Open Access Use of a Clinically Approved Iron Oxide MRI Contrast Agent to Label Human Hepatocytes

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Abstract:

Reliable noninvasive methods are needed to monitor cell engraftment and graft survival after hepatocyte transplantation. Superparamagnetic iron oxide nanoparticles (SPIOs) have been shown to accumulate in various types of cells, and are currently the labeling agent of choice for cellular magnetic resonance imaging (MRI). However, for successful clinical translation to hepatocyte transplantation, it is important that hepatocytes maintain their viability and synthetic function after labeling. In this study, primary human hepatocytes were incubated with increasing concentrations of clinical grade SPIOs for different time intervals. SPIOs uptake was confirmed by light and fluorescence microscopy, and intracellular iron content quantified by a colorimetric ferrozine-based assay. Studies were performed to determine if labeling affected cell viability and function. Intracellular iron concentrations increased in a time- and dose-dependent manner after incubation with SPIOs. Labeling had minimal short-term effects on cell attachment and mitochondrial function. However, exposure of hepatocytes to SPIOs resulted in a dose- and time-dependent reduction in protein synthesis. Cell labeling for 16 h had no significant effect on hepatocyte-specific function, but longer periods of incubation resulted in a dose-dependent decrease in albumin production. Hepatocytes incorporated SPIOs at sufficient levels for in vitro detection on a 7-T MRI imaging system, with a minimum of 2,000 SPIO-labeled cells/μl detected by a decreased T2 relaxivity compared to controls. Intrasplenic transplantation of human hepatocytes labeled with 50 μg Fe/ml of SPIOs was performed in nonobese diabetic/severe combined immune deficiency (NOD-Scid) mice. Recipient livers showed a clear decrease in signal intensity on T2*-weighted MR images when compared to controls, allowing detection of hepatocytes. With further experiments to optimize the conditions for labeling human hepatocytes, it should be possible to apply this technique to track hepatocyte transplantation in patients with liver disease.

Keywords: Cell labeling; Contrast agents; Cytotoxicity; Hepatocyte transplantation; Magnetic resonance imaging (MRI); Superapragmagnetic iron oxide nanoparticles (SPIOs)

Document Type: Research Article

DOI: http://dx.doi.org/10.3727/096368910X543367

Affiliations: Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, London, UK

Publication date: June 1, 2011

More about this publication?
  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.
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