Iron Administration before Stem Cell Harvest Enables MR Imaging Tracking after Transplantation

Khurana, Aman; Chapelin, Fanny; Beck, Graham; Lenkov, Olga; Donig, Jessica; Nejadnik, Hossein; Messing, Solomon; Derugin, Nikita; Chan, Roger W.; Gaur, Amitabh; Sennino, Barbara; McDonald, Donald M.; Kempen, Paul; Tikhomirov, Grigory; Rao, Jianghong; Daldrup-Link, Heike E.

doi:10.1148/radiol.13130858

Cited by 62 publications

(76 citation statements)

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“…Ferumoxytol (Feraheme™) is a USPIO and FDA-approved iron supplement (11), which exerts strong signal effects on MR images (13, 28) and can thus be applied “off label” for cell labeling and cell tracking purposes in patients. However, due to their small size, ferumoxytol nanoparticles have a reported low cellular uptake and require transfection-agent assisted protocols for cell labeling (12, 13).…”

Section: Discussionmentioning

confidence: 99%

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The Protein Corona around Nanoparticles Facilitates Stem Cell Labeling for Clinical MR Imaging

et al. 2018

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Purpose To evaluate if the formation of protein corona around ferumoxytol nanoparticles can facilitate stem cell labeling for in vivo tracking with MR imaging. Methods Ferumoxytol was incubated in media containing human serum (group 1), fetal bovine serum (group 2), StemPro® media (group 3), protamine (group 4) and protamine+heparin (group 5). Formation of a protein corona was characterized by dynamic light scattering (DLS), zeta potential, and liquid chromatography-mass spectrometry (LC-MS). Iron uptake was evaluated by DAB-Prussian blue, Lysosomal staining, and inductively coupled plasma spectrometry (ICP). To evaluate the effect of protein corona on stem cell labeling, human mesenchymal stem cells (hMSC) were labeled with above formulations, implanted into pig knee specimen and investigated with T2-weighted Fast Spin Echo (FSE) and Multi Echo Spin Echo (MESE) sequences on a 3T MR scanner. Data of different groups were compared with a Kruskal-Wallis test. Results Compared to bare nanoparticles, all experimental groups showed significantly increased negative zeta values (from −37 to less than −10; p=0.008). Nanoparticles in group 1–3 showed an increased size due to the formation of a protein corona. hMSCs labeled with group 1–5 media revealed significantly shortened T2-relaxation times compared to unlabeled controls (p=0.0012). hMSCs labeled with group 3 and 5 had the highest iron uptake after group 1. After implantation into pig knees, hMSCs labeled with group 1 media revealed significantly shorter T2-relaxation times compared to hMSC labeled with group 2–5 (p=0.0022). Conclusion The protein Corona around ferumoxytol nanoparticles can facilitate stem cell labeling for clinical cell tracking with MR imaging.

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Section: Discussionmentioning

confidence: 99%

“…Our team previously reported another clinically applicable approach for in vivo labeling of autologous bone marrow cells (28). After intravenous injection, ferumoxytol is taken up by hMSC in the bone marrow.…”

Section: Discussionmentioning

confidence: 99%

The Protein Corona around Nanoparticles Facilitates Stem Cell Labeling for Clinical MR Imaging

et al. 2018

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“…Cell tracking of large cohorts of magnetically labeled MSC has been demonstrated in rat models of nephropathy after intravenous [32] and intraarterial [33] injection and after intramyocardial cell injection in a porcine model of myocardial infarction [34]. Furthermore, at least four clinical trials using MRI cell tracking with superparamagnetic iron oxides have been performed with promising results and it is most likely that MSC-based therapies will become more and more popular over the next decades [35,36] This study investigates the possibility of in-vivo single cell detection of MSC by MRI, which would be a valuable technique to track the migration of even small numbers of MSC in living animals and may help to improve the understanding of the timeline of cell-based therapies, the cells immediate and long-term fate as well as the exclusion of graft failure or tumor formation at the injection side [37]. Therefore, the aims of this study were I) to magnetically and fluorescently co-label MSC, II) to detect co-labeled MSC by in-vivo MRI after minimally invasive intracardial injection of cells in mice and III) to validate MRI findings by verification of single cell distribution in different organs by fluorescent microscopy.…”

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Magnetic Resonance Imaging of Single Co-Labeled Mesenchymal Stromal Cells after Intracardial Injection in Mice

