Magnetic nanoparticles for oligodendrocyte precursor cell transplantation therapies: progress and challenges
© Jenkins et al.; licensee BioMed Central Ltd. 2014
Received: 13 May 2014
Accepted: 20 July 2014
Published: 28 July 2014
Oligodendrocyte precursor cells (OPCs) have shown high promise as a transplant population to promote regeneration in the central nervous system, specifically, for the production of myelin – the protective sheath around nerve fibers. While clinical trials for these cells have commenced in some areas, there are currently key barriers to the translation of neural cell therapies. These include the ability to (a) image transplant populations in vivo; (b) genetically engineer transplant cells to augment their repair potential; and (c) safely target cells to sites of pathology. Here, we review the evidence that magnetic nanoparticles (MNPs) are a ‘multifunctional nanoplatform’ that can aid in safely addressing these translational challenges in neural cell/OPC therapy: by facilitating real-time and post-mortem assessment of transplant cell biodistribution, and biomolecule delivery to transplant cells, as well as non-invasive ‘magnetic cell targeting’ to injury sites by application of high gradient fields. We identify key issues relating to the standardization and reporting of physicochemical and biological data in the field; we consider that it will be essential to systematically address these issues in order to fully evaluate the utility of the MNP platform for neural cell transplantation, and to develop efficacious neurocompatible particles for translational applications.
KeywordsOPC Uptake Labeling Tracking Iron oxide Magnetic targeting Neural cell Cell therapy
OPC transplantation therapies for regenerative neurology
Transplantation of OPCs derived from a range of cell sources enhances myelin repair in animal models, including extensive myelin genesis and rescue from lethal conditions in dysmyelinating/ hypomyelinating mutant rodents[6–9]. Introduction of human OPCs into newborn shiverer mice resulted in extensive myelination, neurological improvement and enhanced survival in ~26% of mice. Givogri et al. transplanted primary OPCs into a neonatal mouse model of metachromatic leukodystrophy, a genetic disorder leading to demyelination and extensive loss of oligodendrocytes; transplant populations generated myelinating oligodendrocytes, identifiable one year post-transplantation, with motor function significantly improved compared with controls. Human embryonic stem cell (ESC)-derived OPCs, transplanted into adult rodent models of SCI, demonstrated remyelination and associated improvement in motor function. From a clinical perspective, OPC transplant populations can be derived from numerous sources[13–16], expanded in vitro[14–16], have a good preclinical safety record and have been approved for clinical trial (Geron Corporation, California; GRNOPC1 cells; phase I clinical trial for transplantation of human ESC-derived OPCs into acute SCI[17–19]). This trial recruited 5 of the 10 patients originally intended, but has now stopped enrolling, a decision taken by Geron on financial grounds[18, 21–23]. No adverse effects have been reported within one year of transplantation, and a US clinical trials database now lists this study as ‘complete’ (http://www.clinicaltrials.gov, trial identifier NCT01217008, accessed 01 July 2014)[18, 22]. Patients will be followed-up at both 5 and 15 years post-transplantation. Through a deal with BioTime, Asterias Biotherapeutics have acquired the GRNOPC1 stocks (renamed AST-OPC1) and ‘plan to seek FDA clearance to reinitiate human clinical trials’ (asteriasbiotherapeutics.com/our-clinical-focus/opc1/, accessed 01 July 2014). In a review of 24 preclinical OPC transplant studies for SCI models, no instances of teratomas, systemic toxicity, allodynia, increased mortality or allogeneic immune responses were recorded.
