Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Arterioscler Thromb Vasc Biol. Author manuscript; available in PMC 2010 May 10.
Published in final edited form as:
PMCID: PMC2866294

In Vivo Imaging of Stem Cells and Beta Cells Using Direct Cell Labeling and Reporter Gene Methods


Cellular transplantation therapy offers a means to stimulate cardiovascular repair either by direct (graft-induced) or indirect (host-induced) tissue regeneration or angiogenesis. Typically, autologous or donor cells of specific subpopulations are expanded exogenously before administration to enrich the cells most likely to participate in tissue repair. In animal models of cardiovascular disease, the fate of these exogenous cells can be determined using histopathology. Recently, methods to label cells with contrast agents or transduce cells with reporter genes to produce imaging beacons has enabled the serial and dynamic assessment of the survival, fate, and engraftment of these cells with noninvasive imaging. Although cell tracking methods for cardiovascular applications have been most studied in stem or progenitor cells, research in tracking of whole islet transplants and particularly insulin producing beta cells has implications to the cardiovascular community attributable to the vascular changes associated with diabetes mellitus. In this review article, we will explore some of the state-of-the art methods for stem, progenitor, and beta cell tracking.

Keywords: stem cells, beta cells, transplantation, cell labeling, reporter gene, MRI, SPECT, PET

The human body is dependent on progenitor and stem cells for normal organ repair. Recently, several studies have shown that the ability of endogenous stem cells to home to ischemic tissue and perform restorative functions are diminished in patients with diabetes and cardiovascular disease.13 In patients with type I diabetes mellitus, destruction of the beta cells leads to insulin dependence for glucose homeostasis. Thus, in many cardiovascular patient populations, the administration of autologous cell therapies may provide suboptimal building blocks for tissue and vessel repair. Because of immunorejection and the hostile engraftment environment, allogeneic cell therapies are likely to lead to increased cellular destruction and a poor therapeutic response. Although cell fate can be determined in animal models of cardiovascular disease and diabetes using histopathologic examination of tissue, noninvasive methods for assessing cell survival and engraftment will be needed to assess therapeutic efficacy in patients. Like detecting cells microscopically, cell labeling for noninvasive imaging relies on targeting contrast agents to stem or progenitors cells to increase their conspicuity relative to native tissue.

Direct Cell Labeling

Many of the techniques for cell labeling for detection by noninvasive imaging were developed based on methodologies developed for histopathologic cell labeling. The simplest method is to incubate cells with a contrast agent that is taken up by cells similar to 1,1′-Dioleyl-3,3,3′,3′-tetramethylindocarbocyanine methanesulfonate (DiI) staining, where the fluorescent stain strongly binds cell membranes. Unlike methods that use antibodies to target antigens on the cell for specific binding, such as monoclonal antibodies for cardiac markers used in histological staining, these direct labeling techniques are not species specific, relatively simple to perform, and inexpensive.

Radiotracers for Direct Cell Labeling

The earliest direct cell labeling techniques for clinical use were performed using radionuclide labels. Indium-111 oxine is a radiotracer with a relatively long half-life of ≈2.8 days, which enables serial tracking over 5 to 7 days of cells using single photo electron computed tomography (SPECT) imaging. Since Indium-111 oxine was approved for clinical use for labeling white blood cells to track sites of inflammation more than 20 years ago,4,5 it was a natural extension to label stem cells for noninvasive biodistribution studies.610 Cells are labeled by direct incubation with the tracer. In the case of Indium-111 oxine, it passively diffuses into cells, dissociates, and the Indium-111 is subsequently bound to cytoplasmic components.11 However, this binding is somewhat reversible, which can allow leakage of the radiotracer from the cell.6,7,12 Copper-64-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (64Cu-PTSM) is another attractive radiotracer for positron emission tomgraphic (PET) imaging for cell tracking and biodistribution studies because of the relatively long half-life of 12.7 hours.13 Like Indium-111 oxine, efflux of 64Cu-PTSM occurs over time. Tracer leaking from the cell is a common problem of direct labeling schemes whereby the detection of the label may not always represent the location of the cells of interest. Nonetheless, radiotracers have been used to serially study the redistribution of a variety of stem cells, eg, mesenchymal stem cells, endothelial progenitor cells, and hematopoietic progenitor cells (Figure 1).610 One of the major benefits of exogenous direct cell labeling with radiotracers over direct labeling with MRI contrast agents is the high sensitivity to a small number of cells because of the lack of a preexisting, endogenous background signal. Minimum detection limits using direct radiotracer labeling range from 6250 to 25 000 cells depending on the radiotracer and cell type.6,10,13,14

Figure 1
A, Colorized volume rendered single photon emission computed tomography (SPECT) with grayscale computed tomography (CT) image of a dog with a reperfused myocardial infarction during the first hours after intravenous injection of Indium-111 oxine–labeled ...

These studies have provided insights into the trapping of these cells in nontarget organs after intravenous and intraventricular injections (Figure 1).10,15 As expected, mesenchymal stem cells, which are much larger than endothelial or hematopoietic progenitor cells, have shown a larger percentage of trapping in the pulmonary vasculature after intravenous administration.10,15 In addition, studies in both large and small animals of cardiovascular disease have demonstrated the poor engraftment of stem cells in the heart regardless of the route of administration or cell type despite the administration of millions of cells.10,15 Furthermore, using 2-[18F]-Fluoro-2-deoxy-d-glucose (FDG), a radiotracer with a much shorter half-life than Indium-111 oxine, a recent study has shown that intracoronary injection of a single bolus of bone marrow mononuclear cells (BMMNCs) results in a higher percentage of cardiac engraftment than multiple smaller bolus injections16—suggesting that future clinical trials using a single bolus intracoronary infusion may be preferable to multiple short occlusive injections.

