Highly efficient endosomal labeling of progenitor and stem cells with large magnetic particles allows magnetic resonance imaging of single cells.

Tracking transplanted stem cells using magnetic resonance imaging (MRI) could offer biologic insight into homing and engraftment. Ultrasmall dextran-coated iron oxide particles have previously been developed for uptake into cells to allow MRI tracking. We describe a new application of much larger, micron-scale, iron oxide magnetic particles with enhanced MR susceptibility, which enables detection of single cells at resolutions that can be achieved in vivo. In addition, these larger particles possess a fluorophore for histologic confirmation of cell distribution. We demonstrate highly efficient, nontoxic, endosomal uptake of these particles into hematopoietic CD34+ cells and mesenchymal stem cells documented by confocal and electron microscopy. Labeled cells retain biologic activity with preservation of colony-forming ability and differentiation capacity. MRI studies could detect labeled CD34+ cells and mesenchymal stem cells (MSCs) at single cell resolution. This appears to be a promising tool for serial noninvasive monitoring of in vivo cell homing and localization using MRI.

[1]  J. Bulte,et al.  Selective MR imaging of labeled human peripheral blood mononuclear cells by liposome mediated incorporation of dextran‐magnetite particles , 1993, Magnetic resonance in medicine.

[2]  C. Contag,et al.  Bioluminescence imaging of lymphocyte trafficking in vivo. , 2001, Experimental hematology.

[3]  Haruchika Masuda,et al.  Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization , 1999, Nature Medicine.

[4]  Donald S. Williams,et al.  Detection of single mammalian cells by high-resolution magnetic resonance imaging. , 1999, Biophysical journal.

[5]  T. Lapidot.  Mechanism of Human Stem Cell Migration and Repopulation of NOD/SCID and B2mnull NOD/SCID Mice , 2001, Annals of the New York Academy of Sciences.

[6]  R Weissleder,et al.  In vivo imaging of gene and cell therapies. , 2001, Experimental hematology.

[7]  Xin Wang,et al.  Purified hematopoietic stem cells can differentiate into hepatocytes in vivo , 2000, Nature Medicine.

[8]  Mathias Hoehn,et al.  Monitoring of implanted stem cell migration in vivo: A highly resolved in vivo magnetic resonance imaging investigation of experimental stroke in rat , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Stefan Miltenyi,et al.  Specific MR imaging of human lymphocytes by monoclonal antibody‐guided dextran‐magnetite particles , 1992, Magnetic resonance in medicine.

[10]  Ralph Weissleder,et al.  Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells , 2000, Nature Biotechnology.

[11]  Paul D. Kessler,et al.  Human Mesenchymal Stem Cells Differentiate to a Cardiomyocyte Phenotype in the Adult Murine Heart , 2002, Circulation.

[12]  R E Jacobs,et al.  Magnetic resonance microscopy of embryonic cell lineages and movements. , 1994, Science.

[13]  R. Franklin,et al.  Magnetic resonance imaging of transplanted oligodendrocyte precursors in the rat brain. , 1999, Neuroreport.

[14]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[15]  Chien Ho,et al.  Intracellular labeling of T‐cells with superparamagnetic contrast agents , 1993, Magnetic resonance in medicine.

[16]  J. Bulte,et al.  Magnetic intracellular labeling of mammalian cells by combining (FDA-approved) superparamagnetic iron oxide MR contrast agents and commonly used transfection agents. , 2002, Academic radiology.

[17]  I. Bernstein,et al.  Engraftment after infusion of CD34+ marrow cells in patients with breast cancer or neuroblastoma. , 1991, Blood.

[18]  Michael E. Phelps,et al.  Ex vivo cell labeling with 64Cu–pyruvaldehyde-bis(N4-methylthiosemicarbazone) for imaging cell trafficking in mice with positron-emission tomography , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Pratik Ghosh,et al.  Nuclear Magnetic Resonance (NMR) Imaging of Iron Oxide-Labeled Neural Transplants , 1993, Experimental Neurology.

[20]  Chien Ho,et al.  In Vivo Dynamic MRI Tracking of Rat T‐Cells Labeled with Superparamagnetic Iron‐Oxide Particles , 1995, Magnetic resonance in medicine.

[21]  D. Bodine,et al.  Transplanted Adult Bone Marrow Cells Repair Myocardial Infarcts in Mice , 2001, Annals of the New York Academy of Sciences.

[22]  R. Lauffer,et al.  Paramagnetic metal complexes as water proton relaxation agents for NMR imaging: theory and design , 1987 .

[23]  M. Collector,et al.  Hematopoietic stem cell tracking in vivo: a comparison of short-term and long-term repopulating cells. , 1999, Blood.

[24]  C. Verfaillie,et al.  Characterization of Multipotent Adult Progenitor Cells, a Subpopulation of Mesenchymal Stem Cells , 2001, Annals of the New York Academy of Sciences.

[25]  Peter van Gelderen,et al.  Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells , 2001, Nature Biotechnology.

[26]  David M. Bodine,et al.  Bone marrow cells regenerate infarcted myocardium , 2001, Nature.

[27]  J A Frank,et al.  Neurotransplantation of magnetically labeled oligodendrocyte progenitors: magnetic resonance tracking of cell migration and myelination. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[28]  R. Andrews,et al.  Engraftment after infusion of CD34+ marrow cells in patients with breast cancer or neuroblastoma. , 1991, Blood.