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Use of magnetism to enhance cell transplantation success in regenerative medicine “…magnetic labeling of cells can be considered a ‘theranostic’ approach: a versatile and useful tool in both directing therapeutic cells to target organs and also imaging this trafficking for prolonged periods of time.” KEYWORDS: cell targeting n iron oxide n magnetic nanoparticle n stem cell
An increasingly important need in regenerative medicine is the efficient in vivo targeting and tracking of cells. Locating cells using magnetism and directing their passage along magnetic fields is evolving as a particularly useful noncontact approach in solving these problems. With this in mind, in recent years, a new class of molecules – magnetic nanoparticles (MNPs) – has been developed  . MNPs are particles with magnetic cores surrounded by various biological polymers that can be internalized by cells through endocytosis  . MNPs can be classified as superparamagnetic, paramagnetic, ferimagnetic or ferromagnetic depending on their magnetic cores, and contain manganese, gadolinium or, most commonly, iron oxide  . Significant advances have been made in targeting therapeutic drugs using these molecules and now MNPs are being used to target cells [1,3] . Magnetic fields and MNPs are being used in cell therapies in a number of ways. In most cases, solid magnets are localized to the disease site and then MNP-labeled cells are injected either into the vasculature or sometimes intrathecally to accumulate in the region of the solid magnet. In preclinical studies, magnetic targeting has been successful in directing cells to damaged tissues in many organs, such as the spinal cord  , the muscle microvasculature of an ischemic limb  , arteriosclerosis within larger blood vessels  , the dystrophic retina  and directing natural killer cells to tumors  . MNPs have also been used to augment biomaterial scaffolds used in tissue regeneration  . In addition, magnetism has been used in tissue manufacture in preparation for in vivo work. For example, magnetism has been used to build sheets of mesenchymal stem cells  . Currently, however, the most successful role for MNPs in cell therapies has been their use in imaging and tracking cells. In vivo, MNPs
can be detected by MRI to produce images of high spatial resolution and without the need for exposure to ionizing radiation  . The widespread availability of MRI technology has also helped to drive investigations. In preclinical work to date, numerous studies have shown the feasibility of MRI tracking of MNP-labeled cells in vasculature and the quantifying of their accumulation in target and collateral organs  . The success of this technique is also reflected in the fact that MNPs have now been used for the MRI tracking of cells in human clinical trials. The earliest clinical studies looked at dendritic cells labeled with iron oxide particles and tracked by MRI after intranodal injection  . Another study looked at human neural progenitor cells labeled with Feridex® and injected directly into damaged human temporal lobe, showing that these cells can survive for up to 7 weeks  . Most recently, leukocytes labeled with ferumoxtran were tracked by MRI imaging in myocardial infarction patients  .
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“Reports … suggest that magnetic nanoparticle labeling might affect iron metabolism within cells, migration capacity and cell colony formation, although this does not appear to correlate with poorer cell viability.” Despite these significant successes in both preclinical and clinical work, the widespread application of magnetism in cell medicine has yet to occur. Concerns that have been highlighted in clinical cell tracking include: at least a few hundred labeled cells need to be present in order to be detectable by MRI; the signal from labeled cells can be confused with hemosiderin in local hemorrhage; and MNPs can leak from targeted cells as they die, giving the false impression
Kevin Gregory-Evans Author for correspondence: Department of Ophthalmology & Visual Sciences, University of British Columbia, Eye Care Centre, 2550 Willow Street, Vancouver, BC V5Z 3N9, Canada Tel.: +1 604 875 5275 Fax: +1 604 875 4663 [email protected]
Abu E Bashar Department of Ophthalmology & Visual Sciences, University of British Columbia, Eye Care Centre, 2550 Willow Street, Vancouver, BC V5Z 3N9, Canada
Christopher Laver Department of Ophthalmology & Visual Sciences, University of British Columbia, Eye Care Centre, 2550 Willow Street, Vancouver, BC V5Z 3N9, Canada
Gregory-Evans, Bashar & Laver