Because FDG is more readily available than In-111, a few cardiac cellular patient studies have been performed with FDG-labeled cells. Most notably is the comparison of CD34-positive FDG-labeled BMMNCs, which showed higher retention in the myocardium after intracoronary injection than nonselected BMMNCs.17 Radiotoxicity and impairment of lymphocyte function after Indium-111 oxine labeling has lead to fears that radiolabeled stem cells may also be impaired. Several detailed studies have demonstrated that the proper titration of the radiation dose can minimize alterations to metabolic function and proliferation in several stem cell lineages.10,12,18

Similarly, FDG labeling of islet cells has been used to demonstrate a high liver engraftment after intraportal delivery in both mice and swine.19,20 However, using a large animal model, early damage of up to 50% of the islet also occurred resulting in release of the radiotracer.20 Fortunately, the released radiotracer is phosphorylated, which should limit uptake by other cells in vivo.20 Nonetheless, nonradioactive methods of stem and islet labeling have gained favor, perhaps in part because of the complications involved in handling radioactive substances in the context of interventional catheterization delivery.

MRI Contrast Agents for Direct Cell Labeling

Unlike radiotracers, most stem and progenitor cells do not readily take up clinically approved MRI contrast agents. On the other hand, macrophages and monocytes will readily phagocytize commercially available iron oxide nanoparticles. This has lead to their limited use to identify phagocytic cells in the atherosclerotic plaque after intravenous infusion of iron oxide nanoparticles.2123 Similarly, gadolinium-based compounds have been developed that are selectively taken up by the components of the atherosclerotic plaque.24 One notable exception is the uptake of gadolinium HPDO3A, a commercially available MRI contrast agent, which shows some affinity for uptake by stem cells.25,26 A recent review by Nahrendorf et al of promising molecular agents for the atherosclerotic plaque covers these agents in more extensive detail.27 In a like manner, whole islets when incubated with iron oxides show an uneven distribution of the label because of the avidity for uptake by the monocytic lineages within the islet.28 This will vary based on a number of variables: (1) the purity of the islet preparation; (2) the specific preparation of iron oxides used; and (3) the length of iron oxide incubation time. Therefore, it is not surprising that different labeling results have been reported among different investigators. Immunorejection of transplanted hearts has also shown promise by monitoring macrophage infiltrates, which will engulf intravenously administered iron oxide compounds as well.29

The addition of a transfection agent (TA), greatly facilitates the uptake of iron oxide nanoparticles by stem and progenitor cells resulting in stable intracellular incorporation in endosomes with minimal toxicity.30,31 Because of the simplicity of TA–iron oxide labeling, these techniques have been used extensively in both small and large preclinical animal models of cardiovascular disease.10,3245 Typically, T2*-weighted MR imaging is performed to detect iron oxide–labeled cells as hypointensities. Because the underlying anatomy is obscured using these imaging methods, gadolinium-based compounds, which appear as hyperintensities on T1-weighted MRIs, have been explored by several groups for cellular labeling.46,47 However, once inside cells, the ability of gadolinium (Gd)-based compounds to affect tissue water is severely restricted, and the sensitivity is thus markedly reduced.25,47,48 Also, there are concerns about the dechelation of lanthanide compounds, such as gadolinium, and its subsequent systemic redistribution and potential toxicity after death of transplanted cells. On the other hand, sufficient sensitivity to 105 iron oxide–labeled cells by cardiac MRI34,49 can be achieved with picograms of iron per cell, and on cell death this free iron can be easily recycled into the normal iron pool. But there has been considerable controversy, as with direct radiolabeling techniques, about the ability to discriminate iron released from exogenously labeled cells, eg, iron taken up by phagocytic cells in vivo or extracellular iron debris, from the original exogeneously labeled cells.42,5052 Another concern is the ability to discriminate hypointensities from iron oxides from other causes of hypointensities such as calcium, air, and hemorrhage. Direct cellular labeling with fluorine, a compound which is not naturally occurring in the body, may provide a means to circumvent these problems,5355 but requires specialized hardware and expertise to image nonproton species with MR imaging and spectroscopy. A relatively new approach is the use of PARACEST agents, which contain lanthanide inducing large chemical shifts of protons. Using a specific off-resonance pulse, these protons can be saturated. After chemical exchange with the water pool, a reduction of signal can be obtained that can be turned “on” and “off.” Initial experiments appear promising,56 although the in vivo sensitivity still needs to be determined.

Besides being a low-cost and facile method to label cells, iron oxide labeling when combined with interventional MRI techniques offers a method to guide cellular delivery to specific portions of the heart or vasculature. Several groups have used conventional percutaneous techniques to delivery iron oxide–labeled stem cells in large animal models and demonstrated that the success of the transplantation and engraftment can be assessed without the use of ionizing radiation (supplemental Figure I).3235,57 Because the number of inteventional cardiologists and radiologists with interventional MRI expertise is limited, a recently proposed alternative is to combine MRI angiograms or cardiac viability maps with conventional X-ray fluoroscopic images to guide delivery and limit overall radiation exposure (supplemental Figure II).58

Another issue with direct labeling techniques is that after a certain number of divisions, the label is sufficiently diluted to be undetectable by MRI.59 Embryonic stem cells (ESC), which may replicate rapidly in vivo, are especially prone to this potential limitation. Fortunately, reporter gene methods have been developed for imaging of many ESC lines.

