Decreased Vascular Density in Mouse Pancreatic Islets After Transplantation

Abstract

An adequate revascularization is crucial for islet survival and function after transplantation. Previous studies have suggested that islet revascularization is concluded within 14 days after transplantation. We investigated if the vascular density of transplanted islets and endogenous pancreatic islets differs. Cultured islets were syngeneically transplanted into the kidney, liver, or spleen of C57BL/6 mice. One month later, the graft-bearing organ was removed, and histological specimens were prepared and stained for endothelium with the lectin Bandeiraea simplicifolia. Pancreata from nontransplanted control animals were prepared similarly. Uniform staining of endothelium within the grafts and endogenous islets was obtained. The vascular density was markedly decreased in transplanted islets at all implantation sites, but preferentially in islets implanted into the spleen. The vascular density in the connective tissue surrounding the transplanted islets was very high compared with that of graft intra-islet capillaries. A much lower vascular density was detected in connective tissue surrounding implanted microspheres of a size similar to the islets, which suggests that the islets per se induced blood vessel formation in their vicinity. We conclude that the vascular density in revascularized transplanted islets is markedly decreased compared with endogenous islets. This has potential implications for islet graft metabolism and function. Diabetes 51: [1362][1363][1364][1365][1366] 2002 T he recent application of a new treatment regimen, the so-called Edmonton protocol, has markedly improved the outcome of clinical islet transplantation (1,2). When applying this protocol, however, transplantation of a large number of islets (Ͼ9,000 islet equivalent [IEQ]/kg body wt) has been shown to be necessary to achieve insulin independence. Because of the limited availability of islet tissue, this severely restricts the number of patients who may be treated with islet transplantation. Methods to reduce the number of islets needed to cure a diabetic individual are therefore warranted.Endogenous pancreatic islets have a unique glomerularlike angioarchitecture with a high blood perfusion of 5-7 ml ⅐ min -1 ⅐ g -1 tissue (3,4). This secures an optimal delivery of oxygen and nutrients to islet cells and ensures an adequate dispersal of secreted hormones. When islets are isolated and cultured before transplantation, the islet endothelium dedifferentiates or degenerates (5). A rapid revascularization is therefore crucial for islet function after transplantation, and this has been shown to occur within 7-14 days (6,7). However, the extent of revascularization has not been thoroughly studied, and recent experiments on islets transplanted to the renal, splenic, or hepatic subcapsular space have suggested that this process is insufficient to achieve optimal oxygenation of the transplanted islets (8 -10).The aim of the present study was to compare the vascular density of endogenous pancreatic islets to that of mouse islets syngeneically ...

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

“…An adequate revascularization is crucial for islet survival and function after transplantation. Islet revascularization occurs within 7 to 14 days after transplantation [67], but the islet vascular density of the graft is clearly decreased as compared to endogenous islets [68]. Thus, the high expression of IP-10 in syngeneic NOD islets could contribute to poor graft vascularization and beta-cell survival.…”

Better vascular engraftment and function in pancreatic islets transplanted without prior culture

“…all moving blood cells within the illuminated tissue. A large number of the intragraft capillaries was stroma capillaries, see [20], which are likely to contribute substantially to total graft blood perfusion. In contrast, it could be expected that the blood flow in capillaries in the endocrine parts mainly contributes to the delivery of oxygen to the endocrine cells, due to limitations of oxygen diffusion distance [31].…”

“…However, recent studies suggest that endothelial cells originating from the donor may also contribute significantly, and be important for the revascularisation process [16,17]. In our previous studies, we have observed that grafts composed of cultured rodent or human islets are not sufficiently revascularised, which results in a low graft oxygen tension and tissue acidosis [18][19][20][21][22]. The present study tested the hypothesis that syngeneic islet grafts composed of freshly isolated rodent islets become more efficiently revascularised than islets transplanted after culture, and that this might result in an improved islet graft function.…”

Angiotensin II type 1 receptor inhibition markedly improves the blood perfusion, oxygen tension and first phase of glucose-stimulated insulin secretion in revascularised syngeneic mouse islet grafts

“…Sections (5 μm thick) of the islet grafts and pancreata were prepared and stained with the lectin Bandeiraea simplicifolia (Sigma) [8]. The slides were counterstained with haematoxylin.…”

“…Nevertheless, blood perfusion and partial pressure of oxygen are chronically decreased in transplanted islets irrespective of implantation organ [7]. A reasonable explanation for the insufficient blood supply was provided in experiments where vascular density was found to be decreased in transplanted islets [8].…”