Processing of superparamagnetic iron contrast agent ferucarbotran in transplanted pancreatic islets

Abstract

Labeling of pancreatic islets with superparamagnetic iron oxide (SPIO) nanoparticles enables their post-transplant monitoring by magnetic resonance imaging (MRI). Although the nanoparticles are incorporated into islet cells in culture, little is known about their fate in vivo. We studied the morphology of labeled islets after transplantation, aiming to identify the MRI contrast particles and their relationship to transplantation outcomes. Rat islets labeled with the ferucarbotran were transplanted into the liver or under the kidney capsule of syngeneic and allogeneic rats. After in vivo MRI, morphology was studied by light, fluorescence and transmission electron microscopy. Morphology of syngeneic islets transplanted beneath the kidney capsule vs into the liver was similar. Iron particles were almost completely eliminated from the endocrine cells and remained located in host-derived macrophages surrounding the vital islets for the entire study period. In the allogeneic model, islets lost their function and were completely rejected within nine days following transplantation in both transplant models. However, intercellular transport of the SPIO particles and subsequent MRI findings was different in the liver and kidney. In the liver, the decreasing number of islet-related MRI spots corresponded with clearance of iron particles in rejected islets; in contrast, with renal transplants extensive iron deposits with a high effect on MRI signal persisted in phagocytic cells beneath the capsule. We conclude that MRI detection of the iron contrast agent correlates with islet survival and function in islet transplantation into the liver, while it does not correlate in the case of transplantation beneath the renal capsule.

Quantification of Islet Loss and Graft Functionality During Immune Rejection by 3-Tesla MRI in a Rat Model

“…Herein, in vivo histologic analysis showed iron labeling mainly around functional islets. This observation is in accordance with Zacharovova et al who described translocation of the ferucarbotran particles from the endocrine cells to the host-derived macrophages surrounding the vital islets in a model of intraportal and kidney subcapsular transplantation in rat (27). Although iron labeling was no longer associated with endocrine cells, iron could be detected near the islet as long as the islet was still functioning.…”

“…In our study, when rejection occurred, iron was found in recently rejected islets, explaining why 50% to 60% of the signal temporarily persisted. In a similar model, Zacharovova et al detected iron in macrophages near recently rejected islets on day 9 but only weakly after day 14 (27), suggesting rapid clearance. However, with models of slower rejection, some authors have reported persistence of iron labeling around rejected islets potentially giving false-positive results in further clinical application.…”

In vivo visualization of single native pancreatic islets in the mouse

“…In recent years, several studies were conducted to perform in vivo imaging of transplanted islets, which were labeled before transplantation with, for example, iron oxide-, manganite-or gadolinium-based nanoparticles CAs (8,(10)(11)(12)(13)(14)(15)(16)(17). However, only few attempts were made to noninvasively visualize and monitor endogenous native islets in the pancreas in vivo by means of MRI.…”

“…In both cases, a high concentration of glucose catalyzed the targeted labeling process, which for Mn 2+ resulted in the influx of the contrast agent into the β-cells, and for the gadolinium-based sensor in a release of Zn 2+ ions by glucose-induced insulin secretion. MRI is also capable of visualizing single pancreatic islet grafts after ex vivo labeling with ironoxide or manganite-based nanoparticles (NPs) and subsequent implantation into the liver or a subcutaneous chamber (8,(10)(11)(12)(13)(14)(15)(16)(17). Individual native islets have been recently observed in vivo after systemic administration of Mn 2+ in the externalized and immobilized pancreas (18).…”

Imaging of transplanted islets by positron emission tomography, magnetic resonance imaging, and ultrasonography

“…Many studies have shown a positive correlation between islet engraftment and function and islet image, 39 , 70 but there are some obstacles to promoting this methodology at the clinical level. Recently Zacharovova and colleagues confirmed that SPIOs in the transplanted islets were taken into phagocytic cells including macrophages, and that the hypointensive spots on T2WI MRI might not reflect engrafted islets alone 71 . This means that the number of obtained signals might not reflect the number of engrafted islets, which could lead physicians to misinterpret the engraftment of islets (i.e., by leading to false-positive results).…”