Reporter Gene Methods

Like direct labeling, reporter gene methods were originally developed for postmortem tissue analysis of cell fate. For noninvasive reporter gene imaging, a cell is transduced with a reporter gene to produce a nonnative enzyme, receptor, or protein that accumulates and can be detected by the administration of a reporter probe. One of the greatest advantages of reporter gene imaging is that only viable cells will produce the reporter product. Although reporter genes have been developed for MRI,6064 the most widely used reporter genes have been developed for radionuclide imaging.6574 At present, only the artificial lysine-rich protein63 has shown to be a suitable MRI reporter gene for cell tracking. The problem with the other MRI reporter genes is that they rely on metals (eg, gadolinium and iron), which induce long-term background contrast in the surrounding cellular environment, regardless of whether or not the reporter is active (ie, the cell is alive).64 The best known reporter gene for radionuclide imaging is the herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene. The wild-type HSV1-tk can be used in combination with the reporter probe, Iodine-123- or Iodine-124–labeled FIAU, for SPECT or PET imaging; the mutant HSV1-tk is used in combination with Fluorine-18-labeled FIAU or FHBG for PET imaging. Wu and colleagues have used reporter gene imaging to demonstrate teratoma formation after intramyocardial injection of undifferentiated embryonic stem cells in a murine model of myocardial infarction (supplemental Figure III).65 Initially developed for oncological applications (eg, gene therapy for gliomas via “the bystander” effect),75 there is the added benefit that the reporter gene can also act as a suicide gene using the HSV1-tk/gancyclovir combination where the thymidine analog, gancyclovir, can be administered to kill transfected cells that proliferate uncontrollably.65

For reporter gene imaging of pancreatic beta cells, a few studies have used the HSV-tk and the luciferase reporter gene for monitoring islet cell transplantation.7680 Although still in its infancy, these studies have shown that reporter gene–based imaging may result in a better understanding of overall graft function including its immediate and long-term survival.

Hybrid reporter genes have been developed to allow a combination of optical, radionuclide, or MR imaging techniques.6870 Bioluminescence imaging of stem cells transfected with a reporter gene that produces luciferase, an enzyme that in the presence of the reporter probe luciferin, creates light similar to the firefly, has been widely used in cardiovascular mice and rat studies. Although clinical translation of bioluminescence imaging is not possible because of the physical constraints of light scatter and poor penetration, these studies can provide high throughput screening of potential cell types that are most beneficial, immunosuppressive drug therapies that would be most successful, or mechanisms of stem cell engraftment and homing.68,71,72 Recently, multimodality reporters have been translated to large animal models of myocardial infarction, which lends promise to the use of reporter gene methods in clinical trials in the distant future.73 Although fears of gene therapy still persist, most reporter genes are not stably expressed forever. For clinical translation, the silencing of reporter genes may be a blessing in itself in that fears of introducing a genetically altered product in patients will only need monitoring for several months rather than the patient's lifetime.

Microencapsulation of Allogeneic/Xenogenic Cells

Because of the acute nature of many cardiovascular diseases that could be expected to benefit from cellular therapy, the time needed to culture and expand stem cells is frequently not possible. In the case of Type I diabetes mellitus, where the pancreatic beta cells have been destroyed, cadaveric islet transplantation is currently the only option available as alternative to insulin therapy. However, immunosuppressive therapies to prevent rejection of allogeneic cells have the unwanted side effect of cytotoxicity of the implanted islet cells. Thus, microencapsulation methods were developed to provide a porous coating to the transplanted islets that would allow the free flow of nutrients, such as glucose, oxygen, and insulin, but restrict large substances, such as immunoglobulins or antigen presenting cells. The addition to this capsule of MRI-visible contrast agents to an alginate microcapsule provides a method for noninvasive imaging of the fate of individual islets.81,82 Our group has combined these “magnetocapsules” with interventional MRI techniques to enable the real-time monitoring of the Edmonton procedure, ie, intraportal delivery of islets to the liver (supplemental Figure IV).82 Because the MR contrast agent is now within the microcapsule rather than inside cells as occurs with direct labeling,8385 the amount of contrast agent can be increased to enhance sensitivity without increasing cytotoxicity. Fortunately, the addition of MRI contrast agents to the capsule does not have adverse effects on the capsule properties.82 Recently, we have developed a family of imaging-visible microcapsules that would be amenable for not only MRI but also X-ray and CT imaging applications (Figure 2).27,86,87 For stem cell therapies, microencapsulation offers the prospect of enhanced cell survive in a hostile, ischemic environment, but would not allow direct cellular incorporation of stem cells. Because paracrine mechanisms8891 have been implicated in the therapeutic effects of many cardiovascular cellular therapies rather than direct tissue regeneration, the lack of direct cellular engraftment may not be so problematic. The current wide use of X-ray–based interventional techniques and devices should enhance translation of these microencapsulation methods, which may reduce cellular destruction and thereby decrease the number of cells needed to treat a patient.

Figure 2
X-ray angiogram of the peripheral hindlimb of a rabbit before intervention (left) and after creation of a femoral artery occlusion via a platinum coil (black arrow). X-ray–visible microencapsulated stem cell injections injected intramuscularly ...


There has been an increasing interest in cellular therapy for the treatment of cardiovascular disease and diabetes mellitus in the past decade. Noninvasive imaging can provide a means to determine the efficacy of these therapies in patients. Direct labeling of stem, progenitor, and beta cells has provided insights into the underlying mechanisms of action and determining the optimal route, dosing, and cell type. Limited adoption of these techniques has been performed in clinical trials but can be anticipated to increase as these labeling techniques are now reaching maturity. Reporter gene methods offer several advantages over direct labeling techniques but are not as established and more difficult to perform. Thus, these techniques are expected to be adopted but with a longer translational window to the clinical realm. The recent introduction of microencapsulation methods offers an X-ray–visible tracking method that is very attractive because of the widespread use of percutaneous procedures in patients with cardiovascular disease.

Supplementary Material


Sources of Funding: Supported, in part, by NIH grants R01-EB 007825 (to D.K. and J.B.), R21-HL089029 (to D.K. and J.B.), and Maryland Stem Cell Research Fund 2008-MSCRF II-0399 (to D.K. and J.B.).