Salamon

Wicklein

Didié

et al. 2014

Fortschr Röntgenstr

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Ziel: Etablierung einer Doppelmarkierung mesenchymaler Stromazellen (MSZ) zur in-vivo Detektion einzelner MSZ mittels MRT und zur histologischen Validierung. Material und Methoden: Murine MSZ wurden mit fluoreszierenden Eisenmikropartikeln und Carboxyfluorescein Succinimidyl Ester (CFSE) markiert. Der zelluläre Eisengehalt wurde mittels Atomabsorptionsspektrometrie bestimmt. Zellprolieferation und Expression charakteristischer Oberflächenmarker wurden mittels Durchflusszytometrie bestimmt. Die chondrogene Differenzierungskapazität wurde überprüft. Verschiedene Zellanzahlen (n1 = 5000, n2 = 15 000, n3 = 50 000) wurden bei 12 Mäusen in den linken Herzventrikel injiziert. Es erfolgte die sequenzielle MRT der Tiere an einem klinischen 3.0 T MRT. Zur histologischen Validierung wurden Kryostatschnitte fluoreszensmikroskopisch untersucht. Ergebnisse: Die magnetische und fluoreszierende Doppelmarkierung von MSZ wurde etabliert (mittlerer zellulärer Eisengehalt 23,6 ± 4,3 pg). Durchflusszytometrisch zeigten sich ähn-liche Zellprolieferationsraten und Rezeptorexpressionsprofile von markierten und unmarkierten MSZ. Die chondrogene Differenzierung der doppelt markierten MSZ wurde verifiziert. Nach Zellinjektion zeigten sich im MRT multiple Signalauslöschungen im Hirn und geringer in der Niere. Im Hirn fanden sich durchschnittlich 4,6 ± 1,2 (n1), 9,0 ± 3,6 (n2) und 25,0 ± 1,0 (n3) Signalauslöschungen pro Schicht. Durchschnittlich fanden sich 8,7 ± 3,1 (n1), 22,0 ± 6,1 (n2) und 89,8 ± 6,5 (n3) Zellen pro korrespondierendem Kryostatschnitt. Die statistische Korrelation der mittels MRT detektierten Signalauslöschungen und der histologisch nachgewiesenen Zellen ergab einen Korrelationskoeffizienten von r = 0,91. Schlussfolgerung: Die Studie zeigt die erfolgreiche magnetische und fluoreszierende DoppelmarkieAbstract ! Purpose: The aim of this study was to establish co-labeling of mesenchymal stromal cells (MSC) for the detection of single MSC in-vivo by MRI and histological validation. Materials and Methods: Mouse MSC were co-labeled with fluorescent iron oxide micro-particles and carboxyfluorescein succinimidyl ester (CFSE). The cellular iron content was determined by atomic absorption spectrometry. Cell proliferation and expression of characteristic surface markers were determined by flow cytometry. The chondrogenic differentiation capacity was assessed. Different amounts of cells (n1 = 5000, n2 = 15 000, n3 = 50 000) were injected into the left heart ventricle of 12 mice. The animals underwent sequential MRI on a clinical 3.0 T scanner (Intera, Philips Medical Systems, Best, The Netherlands). For histological validation cryosections were examined by fluorescent microscopy. Results: Magnetic and fluorescent labeling of MSC was established (mean cellular iron content 23.6 ± 3 pg). Flow cytometry showed similar cell proliferation and receptor expression of labeled and unlabeled MSC. Chondrogenic differentiation of labeled MSC was verified. After cell injection MRI revealed multiple signal voids in the brain and fewer signal voids...

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“…Recent studies, however, have shown that iron oxide labeling, combined with magnetic targeting, might improve graft retention in the rat heart [29,30,34,36]. Thus, ferumoxytol cell labeling might have utility in both in vivo cardiac graft imaging and cell retention.…”

confidence: 99%

“…Recent studies have described the properties of the ultra-small superparamagnetic iron oxide nanoparticle, ferumoxytol (Feraheme; AMAG Pharmaceuticals, Inc., Waltham, MA, http://www.amagpharma.com) as a labeling agent [7,14,[29][30][31]. Ferumoxytol interacts with cells via a synthetic carbohydrate coating and is currently used for the treatment of iron-deficiency anemia in the presence of chronic kidney disease [32].…”

Section: Introductionmentioning

confidence: 99%

Magnetic Resonance Imaging of Iron Oxide-Labeled Human Embryonic Stem Cell-Derived Cardiac Progenitors

Skelton

Khoja

Almeida

et al. 2015

Stem Cells Translational Medicine

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Given the limited regenerative capacity of the heart, cellular therapy with stem cell-derived cardiac cells could be a potential treatment for patients with heart disease. However, reliable imaging techniques to longitudinally assess engraftment of the transplanted cells are scant. To address this issue, we used ferumoxytol as a labeling agent of human embryonic stem cell-derived cardiac progenitor cells (hESC-CPCs) to facilitate tracking by magnetic resonance imaging (MRI) in a large animal model. Differentiating hESCs were exposed to ferumoxytol at different time points and varying concentrations. We determined that treatment with ferumoxytol at 300 mg/ml on day 0 of cardiac differentiation offered adequate cell viability and signal intensity for MRI detection without compromising further differentiation into definitive cardiac lineages. Labeled hESC-CPCs were transplanted by open surgical methods into the left ventricular free wall of uninjured pig hearts and imaged both ex vivo and in vivo. Comprehensive T 2 *-weighted images were obtained immediately after transplantation and 40 days later before termination. The localization and dispersion of labeled cells could be effectively imaged and tracked at days 0 and 40 by MRI. Thus, under the described conditions, ferumoxytol can be used as a long-term, differentiation-neutral cell-labeling agent to track transplanted hESC-CPCs in vivo using MRI. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:67-74 SIGNIFICANCEThe development of a safe and reproducible in vivo imaging technique to track the fate of transplanted human embryonic stem cell-derived cardiac progenitor cells (hESC-CPCs) is a necessary step to clinical translation. An iron oxide nanoparticle (ferumoxytol)-based approach was used for cell labeling and subsequent in vivo magnetic resonance imaging monitoring of hESC-CPCs transplanted into uninjured pig hearts. The present results demonstrate the use of ferumoxytol labeling and imaging techniques in tracking the location and dispersion of cell grafts, highlighting its utility in future cardiac stem cell therapy trials.

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Iron Administration before Stem Cell Harvest Enables MR Imaging Tracking after Transplantation

Cited by 62 publications

References 82 publications

The Protein Corona around Nanoparticles Facilitates Stem Cell Labeling for Clinical MR Imaging

The Protein Corona around Nanoparticles Facilitates Stem Cell Labeling for Clinical MR Imaging

Magnetic Resonance Imaging of Single Co-Labeled Mesenchymal Stromal Cells after Intracardial Injection in Mice

Magnetic Resonance Imaging of Iron Oxide-Labeled Human Embryonic Stem Cell-Derived Cardiac Progenitors

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