Background There is a recent focus on embolization of the portal vein by transplanted islets as a major cause of early graft loss. The resultant ischemia causes necrosis and/or apoptosis of cells within the liver. Thus, non-invasive assessment of the liver receiving the islet transplant is important to evaluate the status islet grafts. Methods In this study, we utilized non-invasive magnetic resonance imaging (MRI) for assessment of the post-transplant ischemic liver. Syngeneic islets in streprozotocin-induced diabetic mice were utilized. MRI and morphological liver assessments were performed at 0, 2, and 28 days after transplantation. Histological assessment of insulin, hypoxia induced factor 1-α and apoptosis were undertaken at similar time-points. Results Ischemic/necrotic regions in the liver were detected with MRI at 2 but not at 28 days after transplantation and were confirmed histologically. Liver injury was quantified from high intensity areas on T2-weighted images. Insulin release showed a peak 2 days after transplantation. Conclusion Onset and reversal of liver ischemia due to intraportal islet transplantation are detectable using T2-weighted MRI. These changes coincide with periods of maximum insulin release likely due to partial islet destruction. We propose that MRI, as a noninvasive monitor of graft-related ischemia, may be useful in assessment of liver and islet engraftment after intraportal islet transplantation in a clinical setting.

Vascularization of transplanted islets must be maintained to provide long-term graft function. In vivo assessment of new vessel formation in islet grafts has been poorly documented. The purpose of this study was to investigate whether neovascularization was detectable in vivo in a Feridex-labeled murine syngeneic subcapsular islet mass using DCE MRI over 180 days. Subcapsular transplants could be visualized at post-transplant days three, seven, 14, and 28 using T2-weighted MRI and at post-transplant day 180 by immunohistochemistry. Injection of the contrast agent gadolinium (Gd)-DTPA for DCE at three, seven, and 14 days showed increased signal in the transplant area consistent with new vessel formation. Areas under contrast enhancement curves suggested peak angiogenesis at 14 days. At 180 days, there was no observable change in signal intensity after contrast injection suggesting established vascularization or islet mass reduction. Immunohistochemistry confirmed MRI and DCE findings. These data suggest that islet angiogenesis occurs early after transplantation and is likely established after one month of transplantation. This study provides an in vivo time-line of neovascularization in subcapsular islet grafts. We anticipate that contrast extravasation captured by MRI may provide useful monitoring of graft angiogenesis if reproduced in a clinically relevant intraportal model. Keywords islet transplantation; imaging; vascularization; in vivo; MRIPancreatic islet transplantation is a promising therapy for patients with type 1 diabetes (1,2). However, long-term insulin independence is frequently not sustainable presumably because of hypoxic, inflammatory, and immune damage to islets (3). In a healthy pancreas, islets are in a nutrient-rich environment with highly oxygenated blood. After transplantation, islets are subject to hypoxia from initial avascularity (4,5), and it is estimated that approximately 50-70% of islets are lost in the immediate post-transplantation period (50-70%), along with functional impairment of the remaining surviving islets (3,6,7). A total of two to four pancreatic donors are sometimes required for a sufficiently functional islet transplant (1). Despite the above challenges, there is an obvious paucity of in vivo methods to monitor islet fate and in particular, new vessel formation in islet grafts.Several studies have shown that in vivo MRI of transplanted rodents can be used to localize islets labeled with SPIO under high resolution (8)(9)(10) To chronicle islet graft neovascularization in vivo, we used contrast extravasation to characterize neovascularization. DCE MRI is an imaging modality that can be used to noninvasively measure key hemodynamic parameters such as blood flow, blood volume, interstitial volume and capillary permeability in real time. This method has been used clinically to assess tumor angiogenesis and the vascular effects of anticancer therapies (12-16).In a pilot short-term trial, we previously reported that DCE MRI can be used to evaluate neovascularization n...

To evaluate changes in neovascularization of transplanted islets in vivo, dynamic contrast (gadolinium) enhanced magnetic resonance imaging (MRI) was used. Both iron (Feridex)-labeled and unlabeled syngeneic murine subcapsular islet grafts were studied. Differences in dynamic contrast enhancement of islet grafts were quantified after gadolinium injection at post-transplant days 3 and 14. Normalized contrast concentrations at day 14 in transplanted islets were increased relative with that on day 3. Time to peak contrast enhancement was faster by 12 min at day 14 compared to day 3 islets (while kidney and muscle peak times remained the same). Areas under the curve for contrast concentration versus time plots were larger in 14-day relative to 3-day islet grafts. In conclusion, noninvasive assessment of neovascularization is achievable. In vivo dynamic contrast-enhanced MRI can be used to detect and quantify changes in vascularization following islet transplantation. This technique may be useful in developing pro-angiogenic strategies to improve the transplantation outcome in experimental and clinical settings.