Data Supplement (unedited) at:

Reprints: Information about reprints can be found online at:

Disclosures: None.

Contributor Information

Dara L. Kraitchman, Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research, Baltimore, Md.

Jeff W.M. Bulte, Russell H. Morgan Department of Radiology and Radiological Science, Division of MR Research and the Department of Biomedical Engineering, Department of Chemical & Biomolecular Engineering, Cellular Imaging Section, and Vascular Biology Program, Institute for Cell Engineering, Baltimore, Md.


1. Fadini GP, Sartore S, Albiero M, Baesso I, Murphy E, Menegolo M, Grego F, Vigili de Kreutzenberg S, Tiengo A, Agostini C, Avogaro A. Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy. Arterioscler Thromb Vasc Biol. 2006;26:2140–2146. [PubMed]
2. Thum T, Fraccarollo D, Schultheiss M, Froese S, Galuppo P, Widder JD, Tsikas D, Ertl G, Bauersachs J. Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. Diabetes. 2007;56:666–674. [PubMed]
3. Heeschen C, Lehmann R, Honold J, Assmus B, Aicher A, Walter DH, Martin H, Zeiher AM, Dimmeler S. Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease. Circulation. 2004;109:1615–1622. [PubMed]
4. Lavender JP, Goldman JM, Arnot RN, Thakur ML. Kinetics of indium-III labelled lymphocytes in normal subjects and patients with Hodgkin's disease. BMJ. 1977;2:797–799. [PMC free article] [PubMed]
5. Segal AW, Arnot RN, Thakur ML, Lavender JP. Indium-111-labelled leucocytes for localisation of abscesses. Lancet. 1976;2:1056–1058. [PubMed]
6. Chin BB, Nakamoto Y, Bulte JW, Pittenger MF, Wahl R, Kraitchman DL. 111In oxine labelled mesenchymal stem cell SPECT after intravenous administration in myocardial infarction. Nucl Med Commun. 2003;24:1149–1154. [PubMed]
7. Brenner W, Aicher A, Eckey T, Massoudi S, Zuhayra M, Koehl U, Heeschen C, Kampen WU, Zeiher AM, Dimmeler S, Henze E. 111In-labeled CD34+ hematopoietic progenitor cells in a rat myocardial infarction model. J Nucl Med. 2004;45:512–518. [PubMed]
8. Aicher A, Brenner W, Zuhayra M, Badorff C, Massoudi S, Assmus B, Eckey T, Henze E, Zeiher AM, Dimmeler S. Assessment of the tissue distribution of transplanted human endothelial progenitor cells by radioactive labeling. Circulation. 2003;107:2134–2139. [PubMed]
9. Gao J, Dennis JE, Muzic RF, Lundberg M, Caplan AI. The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cell Tissues Organs. 2001;169:12–20. [PubMed]
10. Kraitchman DL, Tatsumi M, Gilson WD, Ishimori T, Kedziorek D, Walczak P, Segars WP, Chen HH, Fritzges D, Izbudak I, Young RG, Marcelino M, Pittenger MF, Solaiyappan M, Boston RC, Tsui BM, Wahl RL, Bulte JW. Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction. Circulation. 2005;112:1451–1461. [PMC free article] [PubMed]
11. Thakur ML, Segal AW, Louis L, Welch MJ, Hopkins J, Peters TJ. Indium-111-labeled cellular blood components: mechanism of labeling and intracellular location in human neutrophils. J Nucl Med. 1977;18:1022–1026. [PubMed]
12. Jin Y, Kong H, Stodilka RZ, Wells RG, Zabel P, Merrifield PA, Sykes J, Prato FS. Determining the minimum number of detectable cardiactransplanted 111In-tropolone-labelled bone-marrow-derived mesenchymal stem cells by SPECT. Phys Med Biol. 2005;50:4445–4455. [PubMed]
13. Adonai N, Nguyen KN, Walsh J, Iyer M, Toyokuni T, Phelps ME, McCarthy T, McCarthy DW, Gambhir SS. Ex vivo cell labeling with 64Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) for imaging cell trafficking in mice with positron-emission tomography. Proc Natl Acad Sci U S A. 2002;99:3030–3035. [PubMed]
14. Huang J, Lee CC, Sutcliffe JL, Cherry SR, Tarantal AF. Radiolabeling rhesus monkey CD34+ hematopoietic and mesenchymal stem cells with 64Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) for microPET imaging. Mol Imaging. 2008;7:1–11. [PubMed]
15. Hou D, Youssef EA, Brinton TJ, Zhang P, Rogers P, Price ET, Yeung AC, Johnstone BH, Yock PG, March KL. Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: implications for current clinical trials. Circulation. 2005;112:I150–I156. [PubMed]
16. Doyle B, Kemp BJ, Chareonthaitawee P, Reed C, Schmeckpeper J, Sorajja P, Russell S, Araoz P, Riederer SJ, Caplice NM. Dynamic tracking during intracoronary injection of 18F-FDG-labeled progenitor cell therapy for acute myocardial infarction. J Nucl Med. 2007;48:1708–1714. [PubMed]
17. Hofmann M, Wollert KC, Meyer GP, Menke A, Arseniev L, Hertenstein B, Ganser A, Knapp WH, Drexler H. Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation. 2005;111:2198–2202. [PubMed]
