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Biomedical subjects

Jeff W M Bulte

Publications and source records attributed to Jeff W M Bulte.

At least 19 recordsLinked to original sources
PubMed2007

Sensitivity of magnetic resonance imaging of dendritic cells for in vivo tracking of cellular cancer vaccines.

Success of immunotherapy with dendritic cells (DC) to treat cancer is highly dependent on their interaction with and activation of antigen specific T cells. To maximize DC-T cell contact accurate delivery of the therapeutic cells into the lymph node, or efficient trafficking of DC to the lymph nodes of the patient is essential. Since responses are seen in some patients but not in others, monitoring of the injected cells may be of major importance. Tracking of cells with magnetic resonance (MR) imaging is a non-invasive method that provides detailed anatomical information and is therefore more informative for the evaluation of the localization of therapeutic cells after injection than e.g. scintigraphic imaging. To challenge the sensitivity of this novel technique, we investigated the minimum amount of label and the number of cells required for MR imaging and the effect of labeling on DC function. DC were labeled with different concentrations of a clinically approved MR contrast agent consisting of superparamagnetic iron oxide particles and were imaged at both 3 and 7 T. Our results demonstrate the following: (i) When loaded with 30 (+/-4) pg Fe/cell, cell numbers as low as 1,000 cells/mm3 at 3 T and 500 cells/mm3 at 7 T could be readily imaged; (ii) Labeling does not affect cell viability and function; (iii) Because of its high spatial resolution and sensitivity, MRI is ideally suited to track therapeutic cells in vivo.

Cancer Vaccines↗
PubMed2007

Serial in vivo MR tracking of magnetically labeled neural spheres transplanted in chronic EAE mice.

Neural stem cell (NSC) transplantation has been shown to attenuate the severity of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Central to the future success of NSC transplantation in MS is the ability of transplanted cells to migrate from the site of transplantation to relevant foci of disease. Using magnetically labeled mouse neurospheres and human embryonic stem cell (hESC)-derived neurospheres, we applied serial magnetic resonance imaging (MRI) to assess the biodynamics of transplanted cell migration in a chronic mouse EAE model. Magnetic labeling did not affect the in vitro and in vivo characteristics of cells as multipotential precursors. Cell migration occurred along white matter (WM) tracts (especially the corpus callosum (CC), fimbria, and internal capsule), predominantly early in the acute phase of disease, and in an asymmetric manner. The distance of cell migration correlated well with clinical severity of disease and the number of microglia in the WM tracts, supporting the notion that inflammatory signals promote transplanted cell migration. This study shows for the first time that hESC-derived neural precursors also respond to tissue signals in an MS model, similarly to rodent cells. The results are directly relevant for designing and optimizing cell therapies for MS, and achieving a better understanding of in vivo cell dynamics and cell-tissue interactions.

Animals↗
PubMed2006

Brain engraftment and therapeutic potential of stem/progenitor cells derived from mouse skin.

Skin stem/progenitor cells (SKPs) derive from the dermis and in culture can generate mesodermal and neural progenies. To investigate their potential for the treatment of brain diseases, we first injected SKPs into the brain of syngeneic mice. Brain histology indicated that most SKPs remained undifferentiated and clustered at the injection site, while, in vitro, 17% of SKPs expressed neural markers, as assessed by flow cytometry. After labeling with magnetodendrimers, murine and human SKPs were detected by magnetic resonance imaging even 5 months after brain injection. To evaluate their therapeutic potential on malignant gliomas, IL-4 SKPs (i.e. SKPs transduced by a lentiviral vector carrying the cDNA of the anti-glioma cytokine interleukin-4) were injected into GL261 experimental gliomas. IL-4-SKPs prolonged significantly the survival of tumor-bearing mice: furthermore, GL261 gliomas attracted SKPs originally injected into the contralateral hemisphere. Thus, prolonged survival, capacity for transgene expression, and lack of uncontrolled proliferation suggest that SKPs warrant further consideration as therapeutic tools for brain tumors and, possibly, other neurological disorders.

Animals↗
PubMed2006

Dual in vivo magnetic resonance evaluation of magnetically labeled mouse embryonic stem cells and cardiac function at 1.5 t.