Background It is important to determine the efficacy of intraportal islet transplantation in comparison with other transplant sites. In this study, we tried to determine the optimal number of islets to achieve normoglycemia following transplantation into the liver versus kidney using a mouse model. Methods Streptozotocin induced diabetic mice (Balb/C) were transplanted with syngeneic islets via the intraportal (IP) and renal subcapsular (SC) routes. The transplanted islet numbers were zero to 800 (n=3 to 5). We calculated the parameters indicated below, assessed the correlation between these parameters and islet numbers and compared the parameters in the IP versus SC groups. The parameters were: (1) Percentage of normoglycemia; (2) Postoperative days to normoglycemia; (3) Mean blood glucose level at various points from pre-transplantation to end of the study (postoperative day 28); (4) Mean serum insulin; and (5) Area under the curve (AUC) of blood glucose levels after injection of glucose. Results Two hundred islets yielded normoglycemia in renal subcapsular grafts, while 800 islets were the minimum required in intraportal transplantation. The transplant efficacy in subcapsular transplantation was 2 to 5 times that of intraportal transplantation. The days to normoglycemia were significantly different between intraportal and renal subcapsular islets (13.25 ± 4.38 days vs. 4.50 ± 0.81 days, p = 0.007). Conclusion Efficacy of islet transplantation in murine diabetic models is significantly higher under the kidney capsule. Clinical islet transplantation could benefit from trials of alternative transplantation sites.

No abstract

No abstract

Background: Islet transplantation is a useful therapeutic option for type 1 diabetes mellitus. Intraportal transplantation is the most effective method at present. However, transplanted islets are very unstable partly due to nonspecifi c infl ammation, hypoxia, and the metabolic condition of the recipient. Approximately 60% of transplanted islets are lost in the fi rst couple of days. In clinical practice, multiple transplantations are often required for one recipient to maintain normoglycemia. Therefore, it is important to determine the effi cacy of intraportal transplantation in comparison with other transplant sites. In this study, we tried to determine the optimal number of islets to achieve normoglycemia following transplantation into the liver versus kidney using a mouse model. Methods: Balb/C female mice were used as donors and recipients. Streptozotocin induced diabetic mice were transplanted with syngeneic islets via the intraportal (IP) and renal subcapsule (SC) routes. The transplanted islet numbers were: zero (n=4, as a control), 100 (n=5 for IP and n=4 for SC), 200 (n=5 for IP and SC), 300 (n=4 for IP and SC), 500 (n=6 for IP and n=4 for SC) and 800 (n=5 for IP only). Blood glucose levels of the transplanted mice were measured through postoperative day (POD) 28. We calculated the parameters indicated below, assessed the correlation between these parameters and islet numbers and compared the parameters in the IP versus SC groups. The parameters were, (1) Percentage achieving normoglycemia in each group; (2) Postoperative days to normoglycemia; (3) Mean blood glucose level at various points from pre-transplantation to end of the study (POD28). We also tested the correlation between mean blood glucose levels and islet number. Results: Two hundred islets could achieve normoglycemia in renal subcapsular grafts, while 800 islets were the minimum required in intraportal transplantation. Data from both groups were approximated using the quadratic function, and showed that intraportal transplants required 5 times the number of islets as renal subcapsular transplants for an equivalent percentage of normoglycemia. The days to normoglycemia did not signifi cantly differ by the number of transplanted islets, however, they were signifi cantly different between intraportal and renal subcapsular islets (13.25 ± 4.38 days vs. 3.33 ± 0.70 days, p = 0.007). There was a signifi cant negative correlation between islet number and mean blood glucose level in both intraportal and subcapsular transplantation. The transplantation effi cacy of the liver was one fourth that of the kidney in this assessment. Conclusion: Effi cay of islet transplantation in murine diabetic models is signifi cantly higher under the kidney capsule. This may refl ect an advantage of maintained juxtaposition versus dispersion of islet cells. Clinical islet transplantation could benefi t from trials of alternative transplantation sites. Background: During pregnancy the placenta expresses Syncytin, an immunosuppressive retroviral envelope protein, and ...

No abstract