18. Bindslev L, Haack-Sorensen M, Bisgaard K, Kragh L, Mortensen S, Hesse B, Kjaer A, Kastrup J. Labelling of human mesenchymal stem cells with indium-111 for SPECT imaging: effect on cell proliferation and differentiation. Eur J Nucl Med Mol Imaging. 2006 [PubMed]
19. Toso C, Zaidi H, Morel P, Armanet M, Andres A, Pernin N, Baertschiger R, Slosman D, Buhler LH, Bosco D, Berney T. Positron-emission tomography imaging of early events after transplantation of islets of Langerhans. Transplantation. 2005;79:353–355. [PubMed]
20. Eich T, Eriksson O, Sundin A, Estrada S, Brandhorst D, Brandhorst H, Langstrom B, Nilsson B, Korsgren O, Lundgren T. Positron emission tomography: a real-time tool to quantify early islet engraftment in a preclinical large animal model. Transplantation. 2007;84:893–898. [PubMed]
21. Trivedi R, Mallawarachi C, UK-I JM, Graves M, Horsley J, Goddard M, Brown A, Wang L, Kirkpatrick P, Brown J, Gillard J. Identifying inflamed carotid plaques using in vivo USPIO-enhanced MR imaging to label plaque macrophages. Arterioscler Thromb Vasc Biol. 2006;26:1601–1606. [PubMed]
22. Kooi ME, Cappendijk VC, Cleutjens KB, Kessels AG, Kitslaar PJ, Borgers M, Frederik PM, Daemen MJ, van Engelshoven JM. Accumulation of ultrasmall superparamagnetic particles of iron oxide in human atherosclerotic plaques can be detected by in vivo magnetic resonance imaging. Circulation. 2003;107:2453–2458. [PubMed]
23. Ruehm SG, Corot C, Vogt P, Kolb S, Debatin JF. Magnetic resonance imaging of atherosclerotic plaque with ultrasmall superparamagnetic particles of iron oxide in hyperlipidemic rabbits. Circulation. 2001;103:415–422. [PubMed]
24. Amirbekian V, Lipinski M, Briley-Saebo K, Amirbekian S, Aguinaldo J, Weinreb D, Vucic E, Frias J, Hyafil F, Mani V, Fisher E, Fayad Z. Detecting and assessing macrophages in vivo to evaluate atherosclerosis noninvasively using molecular MRI. Proc Natl Acad Sci U S A. 2007;104:961–966. [PubMed]
25. Terreno E, Geninatti Crich S, Belfiore S, Biancone L, Cabella C, Esposito G, Manazza AD, Aime S. Effect of the intracellular localization of a Gd-based imaging probe on the relaxation enhancement of water protons. Magn Reson Med. 2006;55:491–497. [PubMed]
26. Crich SG, Biancone L, Cantaluppi V, Duo D, Esposito G, Russo S, Camussi G, Aime S. Improved route for the visualization of stem cells labeled with a Gd-/Eu-chelate as dual (MRI and fluorescence) agent. Magn Reson Med. 2004;51:938–944. [PubMed]
27. Nahrendorf M, Sosnovik D, French B, Swirski FK, Bengel FM, Sadeghi M, Lindner J, Wu J, Kraitchman D, Fayad Z, Sinusas A. Multimodality cardiovascular molecular imaging-Part II. Circulation Cardiovascular Imaging. 2009 [PMC free article] [PubMed]
28. Kriz J, Jirak D, Girman P, Berkova Z, Zacharovova K, Honsova E, Lodererova A, Hajek M, Saudek F. Magnetic resonance imaging of pancreatic islets in tolerance and rejection. Transplantation. 2005;80:1596–1603. [PubMed]
29. Ye Q, Wu YL, Foley LM, Hitchens TK, Eytan DF, Shirwan H, Ho C. Longitudinal tracking of recipient macrophages in a rat chronic cardiac allograft rejection model with noninvasive magnetic resonance imaging using micrometer-sized paramagnetic iron oxide particles. Circulation. 2008;118:149–156. [PMC free article] [PubMed]
30. Frank JA, Zywicke H, Jordan EK, Mitchell J, Lewis BK, Bryant LH, Jr, Bulte JWM. Magnetic intracellular labeling of mammalian cells by combining (FDA-approved) superparamagnetic iron oxide MR contrast agents and commonly used transfection agents. Acad Radiol. 2002;9:S484–S487. [PubMed]
31. Bulte JW, Kraitchman DL. Iron oxide MR contrast agents for molecular and cellular imaging. NMR Biomed. 2004;17:484–499. [PubMed]
32. Kraitchman DL, Heldman AW, Atalar E, Amado LC, Martin BJ, Pittenger MF, Hare JM, Bulte JW. In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction. Circulation. 2003;107:2290–2293. [PubMed]
33. Garot J, Unterseeh T, Teiger E, Champagne S, Chazaud B, Gherardi R, Hittinger L, Gueret P, Rahmouni A, Sonnet C, Le Corvoisier P, Benhaiem-Sigaux N, Su J, Merlet P. Magnetic resonance imaging of targeted catheter-based implantation of myogenic precursor cells into infarcted left ventricular myocardium. J Am Coll Cardiol. 2003;41:1841–1846. [PubMed]
34. Hill JM, Dick AJ, Raman VK, Thompson RB, Yu ZX, Hinds KA, Pessanha BS, Guttman MA, Varney TR, Martin BJ, Dunbar CE, McVeigh ER, Lederman RJ. Serial cardiac magnetic resonance imaging of injected mesenchymal stem cells. Circulation. 2003;108:1009–1014. [PMC free article] [PubMed]
