Imaging Stem Cells Implanted in Infarcted Myocardium
Rong Zhou, PhD*,*,
Paul D. Acton, PhD and
Victor A. Ferrari, MD
* Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania
Department of Medicine (Cardiovascular), University of Pennsylvania, Philadelphia, Pennsylvania
Department of Radiology, Thomas Jefferson University, Philadelphia, Pennsylvania.
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Figure 1 Diagrams of detection of (A) enzyme-based (e.g., herpes simple virus type 1 thymidine kinase [HSV1-tk]), (B) receptor-based (e.g., dopamine type 2 receptor [D2R]), and (C) transporter-base (e.g., sodium-iodide symporter [NIS]) reporter genes detected by positron emission tomography using F-18–labeled tracers or by single-photon emission tomography using I-123 (reprinted from Acton and Zhou [44] with permission from Edizioni Minerva Medica). In A, 9-[3-fluoro-1-hydroxy-2-(propoxymethyl)]guanine tracers that are bound and metabolized by the HSV1-TK will be trapped inside the cells, whereas unbound ones will diffuse out of cells. In B, tracers binding to D2R on cell surface will contribute to the imaging signal, whereas unbound ones will be washed out. In C, tracers will be transported into and out of cells by NIS; cells from nonthyroid tissues, however, cannot retain the iodine inside through organification (see the section "Radionucleotide Imaging" for details). (D) In vivo assessment of cell survival and proliferation over time. Ten million (107) murine embryonic stem cells transfected with a truncated version of HSV1-tk were injected into the myocardium of a noninfarcted nude rat; positron emission tomography was performed at day 4 and weeks 1, 2, 3, and 4. Approximately 1 mCi [F-18]9-[3-fluoro-1-hydroxy-2-(propoxymethyl)]guanine was injected intravenously for visualization of HSV1-tk–expressing cells. Positive signal was observed at week 1 in animals receiving cells, but control animals had background activities only. Quantification of imaging signals showed a drastic increase of thymidine kinase activity from week 2 to week 4, corresponding to proliferation of embryonic stem cells into intracardiac and extracardiac tumors, that is, teratoma (reprinted from Cao et al. [45] with permission).
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Figure 2 Detection using magnetic resonance imaging (MRI) at 1.5 T, of Feridex-labeled mesenchymal stem cells (107 to 108 cells) injected into the myocardium of a swine; MRI was performed 24 h after injection. (B) Magnification of view inside the yellow box in A (reprinted from Kraitchman et al. [15] with permission). (C) Detection using MRI at 1.5 T of micrometer-sized superparamagnetic iron oxide–labeled mesenchymal stem cells (105 cells) implanted in the myocardium of a swine (reprinted from Hill et al. [77] with permission). (D) The color map corresponds to T2* values indicated on the scale immediately to the right; T2* values of micrometer-sized superparamagnetic iron oxide–labeled cells are very close to those of lateral myocardial wall at the heart/lung boundary. Obviously, the reduction of T2* at myocardium and air interface is a source of interference for detection of cells. LV = left ventricle; RV = right ventricle.
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Figure 3 (A) In vivo single-photon emission computed tomography (SPECT) imaging of In-111–labeled stem cells implanted in the infarcted rat heart; a dual-energy window detects simultaneously Tc-99m (pseudo-colored in yellow) and In-111 (blue) signals; the SPECT images were coregistered on a magnetic resonance image (grey) (reprinted from Shen et al. [113] with kind permission of Springer Science and Business Media). (B) Autoradiographs of heart slices obtained after In-111 and Feridex double-labeled stem cells were implanted in the infarcted heart of a rat; (C and D) Prussian blue staining of iron for localization of stem cells (reprinted by permission of the Society of Nuclear Medicine from Zhou et al. [109)]. (E and F) Homing of In-111–labeled bone marrow–derived mesenchymal stem cells to infarcted heart (dog) after intravenous injection at day 1 (E), day 2 (F) and day 7 (G) by SPECT imaging is shown. For each panel, sagittal (left) and coronal (right) view of fused SPECT (color) and CT (grey) images are shown. Initial retention of cells in the lung is indicated by strong In-111 signal in the lung (reprinted from Kraitchman et al. [110] with permission). LV = left ventricle; RV = right ventricle.
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