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WIREs Nanomed Nanobiotechnol
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Genetically encoded iron‐associated proteins as MRI reporters for molecular and cellular imaging

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All cell imaging applications rely on some form of specific cell labeling to achieve visualization of cells contributing to disease or cell therapy. The purpose of this review article is to summarize the published data on genetically encoded iron‐based imaging reporters. The article overviews regulation of iron homeostasis as well as genetically encoded iron‐associated molecular probes and their applications for noninvasive magnetic resonance imaging (MRI) of transplanted cells. Longitudinal repetitive MRI of therapeutic cells is extremely important for providing key functional endpoints and insight into mechanisms of action. Future directions in molecular imaging and techniques for improving sensitivity, specificity and safety of in vivo reporter gene imaging are discussed. WIREs Nanomed Nanobiotechnol 2018, 10:e1482. doi: 10.1002/wnan.1482 This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
Mechanisms for cell labeling through (semi‐) genetic control of MR imaging contrast. LacZ is the gene that encodes β‐galactosidase. TfR: transferrin receptor. (a) A genetically expressed enzyme (blue) alters an exogenously administered imaging probe (green) that becomes active (green halo) upon enzyme processing (e.g., lacZ). (b) Gene expression leads to the synthesis of a cell surface protein (blue) that acts as a receptor for an exogenous contrast agent (green) and subsequently promotes agent internalization (e.g., TfR). (c) A gene directs endogenous production of protein (blue) that becomes a MRI contrast agent in complex with endogenous ions (green) (e.g., ferritin, magA).
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MR imaging of iron‐oxide reporters in cancer applications. Study 1: In vivo R2 maps of C6 tumors expressing ferritin in hind limb of CD1‐nude mice. Scalebar 2.5 mm (Reprinted with permission from Ref . Copyright 2005 Elsevier). Study 2: In vivo MRI of a mouse with transplanted glyosarcoma cells expressing human transferrin receptor (left arrowheads) and naïve (right arrowheads) flank tumors. (a) T1‐weighted coronal spin‐echo image. (b) T2‐weighted gradient‐echo image corresponding to the image in (a). Transferrin‐mediated cellular accumulation of the superparamagnetic probe decreases signal intensity. (c) Composite image of a T1‐weighted spin‐echo image obtained for anatomic detail with superimposed R2 changes after Tf‐MION administration, as a color map (Reprinted with permission from Ref . Copyright 2000 Nature). Study 3: In vivo T2‐ and T2*‐weighted MRI of F‐98 tumor 2 weeks after subcutaneous transplantation of myc‐hFTH and mock cells (left) and T2* relaxation times of mock and myc‐hFTH tumors were measured from T2*‐weighted images (right) (Reprinted with permission from Ref . Copyright 2010 AACR). Study 4: In vivo MRI detection of FTH transgene‐induced MRI contrast in mES cell grafts. (A, D) Representative T2‐weighted fast spin echo (FSE) images showing the same pair of tumors grown from mES grafts (left, WT; right, FTH transgenic), at days 14 and 21 postinoculation. (B, E) Corresponding color‐coded T2 maps from multiecho measurements of T2 relaxation time showed significant reduction of T2 relaxation time in the tumor overexpressing FTH transgene at both time points (Reprinted with permission from Ref . Copyright 2009 Mary Ann Liebert Inc).
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MRI detection of ferritin‐tagged graft in the infarcted mouse heart using T2* iMSDE and T2* GRE pulse sequences and correlation of the graft size measurements between MRI and histology (Reprinted with permission from Ref . Copyright 2012 Wiley).
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T2*‐weighted MR images of mouse brain at 7T and changes in R2* relaxivity in transgenic cell samples. (Reprinted with permission from Ref . Copyright 2006 Wiley) (a) Schematic of a coronal section of an adult mouse brain shows the location of the MRI images (b, c, e, and f) shown, including the injection site (is), and control regions in cortex (ctx), and striatum (str). T2*‐weighted images from ex vivo mouse brains injected with C17s control cells (b) or C17‐12s transgenic cells (c) clear contrast between the transplanted cells and surrounding brain tissue. (d) Mean R2* measurements (dark bars) were made on ex vivo brains for ROIs within the injection site of either the C17s injected brains or the C17‐12s injected brains, as well as for region of interest (ROIs) within ctx and str. Error bars denote the SD in each case. R2* was significantly increased in is‐12s versus isC17s (**P < 0.04). Light bars indicate the R2* values measured in the same regions from an in vivo multi‐GE acquisition of a C17s injected brain and a C17‐12s injected brain. In vivo T2*‐weighted images from C17s (e) and C17‐12s transplanted mice (f) were acquired from mice later used in ex vivo imaging (data included in b and c, respectively).
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T2*‐weighted image of mouse brain with transplanted magA cells (right) and GFP control cells (left) after 5 days of induction. These cells were neither induced nor incubated with iron supplement prior to transplantation. The magA cells (white arrow) exhibit significantly lower MRI signal, reflecting an increase in R2, suggesting that magA cells are able to use endogenous iron sources. The control cells on the left do not show such an effect. (Reprinted with permission from Ref . Copyright 2008 Harvard Catalyst)
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AAV‐FerrH‐mediated contrast evaluation by MRI. (a) 3D T2*‐weighted in vivo MR image acquired 1 month after injection of AAV‐FerrH‐T2A‐fLuc and AAV‐eGFP‐T2A‐fLuc vectors in the right and left striata, respectively. (b) 3D graphic representations of the contrast volume from the same mouse. (c) Quantification of the contrast volume using the normalized 3D T2*‐weighted in vivo MR images at different time points post‐injection. (d) Immunohistochemical staining for eGFP shows a large area of transgene expression after AAV transduction in the brain. (e) DAB‐enhanced Prussian blue staining, showing the presence of iron at the site of AAV‐FerrH injection in contrast to the contralateral control injection site where very little iron is detectable. (f) immunohistochemical staining on an adjacent section using CD11b antibody, showing very few CD11b‐positive cells at the left and right injection tracts (arrows). White scale bars represent 500 mm, black scale bars 100 mm. (Reprinted with permission from Ref . Copyright 2011 Nature)
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In vivo MRI detection of ferritin expression. (a) T2*‐weighted images of the mouse brain at days 5, 11, and 39 after inoculation of an adenovirus containing the MRI reporter ferritin into the striatum. Images were acquired at 11.7 T with a 0.75‐mm slice thickness and an in‐plane resolution of 102 µm. Bottom image is the Prussian blue staining for iron representing similar pattern to the MRI. v, ventricle (Reprinted with permission from Ref . Copyright 2005 Nature). (b) Representative T2‐weighted images of mice inoculated with tumors over‐expressing ferritin heavy chain in vivo (right tumor) and parent cells (left). External iron supplementation enhances MRI contrast based on ferritin overexpression. (Reprinted with permission from Ref . Copyright 2012 Hindawi)
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