35. Dick AJ, Guttman MA, Raman VK, Peters DC, Pessanha BS, Hill JM, Smith S, Scott G, McVeigh ER, Lederman RJ. Magnetic resonance fluoroscopy allows targeted delivery of mesenchymal stem cells to infarct borders in swine. Circulation. 2003;108:2899–2904. [PMC free article] [PubMed]
36. Weber A, Pedrosa I, Kawamoto A, Himes N, Munasinghe J, Asahara T, Rofsky NM, Losordo DW. Magnetic resonance mapping of transplanted endothelial progenitor cells for therapeutic neovascularization in ischemic heart disease. Eur J Cardiothorac Surg. 2004;26:137–143. [PubMed]
37. Kustermann E, Roell W, Breitbach M, Wecker S, Wiedermann D, Buehrle C, Welz A, Hescheler J, Fleischmann BK, Hoehn M. Stem cell implantation in ischemic mouse heart: a high-resolution magnetic resonance imaging investigation. NMR Biomed. 2005;18:362–370. [PubMed]
38. Cahill KS, Germain S, Byrne BJ, Walter GA. Non-invasive analysis of myoblast transplants in rodent cardiac muscle. Int J Cardiovasc Imaging. 2004;20:593–598. [PubMed]
39. Amado LC, Schuleri KH, Saliaris AP, Boyle AJ, Helm R, Oskouei B, Centola M, Eneboe V, Young R, Lima JA, Lardo AC, Heldman AW, Hare JM. Multimodality noninvasive imaging demonstrates in vivo cardiac regeneration after mesenchymal stem cell therapy. J Am Coll Cardiol. 2006;48:2116–2124. [PubMed]
40. Arai T, Kofidis T, Bulte JW, de Bruin J, Venook RD, Berry GJ, McConnell MV, Quertermous T, Robbins RC, Yang PC. Dual in vivo magnetic resonance evaluation of magnetically labeled mouse embryonic stem cells and cardiac function at 1.5 T. Magn Reson Med. 2006;55:203–209. [PubMed]
41. Stuber M, Gilson WD, Schär M, Kedziorek DA, Hofmann LV, Shah S, Vonken E, Bulte JWM, Kraitchman DL. Positive contrast visualization of iron oxide-labeled stem cells using inversion recovery with ON-resonant water suppression (IRON) Magn Reson Med. 2007;58:1072–1077. [PubMed]
42. Ebert SN, Taylor DG, Nguyen HL, Kodack DP, Beyers RJ, Xu Y, Yang Z, French BA. Noninvasive tracking of cardiac embryonic stem cells in vivo using magnetic resonance imaging techniques. Stem Cells. 2007;25:2936–2944. [PubMed]
43. Carr CA, Stuckey DJ, Tatton L, Tyler DJ, Hale SJ, Sweeney D, Schneider JE, Martin-Rendon E, Radda GK, Harding SE, Watt SM, Clarke K. Bone marrow-derived stromal cells home to and remain in the infarcted rat heart, but fail to improve function: An in vivo cine-MRI study. Am J Physiol Heart Circ Physiol. 2008;295:H533–H542. [PMC free article] [PubMed]
44. Mani V, Adler E, Briley-Saebo KC, Bystrup A, Fuster V, Keller G, Fayad ZA. Serial in vivo positive contrast MRI of iron oxide-labeled embryonic stem cell-derived cardiac precursor cells in a mouse model of myocardial infarction. Magn Reson Med. 2008;60:73–81. [PubMed]
45. Kraitchman DL, Bulte JW. Imaging of stem cells using MRI. Basic Res Cardiol. 2008;103:105–113. [PMC free article] [PubMed]
46. Giesel FL, Stroick M, Griebe M, Troster H, von der Lieth CW, Requardt M, Rius M, Essig M, Kauczor HU, Hennerici MG, Fatar M. Gadofluorine m uptake in stem cells as a new magnetic resonance imaging tracking method: an in vitro and in vivo study. Invest Radiol. 2006;41:868–873. [PubMed]
47. Anderson SA, Lee KK, Frank JA. Gadolinium-fullerenol as a paramagnetic contrast agent for cellular imaging. Invest Radiol. 2006;41:332–338. [PubMed]
48. Vuu K, Xie J, McDonald MA, Bernardo M, Hunter F, Zhang Y, Li K, Bednarski M, Guccione S. Gadolinium-rhodamine nanoparticles for cell labeling and tracking via magnetic resonance and optical imaging. Bioconjug Chem. 2005;16:995–999. [PubMed]
49. Bulte JW, Kraitchman DL. Monitoring cell therapy using iron oxide MR contrast agents. Curr Pharm Biotechnol. 2004;5:567–584. [PubMed]
50. Terrovitis J, Stuber M, Youssef A, Preece S, Leppo M, Kizana E, Schar M, Gerstenblith G, Weiss RG, Marban E, Abraham MR. Magnetic resonance imaging overestimates ferumoxide-labeled stem cell survival after transplantation in the heart. Circulation. 2008;117:1555–1562. [PubMed]
51. Stuckey DJ, Carr CA, Martin-Rendon E, Tyler DJ, Willmott C, Cassidy PJ, Hale SJ, Schneider JE, Tatton L, Harding SE, Radda GK, Watt S, Clarke K. Iron particles for noninvasive monitoring of bone marrow stromal cell engraftment into, and isolation of viable engrafted donor cells from, the heart. Stem Cells. 2006;24:1968–1975. [PubMed]
52. Amsalem Y, Mardor Y, Feinberg MS, Landa N, Miller L, Daniels D, Ocherashvilli A, Holbova R, Yosef O, Barbash IM, Leor J. Iron-oxide labeling and outcome of transplanted mesenchymal stem cells in the infarcted myocardium. Circulation. 2007;116:I-38–I-45. [PubMed]
53. Ruiz-Cabello J, Walczak P, Kedziorek DA, Chacko VP, Schmieder AH, Wickline SA, Lanza GM, Bulte JW. In vivo “hot spot” MR imaging of neural stem cells using fluorinated nanoparticles. Magn Reson Med. 2008;60:1506–1511. [PMC free article] [PubMed]
