Magnetic Resonance Imaging Overestimates Ferumoxide-Labeled Stem Cell Survival After Transplantation in the Heart

Abstract

Background-Stem cell labeling with iron oxide (ferumoxide) particles allows labeled cells to be detected by magnetic resonance imaging (MRI) and is commonly used to track stem cell engraftment. However, the validity of MRI for distinguishing surviving ferumoxide-labeled cells from other sources of MRI signal, for example, macrophages containing ferumoxides released from nonsurviving cells, has not been thoroughly investigated. We sought to determine the relationship between the persistence of iron-dependent MRI signals and cell survival 3 weeks after injection of syngeneic or xenogeneic ferumoxides-labeled stem cells (cardiac-derived stem cells) in rats. Methods and Results-We studied nonimmunoprivileged human and rat cardiac-derived stem cells and human mesenchymal stem cells doubly labeled with ferumoxides and ␤-galactosidase and injected intramyocardially into immunocompetent Wistar-Kyoto rats. Animals were imaged at 2 days and 3 weeks after stem cell injection in a clinical 3-T MRI scanner. At 2 days, injection sites of xenogeneic and syngeneic cells (cardiac-derived stem cells and mesenchymal stem cells) were identified by MRI as large intramyocardial signal voids that persisted at 3 weeks (50% to 90% of initial signal). Histology (at 3 weeks) revealed the presence of iron-containing macrophages at the injection site, identified by CD68 staining, but very few or no ␤-galactosidase-positive stem cells in the animals transplanted with syngeneic or xenogeneic cells, respectively. Conclusions-The persistence of significant iron-dependent MRI signal derived from ferumoxide-containing macrophages despite few or no viable stem cells 3 weeks after transplantation indicates that MRI of ferumoxide-labeled cells does not reliably report long-term stem cell engraftment in the heart. (Circulation. 2008;117:1555-1562.)

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

“…The present study was a proof-of-principle study to establish a reliable imaging technique for tracking transplanted hESC-CPCs that remain viable and differentiate into definite cardiac cell types. However, consistent with previous studies [3,13,37,38], we observed that not all delivered cells were present after 40 days. Similar poor cellular retention was observed between ferumoxytol-labeled and unlabeled transplanted hESC-CPCs.…”

Discrepancies between the fate of myoblast xenograft in mouse leg muscle and NMR label persistency after loading with Gd-DTPA or SPIOs

“…Very similar observations were made in both earlier and very recent publications. 22,37 However, with our head-to-head comparison of labeling time courses obtained with two different classes of CAs and supplemented by histological confrontations at many time points, we clearly demonstrated the severity of the positive bias generated by SPIOs for the long-term monitoring of grafted cells. As SPIOs are avidly phagocytosed by reticulo-histiocytic cells, these compounds were initially developed for intravenous injections to map reticulo-histiocytic cell distribution.…”

Non-Invasive analysis of synthetic and decellularized scaffolds for heart valve tissue engineering

“…For example, the possibility of the dissolution of ferrum particles after implantation of an imaged construct could put patients at medical risk. 33 A further disadvantage pertains to the labeling of the cells for imaging. For MRI visualization, cells of tissue constructs must be labeled with magnetic particles such as ferrumoxide.…”

“…For MRI visualization, cells of tissue constructs must be labeled with magnetic particles such as ferrumoxide. 33 These foreign molecules may potentially affect cell morphology, viability, and proliferation. If used as a method for preoperative valve evaluation, altering these cellular characteristics could negate the benefit aimed for by implanting a tissue-engineered heart valve.…”