In vivo visualization of transplanted pancreatic islets by MRI: comparison between in vivo , histological and electron microscopy findings
ABSTRACT The aim of the work was to compare in vivo MRI visualization of pancreatic islets labeled with clinical-grade superparamagnetic iron oxide (SPIOs) contrast agents with ex vivo examination of liver tissue in an experimental model of marginal mass transplantation in rats. Seven hundred IEq (Islet Equivalent) from Wistar rats, labeled by incubation with Endorem or Resovist, were transplanted into Sprague-Dawley rats through the portal vein. Liver MR images of recipient rats were acquired at different time points (3-42 days) after transplantation. Animals were sacrificed during this period and their livers were excised and prepared for histology and electron microscopy. Hypointense spots originating from iron particles were observed in MR images. The number of separate spots was counted. Three days after transplantation one spot for every three or four transplanted islets was observed. Seven days after transplantation, histological sections showed the presence of iron within pancreatic islets. The time course of MR images showed a decrease in the number of spots, at 42 days, amounting to 65 and 22% of the initial value, for Resovist and Endorem respectively, while no immunopositive endocrine cells were detected in histological slices. The present work shows that pancreatic islets can be labeled using clinically approved SPIO contrast agents and visualized using in vivo MRI with high sensitivity, consistently with findings in the literature. Differently from reports in the literature, our findings indicate that iron particles could last in the liver for long periods, independently of the presence of intact pancreatic islets.
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ABSTRACT: The increasing global incidence of diabetes and advancements in clinical pancreatic islet transplantation for the treatment of Type I diabetes have renewed the interest in understanding the variations of beta cell mass and function relative not only to transplant outcome but also to the onset and progression of diabetes. A deeper comprehension of the molecular and cellular processes involved in pancreatic islet inflammation and cytotoxicity is necessary to further improve efficacy of islet transplantation and to develop new therapies aimed at preserving beta cell function in pathological conditions. Available diagnostic methods based on metabolic response are unsuitable as they lack correlation to islet mass, viability and function. Great emphasis has been placed on developing noninvasive imaging technologies which enable the tracking of both endogenous and transplanted islet mass and potentially function overtime, the characterization of changes in islet vasculature and the degree of T-cell infiltration during insulitis. Among the more relevant modalities are magnetic resonance, positron emitted tomography, single photon emission computed tomography, bioluminescence and fluorescence optical imaging. This review focuses on the most recent advancements in magnetic resonance imaging (MRI) of pancreatic islets. In-vitro approaches aimed at characterizing the potency of isolated islets as well as in-vivo advancements in the assessment of transplanted beta cell mass are presented together with the significant progress made in the in-vivo imaging of the endocrine pancreas and islet vasculature and inflammation. Different experimental approaches are compared via their advantages and limitations with respect to their clinical implementation.Current pharmaceutical design 05/2010; 16(14):1582-94. DOI:10.2174/138161210791164171 · 3.29 Impact Factor
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ABSTRACT: Islet transplantation is a promising treatment option for patients with type 1 diabetes (T1D); however, the fate of the graft over time remains difficult to follow, due to the lack of available tools capable of monitoring graft rejection and inflammation prior to islet graft loss. Due to the challenges imposed by the location of the pancreas and the sparsely dispersed beta-cell population within the pancreas, currently, the clinical verification of beta-cell abnormalities can only be obtained indirectly via metabolic studies, which typically is not possible until after a significant deterioration in islet function has already occurred. The development of non-invasive imaging methods for the assessment of the pancreatic beta-cells, however, offers the potential for the early detection of beta-cell dysfunction prior to the clinical onset of T1D and type 2 diabetes (T2D). Ideal islet imaging agents would have an acceptable residence time in the human body, be capable of providing high-resolution images with minimal uptake in surrounding tissues (e.g., the liver), would not be toxic to islets, and would not require pre-treatment of islets prior to transplantation. A variety of currently available imaging techniques, including magnetic resonance imaging (MRI), bioluminescence imaging (BLI), and nuclear imaging have been tested for the study of beta-cell diseases. In this article, we summarize the recent advances made in nuclear imaging techniques for non-invasive imaging of pancreatic beta-cells. The use of radioactive probes for islet imaging is also discussed.Advanced drug delivery reviews 08/2010; 62(11):1125-38. DOI:10.1016/j.addr.2010.09.006 · 12.71 Impact Factor
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ABSTRACT: Ex vivo labeling of islets with superparamagnetic iron oxide (SPIO) nanoparticles allows posttransplant MRI imaging of the graft. In the present study, we compare two clinical grade SPIOs (ferucarbotran and ferumoxide) in terms of toxicity, islet cellular uptake, and MRI imaging. Human islets (80-90% purity) were incubated for 24 h with various concentrations of SPIOs (14-280 μg/ml of iron). Static incubations were performed, comparing insulin response to basal (2.8 mM) or high glucose stimulation (16.7 mM), with or without cAMP stimulation. Insulin and Perl's (assessment of iron content) staining were performed. Electronic microscopy analysis was performed. Labeled islets were used for in vitro or in vivo imaging in MRI 1.5T. Liver section after organ removal was performed in the same plane as MRI imaging to get a correlation between histology and radiology. Postlabeling islet viability (80 ± 10%) and function (in vitro static incubation and in vivo engraftment of human islets in nude mice) were similar in both groups. Iron uptake assessed by electron microscopy showed iron inclusions within the islets with ferucarbotran, but not with ferumoxide. MRI imaging (1.5T) of phantoms and of human islets transplanted in rats, demonstrated a strong signal with ferucarbotran, but only a weak signal with ferumoxide. Signal persisted for >8 weeks in the absence of rejection. An excellent correlation was observed between radiologic images and histology. The hepatic clearance of intraportally injected ferucarbotran was faster than that of ferumoxide, generating less background. A rapid signal decrease was observed in rejecting xenogeneic islets. According to the present data, ferucarbotran is the most appropriate of available clinical grade SPIOs for human islet imaging.Cell Transplantation 12/2010; 19(12):1573-85. DOI:10.3727/096368910X515863 · 3.57 Impact Factor