The MNP platform can address key challenges confronting OPC transplantation therapies
For neural cell therapies, non-invasive tracking of transplanted cells is essential to correlate functional neurological recovery with transplant cell biodistribution. Further, post-mortem histological analyses are required to assess transplant cell survival, rejection, differentiation profiles and integration, including the extent of myelin genesis. MNPs have been shown to be broadly suitable for both non-invasive and histological imaging, serving as contrast agents for MRI and being readily detectable in post-mortem tissue[29–34]. MRI offers critical advantages for non-invasive imaging including (a) detailed anatomical imaging of inflammation, demyelination/remyelination and assessment of lesion size, in parallel with transplant cell detection; (b) lack of potentially harmful radiation (in contrast to CT and PET scanning); and (c) existence of significant infrastructure and expertise in place at clinics worldwide. MNPs provide MRI contrast for imaging through high magnetic moments, which disturb local magnetic field homogeneities, resulting in short relaxivity times in water protons in the immediate vicinity of the particles and loss of signal in T2*-weighted MRI images[35, 37, 38]. The contrast generated is proportional to the magnetization of the metal, and inversely proportional to the distance between metal and water protons, so particles designed with high iron content and/or iron near their surface are likely to provide enhanced contrast[26, 37]. Clinical MRI scanners have a resolution of ~500 μm, but high magnetic field (up to 9 T) research scanners have demonstrated a resolution of ~10 μm (although these are unlikely to be safe for human clinical use), with recent refinements allowing for the identification of individual transplant cells. It should be pointed out here that MRI cannot distinguish between intracellular and extracellular MNPs, and dead/dying MNP-labeled cells can therefore provide false-positives. In order to address this confounding issue, studies have correlated MRI contrast with the presence of transplanted cells by post-mortem analyses such as immunostaining. Other methods, such as spatial correlation of MNPs with transplant cell-associated transgene expression or myelin production have also been used to unambiguously identify MNP-labeled OPCs within host tissue.
Comparative data from MNP studies involving OPCs or oligodendroglial cell lines
Core (nm ± SD)
Size (nm ± SD)
Zeta (mV ± SD)
Uptake/Labeling/Transfection [incubation conditions]
MION-46 L (CMIR, USA)
EM: 4.6 ± 1.2; maghemite or magnetite
-2.0 ± 0.4 (H2O)
None [48 h; 50–500 μg Fe/ml]
No data supplied
Dextran + anti-Tfr antibody OX-26c
“numerous intracellular vesicles”, not quantified [48 h; 2–50 μg Fe/ml]
Myelin deficient (md) rat spinal cord, P7.
Post-mortem excised spinal cord, 14 d; MRI contrast correlated well with iron-staining and new myelin
Trypan blue assay: similar viability for labeled/unlabeled cells
Not tested; <400e
>60% of cells labeled [24 h; 2 μg Fe/ml]
Adult rat ventricles
Labeled cells detected, post-mortem excised brain, 7 d
No data supplied
EM: 7-8; maghemite or magnetite crystals; multiple per particle
Not tested; “highly polarized”; carboxylation implies negative
Primary rat NSC-derived OPCs (LacZ+)
“remarkable high degree of intracellular labeling”; within vesicles/endosomes; relaxometry: 9.3 ± 4.3 pg Fe/cell; Ferrozine: 8.5 ± 2.0 pg Fe/cell [48 h; 25 μg/ml]
Long-Evans Shaker (les) rat ventricles, P0
In vivo, 6 weeks post-transplantation; ‘excellent’ MRI contrast correlation with LacZ expression post-mortem
Labeled cells viable. No difference in growth between labeled/unlabeled cells
10 pg Fe/cell (control: 1 pg); retained at 1 week in vitro [24–48 h; 10–25 μg Fe/ml]
Proliferative capacity and viability unaffected
Primary rat NSC-derived OPCs (LacZ+)
10 pg Fe/cell; retained at 1 week in vitro [24–48 h; 10–25 μg Fe/ml]
Long-Evans Shaker (les) rat ventricles, P0
In vivo, 6 weeks post-transplantation; ‘excellent’ MRI contrast correlation with LacZ expression post-mortem
Proliferative capacity and viability unaffected
Feridex (Berlex, USA)
5; iron oxide
“low” [48 h; 25 μg Fe/ml]
Labeled cells detected in gelatin
No data supplied
Feridex + Lipofectamine
Dextran + Lipofectamine Plus
14.7 ± 1.7 pg Fe/cell (control: 1.9 ± 0.9) [48 h; 25 μg Fe/ml]
Feridex + PLL
Dextran + PLL
3.8 ± 1.2 pg Fe/cell [48 h; 25 μg Fe/ml]
Feridex (Berlex, USA) + PLL
5; iron oxide
Dextran + PLL
Primary rat GRP + NRP (transgenic)
“large numbers of particles were taken up”; localized to endosomes, not nuclear; [48 h, 25 μg Fe/ml]
Adult rat spinal cord
Labeled cells detected, post-mortem excised spinal cord, 5 weeks post-transplantation; 5 mm migration. MNPs correlated well with iron-staining and transgene expression.
