T2* weighted images (Figure 1). While various studies have demonstrated that most cell types can be labeled in this way, several challenges still lie ahead, both in experimental studies and in translational studies. These challenges include issues regarding the most optimal labeling strategies, image acquisition parameters and image analysis and processing techniques.
Figure 1: Labeling and imaging of cells.
Panel A shows a light microscopy image of cells exposed to iron-oxide nanoparticles (black arrow) in a culture disk. Iron-oxide nanoparticles can also be seen inside the cells (white arrow). Panel B shows an MR image of iron-oxide labeled cells. The black dots (signal voids) represent single cells or small cell clusters containing iron-oxide nanoparticles. Panel C shows a single slice of an MR image through the lower body part of a rat injected with iron-labeled cells in the flank.A susceptibility artifact can clearly be seen at the injection site (blue box).
Optimal labeling strategies
Optimal labeling of cells with paramagnetic probes, does not only involve maximal loading of the cells with probe. For cell tracking as an adjunct to cell-based therapy, it is also important that the probe is retained for at least several weeks within the cell, and that the label and/or the labeling procedure do not affect cell survival, cell proliferation and cell function (Figure 2).
A large variety of direct labeling strategies have been used and described for the incorporation of paramagnetic probes into cells. Direct labeling strategies are based on the exposure of the cells to exogenous probe, with or without the use of a transfection agents, leading to incorporation of the probe into the cell via endocytototic pathways. Most of these strategies have been aimed at maximal or sufficient incorporation of probe for in vitro or in vivo visualization without apparent detrimental effects on cell survival and/or cell proliferation. The effects the probe or the labeling procedure may have on cell function and or differentiation capacity has only been addressed on a limited scale. Using a variety of biochemical, cell biological and functional assays, we try to establish optimal labeling strategies for a given cell type (Figure 2). With colleagues from the TU Delft, we are also investigating the use of Gd-based probes, to increase the options for cell imaging in vivo.
Figure 2: Label and
cell
behavior.
Panel A Susceptibility artifact from a scaffold with labeled
mesenchymal stem cells (white arrow) 7 weeks after labeling. Panel
B-D Light microscopy images from labeled mesenchymal stem cells that
have differentiated in to osteocytic, chondrocytic and adipocytic cells
respectively. Panel E-F label distribution in cells as
assessed by Prussian blue staining and FACS-analysis.
Optimal image acquisition
For cell imaging and molecular imaging in general, high resolution, sensitive imaging is required. For optimized signal to noise and contrast to noise, we are using customized coils, modified protocols and pulse sequences (see also High Resolution MRI).
Optimal analysis and processing
A major advantage that Molecular Imaging offers to biomedical research is the ability to visualize dynamic biological or pathological processes in vivo. For cell tracking in vivo in cell-based therapies, an integrated assessment of cell fate, function and response to treatment will be required. Analysis of such multi-parametric data in time series, poses an enormous challenge in terms of image informatics. While much progress has been made in terms of registration techniques and kinetic modeling, existing post-processing techniques do not accommodate the complexities posed by 4D data. In collaboration with the Dept. of Medical Informatics, we are working on novel algorithms for sensitive detection and registration, matching, and anatomical motion correction. (See also Biomedical Image Processing)
Funding: Erasmus MC Translational Research Seed Grant 2004-2006: “MRI tracking of transferred cells in vivo”.
Participating researchers Dept. of Radiology: Sandra van Tiel, Linda van der Graaf, Gabriel Krestin, Erik Meijering, Wiro Niessen, Piotr Wielopolski
Collaborations:
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Country |
City (State) |
Institute |
Department |
Collaborator |
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Germany |
Munich |
GE Medical Systems [ASL Europe] |
Timo Schirmer, PhD |
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the Netherlands |
‘s Hertogenbosch |
GE Medical Systems [ASL Europe] |
Gavin C Houston, PhD |
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the Netherlands |
Delft |
Flick Engineering Solutions |
Herman Flick, MEng |
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the Netherlands |
Delft |
University of Technology |
Reactor Instituut |
Gerben A Koning, PhD |
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the Netherlands |
Eindhoven |
Technical University |
Biomedical Engineering |
Klaas Nicolay, PhD |
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the Netherlands |
Eindhoven |
Technical University |
Biomedical Engineering |
Gustav J. Strijkers, PhD |
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the Netherlands |
Enschede |
University of Twente |
Biomedical Optics |
Kiran Kumar Thumma |
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the Netherlands |
Rotterdam |
Erasmus MC |
Cardiology |
Heleen MM van Beusekom, PhD |
|
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the Netherlands |
Rotterdam |
Erasmus MC |
Cardiology |
Ewout Jan van den Bos, MD, PhD |
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the Netherlands |
Rotterdam |
Erasmus MC |
Cardiology |
Dirk J Duncker, MD, PhD |
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the Netherlands |
Rotterdam |
Erasmus MC |
Cardiology |
Wim J van der Giessen, MD, PhD |
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the Netherlands |
Rotterdam |
Erasmus MC |
Hepatogastroenterology |
Ernst J Kuipers, MD, PhD |
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the Netherlands |
Rotterdam |
Erasmus MC |
Neonatology |
Ingrid B Renes, PhD |
|
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the Netherlands |
Rotterdam |
Erasmus MC |
Nuclear Medicine |
Marion de Jong, PhD |
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the Netherlands |
Rotterdam |
Erasmus MC |
Orthopedics |
Eric J Farrell, PhD |
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the Netherlands |
Rotterdam |
Erasmus MC |
Orthopedics |
Gerjo JVM van Osch, PhD |
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the Netherlands |
Rotterdam |
Erasmus MC |
Orthopedics |
Harrie H Weinans, PhD |
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the Netherlands |
Rotterdam |
Erasmus MC |
Plastic & Reconstructive Surgery |
Ronald I Siphanto, MD |
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the Netherlands |
Rotterdam |
Erasmus MC |
Surgical Oncology |
AMM (Lex) Eggermont, MD, PhD |
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the Netherlands |
Rotterdam |
Erasmus MC |
Surgical Oncology |
Timo LM ten Hagen, PhD |
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the Netherlands |
Rotterdam |
Erasmus MC |
Surgical Oncology |
Gerben A Koning, PhD |
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the Netherlands |
Rotterdam |
Erasmus MC |
Virology |
Fiona Read |
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the Netherlands |
Rotterdam |
Erasmus MC |
Virology |
Thijs Kuiken, DVM, PhD, DACVP |
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USA |
Milwaukee (WI) |
GE Medical Systems [ASL Central] |
Jason A Polzin, PhD |
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USA |
San Francisco (CA) |
University of California |
Radiology |
Robert C Brasch, MD |
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