Clinically Applicable 7-Tesla Magnetic Resonance Visualization of Transplanted Human Adult Stem Cells Labeled with CliniMACS® Nanoparticles

Abstract

Background: Intra-myocardial transplantation of bone marrow derived cells is currently under clinical evaluation as a therapy for heart failure. A major limitation of all clinical studies for myocardial restoration through cell transfer is the inability to track the fate of the transplanted cells. We present a clinically applicable technique using advanced ultra high-field 7-Tesla (7T) magnetic resonance imaging (MRI) of nanoparticle-labeled transplanted human EPCs in porcine ischemic hearts. Methods: CD133 positive cells were isolated from bone marrow by magnetic bead selection. Positive cells (5 - 8 × 10⁶ cells) were transplanted into porcine ischemic myocardium (n = 8). Control animals (n = 3) received a medium injection. MRI on a 7T scanner was performed to demonstrate the distribution of the EPCs. Results: CD133+ cells were identified on gradient echo images (T₁-weighted) within the myocardium 4 weeks after transplantation. Conclusions: Magnetically labeled EPCs transplanted for therapeutic neovascularization or reduction of infarct size in myocardial ischemia can be visualized by MRI at high-field strengths.

Cardiovascular surgery - myocardial infarction - heart disease - cell transplantation - bio-imaging

References

• 1 Soonpaa M H, Koh G Y, Klug M G, Field L J. Formation of nascent intercalated disks between grafted fetal cardiomyocytes and host myocardium.  Science. 1994;  264 98-101
• 2 Roell W. et al . Cellular cardiomyoplasty in a transgenic mouse model.  Transplantation. 2002;  73 462-465
• 3 Ruhparwar A. et al . Transplanted fetal cardiomyocytes as cardiac pacemaker.  Eur J Cardiothorac Surg. 2002;  21 853-857
• 4 Ruhparwar A. et al . Intra-vital fluorescence microscopy for intra-myocardial graft detection following cell transplantation.  Intern J Cardiovasc Imag. 2005;  21 569-574
• 5 Tomita S. et al . Autologous transplantation of bone marrow cells improves damaged heart function.  Circul. 1999;  100 (19 Suppl) II247-II256
• 6 Orlic D. et al . Bone marrow cells regenerate infarcted myocardium.  Nature. 2001;  410 701-705
• 7 Kocher A A. et al . Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function.  Nat Med. 2001;  7 430-436
• 8 Fuchs S. et al . Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia.  J Am Coll Cardiol. 2001;  37 1726-1732
• 9 Toma C, Pittenger M F, Cahill K S, Byrne B J, Kessler P D. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart.  Circul. 2002;  105 93-98
• 10 Strauer B E. et al . Intracoronary, human autologous stem cell transplantation for myocardial regeneration following myocardial infarction.  Dtsch Med Wochenschr. 2001;  126 932-938
• 11 Ghodsizad A. et al . Autologous bone marrow derived stem therapy in combination with TMLR: a novel therapeutic option for endstage coronary heart disease.  Heart Surg Forum. 2004;  7 E416-E419
• 12 Hamano K. et al . Local implantation of autologous bone marrow cells for therapeutic angiogenesis in patients with ischemic heart disease: clinical trial and preliminary results.  Jpn Circ J. 2001;  65 845-847
• 13 Assmus B. et al . Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE‐AMI).  Circul. 2002;  106 3009-3017
• 14 Perin E C. et al . Improved exercise capacity and ischemia 6 and 12 months after transendocardial injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy.  Circul. 2004;  110 (11 Suppl 1) II213-II218
• 15 Stamm C. et al . Autologus bone marrow stem cell transplantation for myocardial regeneration after myocardial infarction.  Lancet. 2003;  361 45-46
• 16 Tse H F. et al . Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation.  Lancet. 2003;  361 47-49
• 17 Menasche P. Skeletal muscle satellite cell transplantation.  Cardiovasc Res. 2003;  58 351-357
• 18 Pompilio G. et al . Autologous peripheral blood stem cell transplantation for myocardial regeneration: a novel strategy for cell collection and surgical injection.  Ann Thorac Surg. 2005;  78 1808-1812
• 19 Balsam L B. et al . Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium.  Nature. 2004;  428 668-673
• 20 Nygren J M. et al . Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation.  Nat Med. 2004;  10 494-501
• 21 Kraitchman D L. et al . In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction.  Circul. 2003;  107 2290-2293
• 22 Dick A J. et al . Magnetic resonance fluoroscopy allows targeted delivery of mesenchymal stem cells to infarct borders in swine.  Circul. 2003;  108 2899-2904
• 23 Hill J M. et al . Serial cardiac magnetic resonance imaging of injected mesenchymal stem cells.  Circul. 2003;  108 1009-1914
• 24 van den Bos E J. et al . Improved efficacy of stem cell labelling for magnetic resonance imaging studies by the use of cationic liposomes.  Cell Transplant. 2003;  12 743-756
• 25 Tiwari A, Punshon G, Kidane A, Hamilton G, Seifalian A M. Magnetic beads (Dynebead) toxicity to endothelial cells at high bead concentration: implications for tissue engineering of vascular prothesis.  Cell Biol Toxicol. 2003;  19 265-272
• 26 Richel D J. et al . Highly purified CD34+ cells isolated using magnetically activated cell selection provide rapid engraftment following high-dose chemotherapy in breast cancer patients.  Bone Marrow Transplant. 2000;  25 243-249
• 27 Wu J C. et al . Molecular imaging of cardiac cell transplantation in living animals using optical bioluminescence and positron emission tomography.  Circul. 2003;  108 1302-1305
• 28 Dobert N. Transplantation of progenitor cells after reperfused acute myocardial infarction: evaluation of perfusion and myocardial viability with FDG‐PET and thallium SPECT.  Eur J Nucl Med Mol Imaging. 2004;  31 1146-1151
• 29 Hofmann M. et al . Monitoring of bone marrow cell homing into the infarcted human myocardium.  Circul. 2005;  111 2198-2202
• 30 Ghodsizad A. et al . Intraoperative isolation and processing of CD133+ bone marrow derived stem cells.  Cytotherapy. 2004;  6 523-526

1 * Arjang Ruhparwar, Alireza Ghodsizad and Michael Niehaus contributed equally to this paper. This paper is to be presented at the annual meeting of The German Society for Thoracic and Cardiovascular Surgery 2006 in Hamburg as a permanent poster.