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In Vivo Detection of Embryonic Stem Cell–Derived Cardiovascular Progenitor Cells Using Cy3-Labeled Gadofluorine M in Murine Myocardium

Eric D. Adler, MD^_*,_*, Anne Bystrup, BA^_*, Karen C. Briley-Saebo, PhD^_*, Venkatesh Mani, PhD^_*, Wilson Young, MD, PhD^_*, Steven Giovanonne, MD, Perry Altman, BA^_*, Steven J. Kattman, PhD, Joseph A. Frank, MS, MD, Hans J. Weinmann, PhD^||, Gordon M. Keller, PhD, Zahi A. Fayad, PhD^_*

^_* Cardiovascular Institute and Department of Medicine, Mount Sinai School of Medicine, New York, New York
Department of Medicine, New York University School of Medicine, New York, New York
McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada
National Institutes of Health, Bethesda, Maryland
^|| Schering AG, Berlin, Germany

^_* Reprint requests and correspondence: Dr. Eric D. Adler, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1030, New York, New York 10029 (Email: eric.adler{at}mssm.edu).

Objectives: The aim of the current study is to test the ability to label and detect murine embryonic stem cell–derived cardiovascular progenitor cells (ES-CPC) with cardiac magnetic resonance (CMR) using the novel contrast agent Gadofluorine M-Cy3 (GdFM-Cy3).

Background: Cell therapy shows great promise for the treatment of cardiovascular disease. An important limitation to previous clinical studies is the inability to accurately identify transplanted cells. GdFM-Cy3 is a lipophilic paramagnetic contrast agent that contains a perfluorinated side chain and an amphiphilic character that allows for micelle formation in an aqueous solution. Previous studies reported that it is easily taken up and stored within the cytosol of mesenchymal stem cells, thereby allowing for paramagnetic cell labeling. Investigators in our laboratory have recently developed techniques for the robust generation of ES-CPC. We reasoned that GdFM-Cy3 would be a promising agent for the in vivo detection of these cells after cardiac cell transplantation.

Methods: ES-CPC were labeled with GdFM-Cy3 by incubation. In vitro studies were performed to assess the impact of GdFM-Cy3 on cell function and survival. A total of 500,000 GdFM-Cy3–labeled ES-CPC or control ES-CPC were injected into the myocardium of mice with and without myocardial infarction. Mice were imaged (9.4-T) before and over a 2-week time interval after stem cell transplantation. Mice were then euthanized, and their hearts were sectioned for fluorescence microscopy.

Results: In vitro studies demonstrated that GdFM-Cy3 was easily transfectable, nontoxic, stayed within cells after labeling, and could be visualized using CMR and fluorescence microscopy. In vivo studies confirmed the efficacy of the agent for the detection of cells transplanted into the hearts of mice after myocardial infarction. A correspondence between CMR and histology was observed.

Conclusions: The results of the current study suggest that it is possible to identify and potentially track GdFM-Cy3–labeled ES-CPC in murine infarct models via CMR.

Key Words: cells • cardiac magnetic resonance • myocardial infarction

Abbreviations and Acronyms   CHESS = chemical shift selective suppression   CNR = contrast-to-noise ratio   CPC = cardiovascular progenitor cell   ES = embryonic stem cell   Gd-DTPA = gadopentetate dimeglumine   GdFM = Gadofluorine M   GdFM-Cy3 = Gadofluorine M-Cy3   ICP-MS = inductively coupled plasma mass spectrometry   SNR = signal-to-noise ratio   TE = time of excitation   TR = time of relaxation

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