Published Online
on March 10, 2008

A more recent version of this article appeared on March 25, 2008

This Article Full Text (PDF) Data Supplement All Versions of this Article: 117/12/1555    most recent CIRCULATIONAHA.107.732073v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Terrovitis, J. Articles by Abraham, M. R. Search for Related Content PubMed PubMed Citation Articles by Terrovitis, J. Articles by Abraham, M. R. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB IRON Medline Plus Health Information MRI Scans Related Collections Imaging CT and MRI Related Article

Submitted on December 14, 2006
Accepted on January 23, 2008

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, and 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.

^* To whom correspondence should be addressed. E-mail: mabraha3{at}jhmi.edu.

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.

Key words: magnetic resonance imaging • cells • transplantation

Related Article:

Clinical Summaries
Circulation 2008 117: 1499. [Extract] [Full Text]

This article has been cited by other articles:

				M. R. Loebinger, P. G. Kyrtatos, M. Turmaine, A. N. Price, Q. Pankhurst, M. F. Lythgoe, and S. M. Janes Magnetic Resonance Imaging of Mesenchymal Stem Cells Homing to Pulmonary Metastases Using Biocompatible Magnetic Nanoparticles Cancer Res., December 1, 2009; 69(23): 8862 - 8867. [Abstract] [Full Text] [PDF]

				T. Higuchi, M. Anton, A. Saraste, K. Dumler, J. Pelisek, S. G. Nekolla, F. M. Bengel, and M. Schwaiger Reporter Gene PET for Monitoring Survival of Transplanted Endothelial Progenitor Cells in the Rat Heart After Pretreatment with VEGF and Atorvastatin J. Nucl. Med., November 1, 2009; 50(11): 1881 - 1886. [Abstract] [Full Text] [PDF]

				A. Gianella, U. Guerrini, M. Tilenni, L. Sironi, G. Milano, E. Nobili, S. Vaga, M. C. Capogrossi, E. Tremoli, and M. Pesce Magnetic resonance imaging of human endothelial progenitors reveals opposite effects on vascular and muscle regeneration into ischaemic tissues Cardiovasc Res, October 31, 2009; (2009) cvp325v2. [Abstract] [Full Text] [PDF]

				F.-L. Xiang, X. Lu, L. Hammoud, P. Zhu, P. Chidiac, J. Robbins, and Q. Feng Cardiomyocyte-Specific Overexpression of Human Stem Cell Factor Improves Cardiac Function and Survival After Myocardial Infarction in Mice Circulation, September 22, 2009; 120(12): 1065 - 1074. [Abstract] [Full Text] [PDF]

				D. L. Kraitchman and J. W.M. Bulte In Vivo Imaging of Stem Cells and Beta Cells Using Direct Cell Labeling and Reporter Gene Methods Arterioscler Thromb Vasc Biol, July 1, 2009; 29(7): 1025 - 1030. [Abstract] [Full Text] [PDF]

				R. J. Gibbons, P. A. Araoz, and E. E. Williamson The year in cardiac imaging. J. Am. Coll. Cardiol., January 6, 2009; 53(1): 54 - 70. [Full Text] [PDF]

				M. Nahrendorf, D. E. Sosnovik, B. A. French, F. K. Swirski, F. Bengel, M. M. Sadeghi, J. R. Lindner, J. C. Wu, D. L. Kraitchman, Z. A. Fayad, et al. Multimodality Cardiovascular Molecular Imaging, Part II Circ Cardiovasc Imaging, January 1, 2009; 2(1): 56 - 70. [Full Text] [PDF]

				J. Terrovitis, K. F. Kwok, R. Lautamaki, J. M. Engles, A. S. Barth, E. Kizana, J. Miake, M. K. Leppo, J. Fox, J. Seidel, et al. Ectopic Expression of the Sodium-Iodide Symporter Enables Imaging of Transplanted Cardiac Stem Cells In Vivo by Single-Photon Emission Computed Tomography or Positron Emission Tomography J. Am. Coll. Cardiol., November 11, 2008; 52(20): 1652 - 1660. [Abstract] [Full Text] [PDF]

				J. C. Wu Molecular Imaging: Antidote to Cardiac Stem Cell Controversy J. Am. Coll. Cardiol., November 11, 2008; 52(20): 1661 - 1664. [Full Text] [PDF]

				H. Reinecke, E. Minami, W.-Z. Zhu, and M. A. Laflamme Cardiogenic Differentiation and Transdifferentiation of Progenitor Cells Circ. Res., November 7, 2008; 103(10): 1058 - 1071. [Abstract] [Full Text] [PDF]

				K. E.A. van der Bogt, A. Y. Sheikh, S. Schrepfer, G. Hoyt, F. Cao, K. J. Ransohoff, R.-J. Swijnenburg, J. Pearl, A. Lee, M. Fischbein, et al. Comparison of Different Adult Stem Cell Types for Treatment of Myocardial Ischemia Circulation, September 30, 2008; 118(14_suppl_1): S121 - S129. [Abstract] [Full Text] [PDF]

				F. Togel, Y. Yang, P. Zhang, Z. Hu, and C. Westenfelder Bioluminescence imaging to monitor the in vivo distribution of administered mesenchymal stem cells in acute kidney injury Am J Physiol Renal Physiol, July 1, 2008; 295(1): F315 - F321. [Abstract] [Full Text] [PDF]