Labeling of mesenchymal stem cells for MRI with single-cell sensitivity

Schellenberger, Angela Ariza de; Kratz, Harald; Farr, Tracy D.; Loewa, Norbert; Hauptmann, R.; Wagner, Susanne; Taupitz, Matthias; Schnorr, Joerg; Schellenberger, Eyk

doi:10.2147/ijn.s101141

Cited by 28 publications

(39 citation statements)

References 77 publications

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“…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.…”

Section: Discussioncontrasting

confidence: 66%

“…17 Iron oxide superparamagnetic nanoparticle formulations are considered as simple and effective contrast agents for MRI applications. 18 Such formulations exhibit strong negative contrast properties in both T 2 and T 2 *weighted MRI images, 19 and allow the histochemical detection of labeled cells by simple staining techniques. However, the iron oxide nanoparticle formulations and cell labeling protocols should be designed in a way to avoid any toxic effects or alteration of biological properties or functions of cells.…”

Section: Introductionmentioning

confidence: 99%

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

Ali¹,

Shahror²,

Chen³

2020

IJN

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Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/R_ECxLGJvxw Background: Regenerative medicine field is still lagging due to the lack of adequate knowledge regarding the homing of therapeutic cells towards disease sites, tracking of cells during treatment, and monitoring the biodistribution and fate of cells. Such necessities require labeling of cells with imaging agents that do not alter their biological characteristics, and development of suitable non-invasive imaging modalities. Purpose: We aimed to develop, characterize, and standardize a facile labeling strategy for engineered mesenchymal stem cells without altering their viability, secretion of FGF21 protein (neuroprotective), and differentiation capabilities for non-invasive longitudinal MRI monitoring in live mice brains with high sensitivity. Methods: We compared the labeling efficiency of different commercial iron oxide nanoparticles towards our stem cells and determined the optimum labeling conditions using prussian blue staining, confocal microscopy, transmission electron microscopy, and flow cytometry. To investigate any change in biological characteristics of labeled cells, we tested their viability by WST-1 assay, expression of FGF21 by Western blot, and adipogenic and osteogenic differentiation capabilities. MRI contrast-enhancing properties of labeled cells were investigated in vitro using cell-agarose phantoms and in mice brains transplanted with the therapeutic stem cells. Results: We determined the nanoparticles that showed best labeling efficiency and least extracellular aggregation. We further optimized their labeling conditions (nanoparticles concentration and media supplementation) to achieve high cellular uptake and minimal extracellular aggregation of nanoparticles. Cell viability, expression of FGF21 protein, and differentiation capabilities were not impeded by nanoparticles labeling. Low number of labeled cells produced strong MRI signal decay in phantoms and in live mice brains which were visible for 4 weeks post transplantation. Conclusion: We established a standardized magnetic nanoparticle labeling platform for stem cells that were monitored longitudinally with high sensitivity in mice brains using MRI for regenerative medicine applications.

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Section: Discussioncontrasting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

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

Ali¹,

Shahror²,

Chen³

2020

IJN

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“…This fact is reflected in the SD at each cell concentration. The resolution of MRI cell detection depends on many factors such as the r 2 value of the CA, the amount of internalized nanomaterial per cell, the MRI protocol, scanner specifications, and has reached the point of single-cell detection using Fe x O y -based nanoparticle labels [73]. The limit of cell detection with the core-shell Fe-Fe x O y NWs was not elucidated in our experimental setup.…”