54. Partlow KC, Chen J, Brant JA, Neubauer AM, Meyerrose TE, Creer MH, Nolta JA, Caruthers SD, Lanza GM, Wickline SA. 19F magnetic resonance imaging for stem/progenitor cell tracking with multiple unique perfluorocarbon nanobeacons. Faseb J. 2007;21:1647–1654. [PubMed]
55. Ahrens ET, Flores R, Xu H, Morel PA. In vivo imaging platform for tracking immunotherapeutic cells. Nat Biotechnol. 2005;23:983–987. [PubMed]
56. Aime S, Carrera C, Delli Castelli D, Geninatti Crich S, Terreno E. Tunable imaging of cells labeled with MRI-PARACEST agents. Angew Chem Int Ed Engl. 2005;44:1813–1815. [PubMed]
57. Kraitchman DL, Gilson WD, Lorenz CH. Stem cell therapy: MRI guidance and monitoring. J Magn Reson Imaging. 2008;27:299–310. [PMC free article] [PubMed]
58. de Silva R, Gutierrez LF, Raval AN, McVeigh ER, Ozturk C, Lederman RJ. X-Ray Fused with Magnetic Resonance Imaging (XFM) to target endomyocardial injections. Validation in a swine model of myocardial infarction. Circulation. 2006;114:2342–2350. [PMC free article] [PubMed]
59. Walczak P, Kedziorek DA, Gilad AA, Barnett BP, Bulte JW. Applicability and limitations of MR tracking of neural stem cells with asymmetric cell division and rapid turnover: the case of the shiverer dysmyelinated mouse brain. Magn Reson Med. 2007;58:261–269. [PubMed]
60. Louie AY, Huber MM, Ahrens ET, Rothbacher U, Moats R, Jacobs RE, Fraser SE, Meade TJ. In vivo visualization of gene expression using magnetic resonance imaging. Nat Biotechnol. 2000;18:321–325. [PubMed]
61. Cohen B, Dafni H, Meir G, Harmelin A, Neeman M. Ferritin as an endogenous MRI reporter for noninvasive imaging of gene expression in C6 glioma tumors. Neoplasia. 2005;7:109–117. [PMC free article] [PubMed]
62. Genove G, DeMarco U, Xu H, Goins WF, Ahrens ET. A new transgene reporter for in vivo magnetic resonance imaging. Nat Med. 2005;11:450–454. [PubMed]
63. Gilad AA, McMahon MT, Walczak P, Winnard PT, Jr, Raman V, van Laarhoven HW, Skoglund CM, Bulte JW, van Zijl PC. Artificial reporter gene providing MRI contrast based on proton exchange. Nat Biotechnol. 2007;25:217–219. [PubMed]
64. Gilad AA, Winnard PT, Jr, van Zijl PC, Bulte JW. Developing MR reporter genes: promises and pitfalls. NMR Biomed. 2007;20:275–290. [PubMed]
65. Cao F, Lin S, Xie X, Ray P, Patel M, Zhang X, Drukker M, Dylla SJ, Connolly AJ, Chen X, Weissman IL, Gambhir SS, Wu JC. In vivo visualization of embryonic stem cell survival, proliferation, and migration after cardiac delivery. Circulation. 2006;113:1005–1014. [PubMed]
66. Miyagawa M, Beyer M, Wagner B, Anton M, Spitzweg C, Gansbacher B, Schwaiger M, Bengel FM. Cardiac reporter gene imaging using the human sodium/iodide symporter gene. Cardiovasc Res. 2005;65:195–202. [PubMed]
67. Bengel FM, Anton M, Richter T, Simoes MV, Haubner R, Henke J, Erhardt W, Reder S, Lehner T, Brandau W, Boekstegers P, Nekolla SG, Gansbacher B, Schwaiger M. Noninvasive imaging of transgene expression by use of positron emission tomography in a pig model of myocardial gene transfer. Circulation. 2003;108:2127–2133. [PubMed]
68. Wu JC, Chen IY, Sundaresan G, Min JJ, De A, Qiao JH, Fishbein MC, Gambhir SS. Molecular imaging of cardiac cell transplantation in living animals using optical bioluminescence and positron emission tomography. Circulation. 2003;108:1302–1305. [PubMed]
69. Ray P, De A, Min JJ, Tsien RY, Gambhir SS. Imaging tri-fusion multimodality reporter gene expression in living subjects. Cancer Res. 2004;64:1323–1330. [PubMed]
70. Love Z, Wang F, Dennis J, Awadallah A, Salem N, Lin Y, Weisenberger A, Majewski S, Gerson S, Lee Z. Imaging of mesenchymal stem cell transplant by bioluminescence and PET. J Nucl Med. 2007;48:2011–2020. [PubMed]
71. Sheikh AY, Lin SA, Cao F, Cao Y, van der Bogt KE, Chu P, Chang CP, Contag CH, Robbins RC, Wu JC. Molecular imaging of bone marrow mononuclear cell homing and engraftment in ischemic myocardium. Stem Cells. 2007;25:2677–2684. [PMC free article] [PubMed]
72. van der Bogt KE, Sheikh AY, Schrepfer S, Hoyt G, Cao F, Ransohoff KJ, Swijnenburg RJ, Pearl J, Lee A, Fischbein M, Contag CH, Robbins RC, Wu JC. Comparison of different adult stem cell types for treatment of myocardial ischemia. Circulation. 2008;118:S121–129. [PMC free article] [PubMed]
73. Gyöngysi M, Blanco J, Marian T, Trón L, Petneházy Ö, Petrasi Z, Hemetsberger R, Rodriguez J, Font G, Pvao I, Kertész I, Balkay L, Pavo N, Posa A, Emri M, Galuska L, Kraitchman D, Wojta J, Huber K, Glogar D. Serial non-invasive in vivo positron emission tomographic (PET) tracking of percutaneously intramyocardially injected autologous porcine mesenchymal stem cells modified for transgene reporter gene expression. Circ Cardiovasc Imaging. 2008;1:94–103. [PMC free article] [PubMed]