Transplanted cells differentiate comparably to unlabeled cells. Labeled transplants elicited greater immune response.
159 ± 34 nmol Fe/mg protein, ~2.2 pg Fe/cellf (control: 10 ± 2, ~0.1 pg Fe/cellf); concentration-dependent; in intracellular vesicles [48 h; 300 μM]
No effects on viability, morphology or proliferation. No Fe leaching from MNPs.
5-20; iron oxide
-26 ± 3 (FCS-)
4200 nmol Fe/mg protein, ~57 pg Fe/cellf (control: 7, ~0.1 pg Fe/cellf); concentration-dependent; retained at 24 h [8 h; 4 mM Fe]
Concentration-dependent: altered morphology, increased ROS, decreased GSH, but all reversible and viability unaltered.
957 nmol Fe/mg protein, ~13 pg Fe/cellf (control: 5, ~0.1 pg Fe/cellf); decreased to ~620 nmol Fe/mg at 48 h, ~8 pg Fe/cellf; concentration-dependent; perinuclear accumulation [24 h; 1000 μM; 55 μg Fe/ml]
None evident. No ROS increase. Increased ferritin.
Neuromag (OZ Biosciences, France)
Not tested; ~0.5% Feb
Not tested; proprietary
Not reported; proprietary
Primary culture-derived OPCs
~21% of cells transfected [oscillating magnetic field; 24 h]
Ex vivo, onto organotypic neural tissue slice
None evident by morphology or cell counts. ‘Transplanted’ cells proliferated, differentiated, integrated into slice.
Sphero (Spherotech, USA)
Not tested; Polystyrene, nile red-stained
Carboxylated Fe3O4/ polystyrene; 15-20% Feb
EM: 200–390 (mean 360);b DLS: 843-961
~60% of cells labeled; heterogeneous extent, typically ‘low’. Time- and concentration-dependent. [24 h; 50 μg/ml]
Particles in agar gel show concentration-dependent contrast
None evident by morphology or cell counts. Generated MNP-labeled oligodendrocytes. Intracellular MNPs appear stable.
EM: 24.3 ± 5.7; XRD: 25.5; Fe3O4; ~58% Fe
1800 MW PEI; RITC
~50% [5 μg/ml], ~60% [24 h; 20 μg/ml]. Concentration-dependent.
Particles show concentration-dependent contrast
None evident by morphology or cell counts
DLS: 53 (H2O); 52 ± 2 (medium, FCS-)
-58 ± 4 (H2O); -20 ± 10 (medium, FCS-)
Specific iron: ~1700 nmol/mg protein, ~23 pg Fe/cellf (~30-50% represents extracellular MNPs; control: 69 nmol/mg, ~1 pg Fe/cellf) [FCS-; 4 h, 1 mM]
Unaltered LDH activity
DLS: 109 ± 23 (medium, FCS+)
-9 ± 1 (medium, FCS+)
201 ± 63 nmol/mg protein, ~3 pg Fe/cellf [FCS+]
DMSA + BODIPY
DLS: 63 (H2O); 61 ± 5 (medium, FCS-)
-58 ± 18 (H2O); -28 ± 2 (medium, FCS-)
Specific iron: ~1800 nmol/mg protein, ~24 pg Fe/cellf (~30-50% represents extracellular MNPs; control: 69 nmol/mg, ~1 pg Fe/cellf); Not lysosome-associated. [FCS-; 4 h, 1 mM]
Unaltered LDH activity
DLS: 138 ± 24 (medium, FCS+)
-10 ± 1 (medium, FCS+)
171 ± 15 nmol/mg, ~2 pg Fe/cellf [FCS+]
The Bulte group reported comparable uptake levels in CG4 cells, OPCs and other cell types, concluding that MNP-uptake is non-specific and independent of cell type[31, 45]. However, our group has reported substantial variability in MNP-uptake dynamics between neural cell types. Concentration- and time-dependent uptake of carboxylated polystyrene MNPs was shown for four neural cell types (microglia, astrocytes, OPCs and oligodendrocytes) derived from primary cultures. Up to 60% of OPCs were labeled, with heterogeneity in the extent of MNP-loading. Notably, microglia exhibited very avid and extensive MNP uptake compared with the other cell types, with oligodendrocytes demonstrating the lowest levels of uptake.
