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(Circulation. 2008;117:1555-1562.)
© 2008 American Heart Association, Inc.

Imaging

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

John Terrovitis, MD; Matthias Stuber, PhD; Amr Youssef, MD; Steve Preece, BS; Michelle Leppo, BS; Eddy Kizana, MD, PhD; Michael Schär, PhD; Gary Gerstenblith, MD; Robert G. Weiss, MD; Eduardo Marbán, MD, PhD; M. Roselle Abraham, MD

From Johns Hopkins University, Division of Cardiology, Department of Medicine (J.T., A.Y., S.P., M.L., E.K., G.G., R.G.W., E.M., M.R.A.), and Division of MR Research, Department of Radiology (M. Stuber, M. Schär), Baltimore, Md, and Philips Healthcare (M. Schär), Cleveland, Ohio. Dr Marbán is currently at The Heart Institute, Cedars Sinai Medical Center, Los Angeles, Calif. Dr Youssef is currently at the Ain Shams University, Cairo, Egypt.

Correspondence to M. Roselle Abraham, MD, Johns Hopkins University, Division of Cardiology, Department of Medicine, Rutland Ave, Ross 871, Baltimore, MD 21205. E-mail mabraha3{at}jhmi.edu

Received December 14, 2006; accepted January 23, 2008.

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 β-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 β-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.

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