74. Terrovitis J, Kwok KF, Lautamaki R, Engles JM, Barth AS, Kizana E, Miake J, Leppo MK, Fox J, Seidel J, Pomper M, Wahl RL, Tsui B, Bengel F, Marban E, Abraham MR. Ectopic expression of the sodium-iodide symporter enables imaging of transplanted cardiac stem cells in vivo by single-photon emission computed tomography or positron emission tomography. J Am Coll Cardiol. 2008;52:1652–1660. [PubMed]
75. Yaghoubi SS, Barrio JR, Namavari M, Satyamurthy N, Phelps ME, Herschman HR, Gambhir SS. Imaging progress of herpes simplex virus type 1 thymidine kinase suicide gene therapy in living subjects with positron emission tomography. Cancer Gene Ther. 2005;12:329–339. [PubMed]
76. Lu Y, Dang H, Middleton B, Campbell-Thompson M, Atkinson MA, Gambhir SS, Tian J, Kaufman DL. Long-term monitoring of transplanted islets using positron emission tomography. Mol Ther. 2006;14:851–856. [PubMed]
77. Tai JH, Nguyen B, Wells RG, Kovacs MS, McGirr R, Prato FS, Morgan TG, Dhanvantari S. Imaging of gene expression in live pancreatic islet cell lines using dual-isotope SPECT. J Nucl Med. 2008;49:94–102. [PubMed]
78. Kim SJ, Doudet DJ, Studenov AR, Nian C, Ruth TJ, Gambhir SS, McIntosh CH. Quantitative micro positron emission tomography (PET) imaging for the in vivo determination of pancreatic islet graft survival. Nat Med. 2006;12:1423–1428. [PubMed]
79. Lu Y, Dang H, Middleton B, Zhang Z, Washburn L, Campbell-Thompson M, Atkinson MA, Gambhir SS, Tian J, Kaufman DL. Bioluminescent monitoring of islet graft survival after transplantation. Mol Ther. 2004;9:428–435. [PubMed]
80. Lu Y, Dang H, Middleton B, Zhang Z, Washburn L, Stout DB, Campbell-Thompson M, Atkinson MA, Phelps M, Gambhir SS, Tian J, Kaufman DL. Noninvasive imaging of islet grafts using positron-emission tomography. Proc Natl Acad Sci U S A. 2006;103:11294–11299. [PubMed]
81. Shen F, Li AA, Gong YK, Somers S, Potter MA, Winnik FM, Chang PL. Encapsulation of recombinant cells with a novel magnetized alginate for magnetic resonance imaging. Hum Gene Ther. 2005;16:971–984. [PubMed]
82. Barnett BP, Arepally A, Karmarkar PV, Qian D, Gilson WD, Walczak P, Howland V, Lawler L, Lauzon C, Stuber M, Kraitchman DL, Bulte JW. Magnetic resonance-guided, real-time targeted delivery and imaging of magnetocapsules immunoprotecting pancreatic islet cells. Nat Med. 2007;13:986–991. [PubMed]
83. Jirak D, Kriz J, Herynek V, Andersson B, Girman P, Burian M, Saudek F, Hajek M. MRI of transplanted pancreatic islets. Magn Reson Med. 2004;52:1228–1233. [PubMed]
84. Evgenov NV, Medarova Z, Dai G, Bonner-Weir S, Moore A. In vivo imaging of islet transplantation. Nat Med. 2006;12:144–148. [PubMed]
85. Tai JH, Foster P, Rosales A, Feng B, Hasilo C, Martinez V, Ramadan S, Snir J, Melling CW, Dhanvantari S, Rutt B, White DJ. Imaging islets labeled with magnetic nanoparticles at 1.5 Tesla. Diabetes. 2006;55:2931–2938. [PubMed]
86. Barnett BP, Kraitchman DL, Lauzon C, Magee CA, Walczak P, Gilson WD, Bulte JWM. Radiopaque alginate microcapsules for x-ray visualization and immunoprotection of cellular therapeutics. Molecular Pharmaceutics. 2006;3:531–538. [PubMed]
87. Kraitchman DL, Kedziorek DA, Cosby K, Gilson WD, Huang G, Kohl T, Barnett BP, Bulte JWM, Hofmann LV. X-ray visible stem cell therapy enhances angiogenesis in a rabbit model of peripheral arterial disease. J Am Coll Cardiol. 2008;51:A315.
88. Burchfield JS, Dimmeler S. Role of paracrine factors in stem and progenitor cell mediated cardiac repair and tissue fibrosis. Fibrogenesis Tissue Repair. 2008;1:4. [PMC free article] [PubMed]
89. Doyle B, Sorajja P, Hynes B, Kumar AH, Araoz PA, Stalboerger PG, Miller D, Reed C, Schmeckpeper J, Wang S, Liu C, Terzic A, Kruger D, Riederer S, Caplice NM. Progenitor cell therapy in a porcine acute myocardial infarction model induces cardiac hypertrophy, mediated by paracrine secretion of cardiotrophic factors including TGFbeta1. Stem Cells Dev. 2008;17:941–951. [PMC free article] [PubMed]
90. Imanishi Y, Saito A, Komoda H, Kitagawa-Sakakida S, Miyagawa S, Kondoh H, Ichikawa H, Sawa Y. Allogenic mesenchymal stem cell transplantation has a therapeutic effect in acute myocardial infarction in rats. J Mol Cell Cardiol. 2008;44:662–671. [PubMed]
91. Dimmeler S, Burchfield J, Zeiher AM. Cell-based therapy of myocardial infarction. Arterioscler Thromb Vasc Biol. 2008;28:208–216. [PubMed]