Hohnholt et al. (2010, 2011) used MNPs with the goal of studying iron metabolism and toxicity, rather than labeling, in OLN-93 cells (an oligodendroglial cell line) reporting concentration-dependent uptake of both citrate- and dimercaptosuccinic acid (DMSA) coated MNPs (up to 300-fold increases in average intracellular iron)[47–49]. In a subsequent study, Petters et al. (2014) functionalized these DMSA-coated MNPs with a fluorophore and demonstrated uptake comparable to particles lacking conjugated fluorophores (69 nmol Fe/mg cellular protein control; ~1700 nmol/mg without fluorophore; ~1800 nmol/mg with fluorophore; to aid comparisons with other studies, we have re-calculated these values, as described in Additional file1; respectively, these values are ~1 pg Fe/cell, ~23 pg Fe/cell and ~24 pg Fe/cell). Importantly, the authors characterized these particles before and after functionalization, an oft-omitted step (Table 1;[29, 33]): size increased by 17%, zeta potential changed from -20 to -28 mV. This study noted nine-fold greater levels of uptake in the absence of serum, compared to serum-supplemented medium, illustrating the influence of the biochemical composition of media on particle-cell interactions.
Many MNPs are readily detected due to their metal content, for example by simple histochemical iron staining, which in turn correlates well with MRI observations of MNP-labeled OPCs post-transplantation[29, 32]. For particles not amenable to metal-based detection (e.g. due to low iron content), fluorophores can be incorporated, either internally or attached to the particle surface, facilitating post-mortem detection by fluorescence imaging. For example, Kircher et al. demonstrated detection of a cyanine dye (Cy5.5)-tagged dextran-coated MNP through fluorescence microscopy of post-mortem tissue, although this particle was used to delineate a brain tumor, rather than to track a transplant population.
Long-term tracking of transplanted cells is highly dependent upon label retention, but dilution of MNP-labeling has been observed in vitro and in vivo, being attributed at least in part to cell proliferation[29, 40]. This represents a particular challenge for imaging the biodistribution/migration of proliferative populations such as OPCs. Although MNP retention by OPCs has been reported for 7 d in vitro and 6 weeks post-transplantation (upper limits not determined)[31, 45], no studies have systematically quantified proliferative dilution of MNPs, or distinguished between particle loss due to cell proliferation versus cellular excretion by exocytosis. A further concern is whether particles are retained during differentiation into mature oligodendrocytes, as the primary goal of OPC therapy is to replace lost/damaged oligodendrocytes[1, 5]. Therefore, the ability to image these differentiated cells long-term in areas of regeneration is key for myelinating therapies. Oligodendrocytes are post-mitotic cells, therefore particle loss due to proliferative dilution is eliminated. Indeed in our experiments, when pulse-labeled OPCs were subsequently differentiated and maintained for 30 days, a significant proportion (>50%) of oligodendrocytes displayed MNP-labeling, suggesting that the differentiated progeny can ‘inherit’ MNPs and retain the label for long-term imaging.
MNPs have promising safety profiles in OPCs
In order to develop MNPs for clinical cell therapies, it is of paramount importance to assess their potential cytotoxic effects in neural transplant populations. Oligodendroglial cells contain more iron than any other CNS cell type, but are also the most vulnerable to excess iron, which typically leads to oxidative stress due to reactive oxygen species (ROS). It is of note that oxidative stress has been linked with oligodendrocyte damage in diseases such as Multiple Sclerosis[57, 58], indicating that MNP-induced genesis of ROS could be similarly deleterious to labeled transplanted oligodendroglial cells. In other neural cells, MNPs have been shown to impair cellular function through mechanisms including disruption to the cytoskeleton/cell membrane[59, 60] or intracellular trafficking processes[61, 62], and direct damage to intracellular organelles including by iron release during particle degradation. Through these or other mechanisms, MNP uptake could also perturb cellular behavior, including capacity for migration or proliferation.