Section: Magnetic Resonance Imaging Of Nanowires Internalized In Breamentioning

confidence: 94%

Magnetic core–shell nanowires as MRI contrast agents for cell tracking

et al. 2020

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Background: Identifying the precise location of cells and their migration dynamics is of utmost importance for achieving the therapeutic potential of cells after implantation into a host. Magnetic resonance imaging is a suitable, non-invasive technique for cell monitoring when used in combination with contrast agents. Results: This work shows that nanowires with an iron core and an iron oxide shell are excellent materials for this application, due to their customizable magnetic properties and biocompatibility. The longitudinal and transverse magnetic relaxivities of the core-shell nanowires were evaluated at 1.5 T, revealing a high performance as T 2 contrast agents. Different levels of oxidation and various surface coatings were tested at 7 T. Their effects on the T 2 contrast were reflected in the tailored transverse relaxivities. Finally, the detection of nanowire-labeled breast cancer cells was demonstrated in T 2-weighted images of cells implanted in both, in vitro in tissue-mimicking phantoms and in vivo in mouse brain. Labeling the cells with a nanowire concentration of 0.8 μg of Fe/mL allowed the detection of 25 cells/µL in vitro, diminishing the possibility of side effects. This performance enabled an efficient labelling for high-resolution cell detection after in vivo implantation (~ 10 nanowire-labeled cells) over a minimum of 40 days. Conclusions: Iron-iron oxide core-shell nanowires enabled the efficient and longitudinal cellular detection through magnetic resonance imaging acting as T 2 contrast agents. Combined with the possibility of magnetic guidance as well as triggering of cellular responses, for instance by the recently discovered strong photothermal response, opens the door to new horizons in cell therapy and make iron-iron oxide core-shell nanowires a promising theranostic platform.

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“…16 The higher photon-to-heat conversion efficiency of GNS, which can be tuned to have spectral absorption in the near-infrared region where tissue absorbs least, makes GNS superior in biological imaging and nanotherapeutic capabilities as compared to other commonly used nanoparticles. 14,15,[17][18][19] With regard to in vivo translation, GNS can easily penetrate tumor vasculature via EPR effect that originates from the inherently leaky tumor vasculature. 20,21 Furthermore, once delivered to the tumor microenvironment, there is minimal clearance of nanoparticles that range from 10 to 100 nm in size due to lack of an efficient lymphatic system.…”

Section: Crawford Et Almentioning

confidence: 99%

Photothermal ablation of inflammatory breast cancer tumor emboli using plasmonic gold nanostars

Crawford¹,

Shammas²,

Fales³

et al. 2017

IJN

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Inflammatory breast cancer (IBC) is rare, but it is the most aggressive subtype of breast cancer. IBC has a unique presentation of diffuse tumor cell clusters called tumor emboli in the dermis of the chest wall that block lymph vessels causing a painful, erythematous, and edematous breast. Lack of effective therapeutic treatments has caused mortality rates of this cancer to reach 20%–30% in case of women with stage III–IV disease. Plasmonic nanoparticles, via photothermal ablation, are emerging as lead candidates in next-generation cancer treatment for site-specific cell death. Plasmonic gold nanostars (GNS) have an extremely large two-photon luminescence cross-section that allows real-time imaging through multiphoton microscopy, as well as superior photothermal conversion efficiency with highly concentrated heating due to its tip-enhanced plasmonic effect. To effectively study the use of GNS as a clinically plausible treatment of IBC, accurate three-dimensional (3D) preclinical models are needed. Here, we demonstrate a unique in vitro preclinical model that mimics the tumor emboli structures assumed by IBC in vivo using IBC cell lines SUM149 and SUM190. Furthermore, we demonstrate that GNS are endocytosed into multiple cancer cell lines irrespective of receptor status or drug resistance and that these nanoparticles penetrate the tumor embolic core in 3D culture, allowing effective photothermal ablation of the IBC tumor emboli. These results not only provide an avenue for optimizing the diagnostic and therapeutic application of GNS in the treatment of IBC but also support the continuous development of 3D in vitro models for investigating the efficacy of photothermal therapy as well as to further evaluate photothermal therapy in an IBC in vivo model.

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Labeling of mesenchymal stem cells for MRI with single-cell sensitivity

Cited by 28 publications

References 77 publications

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

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

Magnetic core–shell nanowires as MRI contrast agents for cell tracking

Photothermal ablation of inflammatory breast cancer tumor emboli using plasmonic gold nanostars

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