that these cells are still present. However, most concerns have focused on adverse effects rather than ineffectiveness. These concerns can be sub classified into intracellular complications, local tissue damage and remote organ complications. MNPs have been shown to accumulate within cell endosomes and lysosomes, but with time are released into the cytoplasm, ultimately increasing the total cellular iron pool. Reports therefore suggest that MNP labeling might affect iron metabolism within cells, migration capacity and cell colony formation, although this does not appear to correlate with poorer cell viability  . Other effects include studies that suggested that MNPs induce oxidative stress in cells. For instance, recent studies have found oxidative stress responses in Chinese hamster lung cells, but only after incubation with very high concentrations of l-glutamic acid-coated iron oxide nanoparticles  . It has also been suggested that MNPs can alter cell behavior; for instance, mesenchymal stem cells appear to lose some osteogenic differentiation ability once labeled with ferucarbotran at high concentration, although conversely, other studies have suggested that MNPs might enhance the adipogenic differentiation of mesenchymal stem cells  . By contrast, more recent studies have suggested that the differentiation of stem cells is not affected by MNPs, and gene expression profiling demonstrated only brief effects of iron oxide MNPs on neural stem cell gene expression  .
“…more recent studies have suggested that the differentiation of stem cells is not affected by magnetic nanoparticles, and gene expression profiling demonstrated only brief effects of iron oxide magnetic nanoparticles on neural stem cell gene expression.”
Thoughts on local tissue damage have focused on the accumulation of magnetic elements, particularly iron, in or near the targeted region. Iron is adept at oxidizing a large number of substrates and causing local tissue damage through the Fenton reaction. This could be especially problematic if multiple doses of MNPlabeled cells are required over time. For instance, iron oxide accumulation has been found in the hippocampus and striata after intranasal injection of MNPs in Sprague–Dawley rats. Critically, however, no adverse functional effects were documented. More worryingly, intratracheal instillation of iron oxide MNPs in 2
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Wistar rats has been associated with iron oxide accumulation in the lung and minor pulmonary fibrosis with increasing dose. Notably, however, no significant loss of lung function was documented and no signs of damage in other organs (liver, kidney, heart and spleen) was identified  . Another study in Wistar rats has shown that repeated oral iron oxide MNPs at high doses over 28 days is associated with a significant change in CNS electrolytes, elevated liver function tests and histopathological signs of liver and renal necrosis  . With reference to MNP-labeled cells targeted via the systemic circulation, it has been proposed that such cells can accumulate in the lungs and liver, and, potentially, such cells could undergo agglomeration in the presence of an external magnetic field, causing vascular embolization  . There are also reports of accumulation of cells and MNPs in more distant organs, such as the lung and liver, particularly when cells are being targeted via the systemic circulation  . However, methods to avoid accumulation of MNP-labeled cells as they pass through the vasculature are emerging  . Overall, however, theoretic concerns have yet to be realized in preclinical studies showing large-scale, serious adverse effects at MNP doses that would be applicable in cell therapeutics. In addition, only a few adverse effects (e.g., urticaria, headache, back pain, nausea and diarrhea) have been reported with the use of ferumoxtran-10 in human trials  . In conclusion, magnetic labeling of cells can be considered a ‘theranostic’ approach: a versatile and useful tool in both directing therapeutic cells to target organs and also imaging this trafficking for prolonged periods of time. Although serious adverse effects with this methodology have yet to become apparent, further work is ongoing to modify MNPs in order to avoid even the most minor physiological changes associated with their use. In addition, longer preclinical and clinical prospective studies that are sufficiently powered to identify serious adverse events are required. Financial & competing interests disclosure K Gregory-Evans has been a member of a Pfizer Pharmaceuticals Stem Cell Advisory Panel. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. future science group
Use of magnetism to enhance cell transplantation success in regenerative medicine
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