The Dringen group have used the OLN-93 oligodendroglial cell line to conduct the most detailed MNP-OPC toxicity studies to date, including demonstration of uptake of citrate-coated MNPs without affecting viability, morphology or proliferation, and without evidence of iron leaching. Ferritin was greatly upregulated in response to increased Fe levels, storing Fe in a redox inactive form and protecting against iron-related toxicity. A battery of assays found no evidence of acute cytotoxicity (72 h) for DMSA-coated MNPs. For the same MNPs and cells, another study reported morphological changes, decreased glutathione (an antioxidative molecule) and increased ROS, but these changes were reversible and did not affect viability[48, 65]. Consistent with these data, OPCs labeled with other MNPs are generally reported as having viability and behavior comparable to unlabeled OPCs (Table 1;[29, 31, 32, 45, 52, 53, 55]).
Combinatorial therapies and OPC transplantation: using multimodal MNPs to achieve multiple therapeutic goals
While cell therapy alone is demonstrably efficacious, a widely-held view in the regenerative neurology community is that ‘combinatorial’ therapies (e.g. cell transplantation plus drug/gene delivery) achieve more impactful clinical regenerative outcomes than single therapeutic strategies[66–70]. For example, transplanting OPCs genetically engineered to secrete neurotrophic factors showed significantly greater improvement in SCI injury models than transplanting unmodified OPCs, or fibroblasts secreting the same neurotrophins[68, 71]. A major translational challenge currently is to achieve safe and effective genetic engineering of transplant populations. We have shown that MNPs can deliver both reporter and therapeutic genes to OPCs, a process significantly enhanced by the use of state-of-the-art ‘magnetofection’ strategies (applied static or oscillating magnetic fields to enhance particle-cell contact; up to 21% transfection efficiency in OPCs derived from primary sources). In contrast to the precursor cells, differentiated oligodendrocytes showed far lower transfection levels (up to 6%), suggesting that the proliferative or endocytotic properties of the OPCs may make these cells relatively amenable to MNP-mediated transfection compared with their progeny. As far as we are aware, these are the only reports of MNP-mediated gene delivery to cells of the oligodendrocyte lineage available.
Challenges for cell transplantation therapies and the relevant utility of magnetic nanoparticles
Gene delivery to transplant populations
Non-invasive transplant tracking
Post-mortem transplant identification
• Therapeutic biomolecule delivery for combinatorial therapies.
• Assess on-target/off-target delivery.
• Deliver high number of cells to lesions.
• Assess survival, differentiation, integration into host.
• Transgenes more effective than separate biomolecule delivery.
• Correlate clinical improvement/side-effects with cell presence.
• Reduce cell loss/maximize therapeutic effect.
• Correlate biodistribution of cells with evidence of regeneration.
• Minimize off-target effects.
• Viral vectors efficient but raise clinical safety concerns and require substantial infrastructure.
• Plasmonic resonance of gold nanoparticles: promising, but little infrastructure; gold particles cannot be non-invasively manipulated.
• Invasive injection into lesion parenchyma risks secondary damage.
• Dyes frequently leak and label host cells.
• Many nonviral methods inefficient, unsafe and/or not clinically relevant.
• Radiation exposure is associated with CT scans (X-rays) and PET scans (tracers).
• Distal intravenous/intrathecal delivery limits adherence/accumulation at target.
• LacZ transgene expression confounded by host microglial β-galactosidase activity.
• Cell-seeded scaffolds require invasive delivery at lesion site.
• Mismatched gender/species/mutant transplants are not clinically relevant.
Benefits of MNPs
• Comparable efficiency to other nonviral systems.
• Provide contrast for non-invasive MRI.
• Non-invasive manipulation of MNP-labeled cells using magnetic fields for:
• Provide MRI contrast.
• Safe protocols developed.
• Clinical MRI equipment and expertise widely available.
