Serial in vivo positive contrast MRI of iron oxide‐labeled embryonic stem cell‐derived cardiac precursor cells in a mouse model of myocardial infarction

Myocardial regeneration with stem‐cell transplantation is a possible treatment option to reverse deleterious effects that occur after myocardial infarction. Since little is known about stem cell survival after transplantation, developing techniques for “tracking” cells would be desirable. Iron‐oxide‐labeled stem cells have been used for in vivo tracking using MRI but produce negative contrast images that are difficult to interpret. The aim of the current study was to test a positive contrast MR technique using reduced z‐gradient rephasing (GRASP) to aid in dynamically tracking stem cells in an in vivo model of mouse myocardial infraction. Ferumoxides and protamine sulfate were complexed and used to magnetically label embryonic stem cell‐derived cardiac‐precursor‐cells (ES‐CPCs). A total of 500,000 ES‐CPCs were injected in the border zone of infarcted mice and MR imaging was performed on a 9.4T scanner using T  2* ‐GRE sequences (negative contrast) and positive contrast GRASP technique before, 24 hours, and 1 week after ES‐CPC implantation. Following imaging, mice were sacrificed for histology and Perl's staining was used to confirm iron within myocardium. Good correlation was observed between signal loss seen on conventional T  2* images, bright areas on GRASP, and the presence of iron on histology. This demonstrated the feasibility of in vivo stem cell imaging with positive contrast MRI. Magn Reson Med 60:73–81, 2008. © 2008 Wiley‐Liss, Inc.

[1]  Debiao Li,et al.  Generating positive contrast from off-resonant spins with steady-state free precession magnetic resonance imaging: theory and proof-of-principle experiments , 2006, Physics in medicine and biology.

[2]  Koen L Vincken,et al.  Dephased MRI , 2006, Magnetic resonance in medicine.

[3]  Bernd Hertenstein,et al.  Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial , 2004, The Lancet.

[4]  Jeff W M Bulte,et al.  Clinically applicable labeling of mammalian and stem cells by combining superparamagnetic iron oxides and transfection agents. , 2003, Radiology.

[5]  Antonio Colombo,et al.  From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II. , 2003, Circulation.

[6]  S. Kattman,et al.  Multipotent flk-1+ cardiovascular progenitor cells give rise to the cardiomyocyte, endothelial, and vascular smooth muscle lineages. , 2006, Developmental cell.

[7]  J. Frangioni,et al.  Tracking stem cells in the cardiovascular system. , 2005, Trends in cardiovascular medicine.

[8]  L Gepstein,et al.  Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. , 2001, The Journal of clinical investigation.

[9]  Heather Kalish,et al.  Efficient magnetic cell labeling with protamine sulfate complexed to ferumoxides for cellular MRI. , 2004, Blood.

[10]  Z. Fayad,et al.  Feasibility of in vivo identification of endogenous ferritin with positive contrast MRI in rabbit carotid crush injury using GRASP , 2006, Magnetic resonance in medicine.

[11]  Jeff W M Bulte,et al.  Iron oxide MR contrast agents for molecular and cellular imaging , 2004, NMR in biomedicine.

[12]  Gordon Keller,et al.  Sequential development of hematopoietic and cardiac mesoderm during embryonic stem cell differentiation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[13]  S. Dimmeler,et al.  Cell-based therapies and imaging in cardiology , 2005, European Journal of Nuclear Medicine and Molecular Imaging.

[14]  John M Pauly,et al.  Positive contrast magnetic resonance imaging of cells labeled with magnetic nanoparticles , 2005, Magnetic resonance in medicine.

[15]  Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) , 2002 .

[16]  Atle Bjørnerud,et al.  Hepatic cellular distribution and degradation of iron oxide nanoparticles following single intravenous injection in rats: implications for magnetic resonance imaging , 2004, Cell and Tissue Research.

[17]  Elliot R. McVeigh,et al.  Serial Cardiac Magnetic Resonance Imaging of Injected Mesenchymal Stem Cells , 2003, Circulation.

[18]  J A Frank,et al.  Hepatic hemosiderosis in non‐human primates: Quantification of liver iron using different field strengths , 1997, Magnetic resonance in medicine.

[19]  A. Bjørnerud,et al.  Long‐term imaging effects in rat liver after a single injection of an iron oxide nanoparticle based MR contrast agent , 2004, Journal of magnetic resonance imaging : JMRI.

[20]  M. Entman,et al.  Myocardial ischemia and reperfusion: a murine model. , 1995, The American journal of physiology.

[21]  P. Wernet,et al.  Repair of Infarcted Myocardium by Autologous Intracoronary Mononuclear Bone Marrow Cell Transplantation in Humans , 2002, Circulation.

[22]  Ergin Atalar,et al.  In Vivo Magnetic Resonance Imaging of Mesenchymal Stem Cells in Myocardial Infarction , 2003, Circulation.

[23]  Hung-Fat Tse,et al.  Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation , 2003, The Lancet.

[24]  Raymond C. Boston,et al.  Dynamic Imaging of Allogeneic Mesenchymal Stem Cells Trafficking to Myocardial Infarction , 2005, Circulation.

[25]  A. Lindahl,et al.  In vivo MR imaging of magnetically labeled human embryonic stem cells. , 2004, Life sciences.

[26]  G. Lubec,et al.  L‐Arginine Reduces Heart Collagen Accumulation in the Diabetic db/db Mouse , 1994, Circulation.

[27]  Jeff W M Bulte,et al.  Monitoring cell therapy using iron oxide MR contrast agents. , 2004, Current pharmaceutical biotechnology.

[28]  Max A Viergever,et al.  Passive tracking exploiting local signal conservation: The white marker phenomenon , 2003, Magnetic resonance in medicine.

[29]  J. Pauly,et al.  Design of symmetric‐sweep spectral‐spatial RF pulses for spectral editing , 2004, Magnetic resonance in medicine.

[30]  A. Arbab,et al.  Labeling of cells with ferumoxides–protamine sulfate complexes does not inhibit function or differentiation capacity of hematopoietic or mesenchymal stem cells , 2005, NMR in biomedicine.

[31]  E. Boerwinkle,et al.  From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. , 2003, Circulation.

[32]  J A Frank,et al.  Frequency dependence of MR relaxation times II. Iron oxides , 1993, Journal of magnetic resonance imaging : JMRI.

[33]  J. Frank,et al.  Cellular magnetic resonance imaging: current status and future prospects , 2006, Expert review of medical devices.

[34]  K. Vincken,et al.  White‐marker imaging—Separating magnetic susceptibility effects from partial volume effects , 2007, Magnetic resonance in medicine.

[35]  A. Ganser,et al.  Intracoronary Bone Marrow Cell Transfer After Myocardial Infarction: Eighteen Months’ Follow-Up Data From the Randomized, Controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) Trial , 2006, Circulation.

[36]  Zahi A Fayad,et al.  Gradient echo acquisition for superparamagnetic particles with positive contrast (GRASP): Sequence characterization in membrane and glass superparamagnetic iron oxide phantoms at 1.5T and 3T , 2006, Magnetic resonance in medicine.

[37]  Matthias Stuber,et al.  Positive contrast visualization of iron oxide‐labeled stem cells using inversion‐recovery with ON‐resonant water suppression (IRON) , 2007, Magnetic resonance in medicine.