Cell therapy has demonstrated the potential to restore injured myocardium. A reliable in vivo imaging method to localize transplanted cells and monitor their restorative effects will enable a systematic investigation of this therapeutic modality. The dual MRI capability of imaging both magnetically labeled mouse embryonic stem cells (mESC) and their restorative effects on cardiac function in a murine model of acute myocardial infarction is demonstrated. Serial in vivo MR detection of transplanted mESC and monitoring of the mESC-treated myocardium was conducted over a 4-week period using a 1.5 T clinical scanner. During the 4-week duration, the mESC-treated myocardium demonstrated sustained improvement of the left ventricular (LV) ejection fraction and conservation of LV mass. Furthermore, no significant difference of their restorative effects on the cardiac function was created by the magnetic labeling of mESC. Thus, in vivo MRI enables simultaneous detection of transplanted mESC and their therapeutic effect on the injured myocardium.

Animals↗
PubMed2006

Quantifying exchange rates in chemical exchange saturation transfer agents using the saturation time and saturation power dependencies of the magnetization transfer effect on the magnetic resonance imaging signal (QUEST and QUESP): Ph calibration for poly-L-lysine and a starburst dendrimer.

The ability to measure proton exchange rates in tissue using MRI would be very useful for quantitative assessment of magnetization transfer properties, both in conventional MT imaging and in the more recent chemical exchange saturation transfer (CEST) approach. CEST is a new MR contrast mechanism that depends on several factors, including the exchange rate of labile protons in the agent in a pH-dependent manner. Two new methods to monitor local exchange rate based on CEST are introduced. The two MRI-compatible approaches to measure exchange are quantifying exchange using saturation time (QUEST) dependence and quantifying exchange using saturation power (QUESP) dependence. These techniques were applied to poly-L-lysine (PLL) and a generation-5 polyamidoamine dendrimer (SPD-5) to measure the pH dependence of amide proton exchange rates in the physiologic range. Data were fit both to an analytical expression and to numerical solutions to the Bloch equations. Results were validated by comparison with exchange rates determined by two established spectroscopic methods. The exchange rates determined using the four methods were pooled for the pH-calibration curve of the agents consisting of contributions from spontaneous (k0) acid catalyzed (ka), and base catalyzed (kb) exchange rate constants. These constants were k0 = 68.9 Hz, ka = 1.21 Hz, kb = 1.92 x 10(9) Hz, and k0 = 106.4 Hz, ka = 25.8 Hz, kb = 5.45 x 10(8) Hz for PLL and SPD-5, respectively, showing the expected predominance of base-catalyzed exchange for these amide protons.

Calibration↗
PubMed2006

Stem cell profiling by nuclear magnetic resonance spectroscopy.

The classification of embryonic and adult stem cells, including their derivatives, is still limited, and often these cells are best defined by their functional properties. Recent gene array studies have yielded contradictory results. Also, very little is known about the metabolic properties of these exciting cells. In this study, proton (1H) NMR spectroscopy was used to identify the major low-molecular-weight metabolites in murine embryonic stem cells (ESC) and their neural stem cell (NSC) derivatives. ESC are characterized by an unusually low number of NMR-detectable metabolites, high phosphocholine (PC) content, and nondetectable glycerophosphocholine (GPC). The metabolic profiles of NSC resemble glial cells and oligodendrocyte progenitors, but with considerably higher PC, GPC, and myo-inositol content. The results suggest that NMR spectroscopy in vitro can provide markers to study the effects of differentiation on cell metabolism, and potentially to assess stem cell preparations for differentiation status.

Animals↗
PubMed2006

Structure-specific patterns of neural stem cell engraftment after transplantation in the adult mouse brain.

Transplantation of neural stem cells (NSCs) may be useful for delivering exogenous gene products to the diseased CNS. When NSCs are transplanted into the developing mouse brain, they can migrate extensively and differentiate into cells appropriate to the sites of engraftment, in response to the normal signals directing endogenous cells to their appropriate fates. Much of the prior work on NSC migration in the adult brain has examined directed migration within or toward focal areas of injury such as ischemia, brain tumors, or 6-hydroxydopamine (6-OHDA) lesions. However, treatment of many genetic disorders that affect the CNS will require widespread dissemination of the donor cells in the postnatal brain, because the lesions are typically distributed globally. We therefore tested the ability of NSCs to migrate in the unlesioned adult mouse brain after stereotaxic transplantation into several structures including the cortex and hippocampus. NSC engraftment was monitored in live animals by magnetic resonance imaging (MRI) after superparamagnetic iron oxide (SPIO) labeling of cells. Histological studies demonstrated that the cells engrafted in significantly different patterns within different regions of the brain. In the cerebral cortex, donor cells migrated in all directions from the injection site. The cells maintained an immature phenotype and cortical migration was enhanced by trypsin treatment of the cells, indicating a role for cell surface proteins. In the hippocampus, overall cell survival and migration were lower but there was evidence of neuronal differentiation. In the thalamus, the transplanted cells remained in a consolidated mass at the site of injection. These variations in pattern of engraftment should be taken into account when designing treatment approaches in nonlesion models of neurologic disease.