• Retention of cells at target site, facilitating adhesion.
• Metals (e.g. iron) can be stained.
• ‘Capture’ of cells from blood/cerebrospinal fluid; safe delivery distal to lesion.
• Fluorophores can be incorporated into MNPs (for preclinical testing).
Biological perspectives: the need for standardization of reporting
The MNP platform offers high promise for neural transplantation applications, but the field is still in its relative infancy. In-depth and cross-disciplinary studies between materials chemists and transplantation neurobiologists are required to fully evaluate MNPs as an adjunct tool for OPC transplantation. For example, despite the key advantages offered by multimodal MNPs for OPC transplantation, there is a critical lack of neurocompatible and multimodal MNPs, representing a major scientific and commercial gap. The potential for magnetic cell targeting of OPCs to injury foci has never been assessed, and the processes of proliferative dilution and particle ‘inheritance’ by daughter oligodendrocytes are poorly understood. Further, much of the research investigating MNP uptake and handling by OPCs has relied on cell lines, whose behavior can differ markedly from primary cells – consequently, biological data derived from cell lines may have limited predictive value. For example, Pinkernelle et al. report six-fold greater MNP-labeling in the ‘neuron-like’ cell line PC12 than in primary neurons; similar comparative analyses are required for OPCs.
The standardization of data reporting from MNP-labeling studies is essential to guide advances in nanoparticle synthesis and design. As with many biomaterials studies, MNPs used for OPC labeling are typically not fully characterized, yet these details are essential to identify parameters relevant for improving biomaterial design. There has been little systematic attempt to correlate MNP physicochemical properties with extent of OPC labeling (Table 1), of high relevance from a cell therapy perspective. Findings regarding the ability of oligodendroglial cells to take up MNPs without conjugated targeting molecules/transfection agents are contradictory (e.g. Bulte and Frank versus Franklin, all using dextran-coated MNPs); the reasons underpinning these differences are difficult to address in the absence of detailed particle characterization. Typically, reports should include size, shape and surface charge/functionalities of the final particle, measured within physiologically relevant media. The evaluation of OPC interactions with MNPs possessing a wider range of physicochemical properties can inform the tailored development of MNPs for specific transplantation applications. Such investigations should ideally include ultrastructural analyses of particle-cell interactions, along with evaluations of intracellular handling and particle fate to establish cellular processing mechanisms for different particles. This information can guide the development of MNPs with potential for endosomal escape, or suggest specific uptake mechanisms to which MNPs should be preferentially targeted for optimal labeling.
Other substantial knowledge gaps are apparent from the literature. Few studies report the proportions of OPCs exhibiting MNP-labeling, or conduct assessments of the extent of MNP-loading and its correlation with imaging capacity. More often, researchers provide an average iron content per cell measurement, which will mask any heterogeneity of particle accumulation within a cell population. This is particularly relevant to primary populations (the most likely cell source for transplantation therapies) which show considerable heterogeneity in behavior including particle uptake, unlike cell lines which behave in a relatively clonal manner. Most studies report limited MNP-associated cytotoxicity in OPCs, but generally without numerical viability/safety data, a significant shortcoming as this information is vital to developing biocompatible particles and safe labeling protocols. Microarray/proteomic analyses are essential for detailed molecular analyses of MNP toxicity, particularly the long term safety of transplant populations. This should progress in parallel with functional assays of the regenerative capacity of transplanted MNP-labeled OPCs (e.g. cell migration and myelin genesis). It can be predicted that such work can facilitate the development and application of this platform technology to neural cell therapies, in order to promote repair mechanisms following neurological pathology – currently a key goal for regenerative medicine globally.
Oligodendroglial cell line
Central nervous system
Embryonic stem cell
Myelin basic protein
Oligodendroglial cell line
Oligodendrocyte precursor cell
Rhodamine B isothiocyanate
Reactive oxygen species
Spinal cord injury.
SJ is funded by an Engineering and Physical Sciences Research Council (EPSRC; UK) Engineering Tissue Engineering and Regenerative Medicine (E-TERM) Landscape Fellowship. DC is funded by a Biotechnology and Biological Sciences Research Council (BBSRC; UK) grant.
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