MagA is sufficient for producing magnetic nanoparticles in mammalian cells, making it an MRI reporter

Magnetic resonance imaging (MRI) is routinely used to obtain anatomical images that have greatly advanced biomedical research and clinical health care today, but the full potential of MRI in providing functional, physiological, and molecular information is only beginning to emerge. In this work, we sought to provide a gene expression marker for MRI based on bacterial magnetosomes, tiny magnets produced by naturally occurring magnetotactic bacteria. Specifically, magA, a gene in magnetotactic bacteria known to be involved with iron transport, is expressed in a commonly used human cell line, 293FT, resulting in the production of magnetic, iron‐oxide nanoparticles by these cells and leading to increased transverse relaxivity. MRI shows that these particles can be formed in vivo utilizing endogenous iron and can be used to visualize cells positive for magA. These results demonstrate that magA alone is sufficient to produce magnetic nanoparticles and that it is an appropriate candidate for an MRI reporter gene. Magn Reson Med 59:1225–1231, 2008. © 2008 Wiley‐Liss, Inc.

[1]  S. Emr,et al.  Receptor downregulation and multivesicular-body sorting , 2002, Nature Reviews Molecular Cell Biology.

[2]  C. Nakamura,et al.  An Iron-regulated Gene, magA, Encoding an Iron Transport Protein of Magnetospirillum sp. Strain AMB-1 (*) , 1995, Journal of Biological Chemistry.

[3]  Damien Faivre,et al.  An acidic protein aligns magnetosomes along a filamentous structure in magnetotactic bacteria , 2006, Nature.

[4]  Target‐specific superparamagnetic MR contrast agents , 1991, Magnetic resonance in medicine.

[5]  C. Nakamura,et al.  Iron-regulated expression and membrane localization of the magA protein in Magnetospirillum sp. strain AMB-1. , 1995, Journal of biochemistry.

[6]  R. Frankel,et al.  Magnetosome formation in prokaryotes , 2004, Nature Reviews Microbiology.

[7]  Ralph Weissleder,et al.  Magnetic relaxation switches capable of sensing molecular interactions , 2002, Nature Biotechnology.

[8]  R. Muller,et al.  Relaxation induced by ferritin: a better understanding for an improved MRI iron quantification , 2004, NMR in biomedicine.

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

[10]  Rika Takikawa,et al.  [In-vivo visualization of gene expression using magnetic resonance imaging]. , 2007, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[11]  R Weissleder,et al.  Monocrystalline iron oxide nanocompounds (MION): Physicochemical properties , 1993, Magnetic resonance in medicine.

[12]  T. Matsunaga,et al.  Dynamic analysis of a genomic island in Magnetospirillum sp. strain AMB‐1 reveals how magnetosome synthesis developed , 2006, FEBS letters.

[13]  M. Garrick,et al.  Separate pathways for cellular uptake of ferric and ferrous iron. , 2000, American journal of physiology. Gastrointestinal and liver physiology.

[14]  R. Blakemore Magnetotactic bacteria , 1975, Science.

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

[16]  Piotr Walczak,et al.  Artificial reporter gene providing MRI contrast based on proton exchange , 2007, Nature Biotechnology.

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

[18]  R. Zhou,et al.  In vivo detection of gene expression in liver by 31P nuclear magnetic resonance spectroscopy employing creatine kinase as a marker gene , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Anna Moore,et al.  In vivo magnetic resonance imaging of transgene expression , 2000, Nature Medicine.

[20]  T. Matsunaga,et al.  Complete genome sequence of the facultative anaerobic magnetotactic bacterium Magnetospirillum sp. strain AMB-1. , 2005, DNA research : an international journal for rapid publication of reports on genes and genomes.

[21]  Dmitri Artemov,et al.  MR molecular imaging of the Her‐2/neu receptor in breast cancer cells using targeted iron oxide nanoparticles , 2003, Magnetic resonance in medicine.

[22]  R Weissleder,et al.  MR of carcinoma-specific monoclonal antibody conjugated to monocrystalline iron oxide nanoparticles: the potential for noninvasive diagnosis. , 1996, AJNR. American journal of neuroradiology.

[23]  Grant J. Jensen,et al.  Magnetosomes Are Cell Membrane Invaginations Organized by the Actin-Like Protein MamK , 2006, Science.

[24]  R. Mason,et al.  Imaging β-galactosidase activity using 19F chemical shift imaging of LacZ gene-reporter molecule 2 -fluoro -4-nitrophenol -β -D -galactopyranoside , 2006 .

[25]  T. Matsunaga,et al.  Biotechnological application of nano-scale engineered bacterial magnetic particles , 2004 .

[26]  Xiaoping P. Hu,et al.  Functionalization and peptide-based delivery of magnetic nanoparticles as an intracellular MRI contrast agent , 2004, JBIC Journal of Biological Inorganic Chemistry.

[27]  R Weissleder,et al.  Measuring transferrin receptor gene expression by NMR imaging. , 1998, Biochimica et biophysica acta.

[28]  A. Louie Design and characterization of magnetic resonance imaging gene reporters. , 2006, Methods in molecular medicine.

[29]  E. Ahrens,et al.  A new transgene reporter for in vivo magnetic resonance imaging , 2005, Nature Medicine.

[30]  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.

[31]  Yoshiko Okamura,et al.  Global Gene Expression Analysis of Iron-Inducible Genes in Magnetospirillum magneticum AMB-1 , 2006, Journal of bacteriology.

[32]  P. Harrison,et al.  The ferritins: molecular properties, iron storage function and cellular regulation. , 1996, Biochimica et biophysica acta.

[33]  H. Stenmark,et al.  Protein sorting into multivesicular endosomes. , 2003, Current opinion in cell biology.

[34]  Michal Neeman,et al.  Ferritin as an endogenous MRI reporter for noninvasive imaging of gene expression in C6 glioma tumors. , 2005, Neoplasia.