Animals↗
PubMed2006

MR evaluation of the glomerular homing of magnetically labeled mesenchymal stem cells in a rat model of nephropathy.

PURPOSE: To assess renal glomerular homing of intravenously injected superparamagnetic iron oxide (SPIO)-labeled mesenchymal stem cells (MSCs) at in vivo and ex vivo magnetic resonance (MR) imaging in an experimental rat model of mesangiolysis. MATERIALS AND METHODS: Animal procedures were performed in accordance with protocols approved by Institutional Animal Care and Use Committee. Fourteen rats were divided into two groups: one pathologic (n = 10), with persistent mesangiolysis following simultaneous injection of OX-7 monoclonal antibody and puromycin aminonucleoside in which 10(7) SPIO- and DiI-labeled MSCs were injected, and one control (n = 4). In vivo and ex vivo MR imaging examinations were performed with 4.7- and 9.4-T spectrometers, respectively, and T2*-weighted sequences. In vivo signal intensity variations were measured in the liver and kidney before and 6 days after MSC injection. Intrarenal signal intensity variations were correlated with histopathologic data by means of colocalization of DiI fluorescence, alpha-actin, and Prussian blue stain-positive cells. Histologic differences between the glomerular homing of MSCs in different kidney portions were correlated to the areas of MR signal intensity decrease with nonparametric statistical tests. RESULTS: On in vivo images, signal intensity measurements of pathologic kidneys following MSC injection did not show any signal intensity decrease (P = .7), whereas a 34% +/- 14 (mean +/- standard deviation) signal intensity decrease was observed in the liver (P < .01), where a substantial number of labeled cells were trapped. On ex vivo images, pathologic kidneys showed focal cortical (glomerular) areas of signal intensity loss, which was absent in controls. The areas of low signal intensity correlated well with alpha-actin and Prussian blue stain- and DiI-positive areas (P < .01), which indicates that MSCs specifically home to injured tissue. No MSCs were detected in the kidneys of control animals. CONCLUSION: Intravenously injected MSCs specifically home to focal areas of glomerular damage and can be detected at ex vivo MR imaging.

Animals↗
PubMed2006

Magnetic resonance microscopy of mouse brain development.

Magnetic resonance imaging (MRI) is increasingly becoming an important tool to study anatomy of rodent brains. Compared with histology, it has clear advantages because the entire 3D object can be captured as an image nondestructively. However, low imaging resolution and a small number of available contrast mechanisms are two critical disadvantages. In this article, the future potential of magnetic resonance (MR) microimaging is discussed, with special emphasis on diffusion tensor microimaging as an effective contrast mechanism for the developing central nervous system.

Animals↗
PubMed2006

Intracellular endosomal magnetic labeling of cells.

Cellular imaging encompasses the noninvasive and repetitive imaging of targeted cells and cellular processes in living organisms. Magnetic resonance imaging (MRI), with its excellent spatial resolution, is ideally suited to provide unique information on the location and migration of cells after transplantation or transfusion. This approach requires magnetic prelabeling of the cells of choice. In this chapter, several methods and techniques will be described that can be applied for an efficient intracellular magnetic labeling of cells. In addition, a few basic protocols for the analysis and evaluation of cell labeling will be provided. The chapter will focus on the use of superparamagnetic iron oxides, because they are biocompatible and have strong effects on T2* relaxation. With the currently available magnetic labeling methods, it is anticipated that cellular MRI will find broad applications in biology and medicine.

Animals↗
PubMed2006

Noninvasive MRI of endothelial cell response to human breast cancer cells.

We have developed a noninvasive magnetic resonance imaging (MRI) assay to characterize human umbilical vein endothelial cell (HUVEC) motility, invasion, and network formation in response to the presence of cancer cells. HUVECs were labeled with a superparamagnetic iron oxide T(2) contrast agent and cocultured with MDA-MB-231 breast cancer cells in the presence of an extracellular matrix (ECM) gel. Invasion into the ECM gel by HUVECs in response to paracrine factors secreted by MDA-MB-231 cancer cells, as well as network formation by HUVECs, was easily tracked with MRI. The invasive behavior of HUVECs was not observed in the absence of cancer cells. This noninvasive assay used to characterize the response of endothelial cells (ECs) can be used to understand the role of proangiogenic or antiangiogenic stimuli, and to study the interactions between ECs and other disease-specific cells in pathologies with aberrant angiogenesis, such as retinopathy and arthritis.

Adenocarcinoma↗
PubMed2005

Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy.

The success of cellular therapies will depend in part on accurate delivery of cells to target organs. In dendritic cell therapy, in particular, delivery and subsequent migration of cells to regional lymph nodes is essential for effective stimulation of the immune system. We show here that in vivo magnetic resonance tracking of magnetically labeled cells is feasible in humans for detecting very low numbers of dendritic cells in conjunction with detailed anatomical information. Autologous dendritic cells were labeled with a clinical superparamagnetic iron oxide formulation or (111)In-oxine and were co-injected intranodally in melanoma patients under ultrasound guidance. In contrast to scintigraphic imaging, magnetic resonance imaging (MRI) allowed assessment of the accuracy of dendritic cell delivery and of inter- and intra-nodal cell migration patterns. MRI cell tracking using iron oxides appears clinically safe and well suited to monitor cellular therapy in humans.

Cell Movement↗
PubMed2005

Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction.

BACKGROUND: Recent results from animal studies suggest that stem cells may be able to home to sites of myocardial injury to assist in tissue regeneration. However, the histological interpretation of postmortem tissue, on which many of these studies are based, has recently been widely debated. METHODS AND RESULTS: With the use of the high sensitivity of a combined single-photon emission CT (SPECT)/CT scanner, the in vivo trafficking of allogeneic mesenchymal stem cells (MSCs) colabeled with a radiotracer and MR contrast agent to acute myocardial infarction was dynamically determined. Redistribution of the labeled MSCs after intravenous injection from initial localization in the lungs to nontarget organs such as the liver, kidney, and spleen was observed within 24 to 48 hours after injection. Focal and diffuse uptake of MSCs in the infarcted myocardium was already visible in SPECT/CT images in the first 24 hours after injection and persisted until 7 days after injection and was validated by tissue counts of radioactivity. In contrast, MRI was unable to demonstrate targeted cardiac localization of MSCs in part because of the lower sensitivity of MRI. CONCLUSIONS: Noninvasive radionuclide imaging is well suited to dynamically track the biodistribution and trafficking of mesenchymal stem cells to both target and nontarget organs.

Animals↗
PubMed2005

Paramagnetic viral nanoparticles as potential high-relaxivity magnetic resonance contrast agents.

In order to compensate for the inherent high threshold of detectability of MR contrast agents, there has been an active interest in the development of paramagnetic nanoparticles incorporating high payloads of Gd(3+) with high molecular relaxivities. Toward this end, the protein cage of Cowpea chlorotic mottle virus (CCMV), having 180 metal binding sites, is being explored. In vivo CCMV binds Ca(2+) at specific metal binding sites; however, Gd(3+) can also bind at these sites. Using fluorescence resonance energy transfer we have characterized the binding affinity of Gd(3+) to the metal binding sites by competition experiments with Tb(3+). The measured dissociation constant (K(d)) for Gd(3+) bound to the virus is 31 microM. The T(1) and T(2) relaxivities of solvent water protons in the presence of Gd(3+)-bound CCMV were 202 and 376 mM(-1) s(-1), respectively, at 61 MHz Larmor frequency. The unusually high relaxivity values of the Gd(3+)-CCMV are largely a result of the nanoparticle virus size and the large number of Gd(3+) ions bound to the virus. These preliminary results should encourage further investigations into the use of viral protein cages as a new platform for MR contrast agents.

Contrast Media↗
PubMed2005

Stem cell therapy for myelin diseases.

Advances in cell biology have encouraged the hope that stem cell-based therapy can be used to heal central nervous system (CNS) diseases. Here, we will review the potential application of neural cell transplantation for the treatment of multiple sclerosis (MS) and other demyelinating disorders, mention some problematic issues that still face this therapeutic approach, and describe novel noninvasive methods for in vivo tracking of transplanted cells.

Animals↗