Intraislet Endothelial Cells Contribute to Revascularization of Transplanted Pancreatic Islets

Abstract

Pancreatic islet transplantation is an emerging therapy for type 1 diabetes. To survive and function, transplanted islets must revascularize because islet isolation severs arterial and venous connections; the current paradigm is that islet revascularization originates from the transplant recipient. Because isolated islets retain intraislet endothelial cells, we determined whether these endothelial cells contribute to the revascularization using a murine model with tagged endothelial cells (lacZ knock-in to Flk-1/VEGFR2 gene) and using transplanted human islets. At 3-5 weeks after transplantation beneath the renal capsule, we found that islets were revascularized and that the transplant recipient vasculature indeed contributed to the revascularization process. Using the lacZ-tagged endothelial cell model, we found that intraislet endothelial cells not only survived after transplantation but became a functional part of revascularized islet graft. A similar contribution of intraislet endothelial cells was also seen with human islets transplanted into an immunodeficient mouse model. In the murine model, individual blood vessels within the islet graft consisted of donor or recipient endothelial cells or were a chimera of donor and recipient endothelial cells, indicating that both sources of endothelial cells contribute to the new vasculature. These observations suggest that interventions to activate, amplify, or sustain intraislet endothelial cells before and after transplantation may facilitate islet revascularization, enhance islet survival, and improve islet transplantation. Diabetes 53:1318 -1325, 2004 P ancreatic islet transplantation holds great promise for the treatment of type 1 diabetes since recent advances in islet isolation and immunosuppression have led to greatly improved results (1-3). However, several major challenges currently prevent islet transplantation from being widely adapted as a treatment for type 1 diabetes. For example, less-toxic immunologic interventions are needed to prevent allograft rejection and the recurrence of the autoimmune process that originally caused type 1 diabetes. Another major challenge is that most patients must receive islets isolated from at least two pancreata to become insulin independent and often insulin independence is not permanent (4). Why islets from at least two pancreata are required to reverse diabetes is perplexing as the majority of the pancreas can be surgically removed without a normal individual becoming diabetic. One possible explanation for the requirement of islets from at least two pancreata is that many islets die in the first days after transplantation, before adequate vascular supply is reestablished. Davalli and colleagues (5-7) found that islet cell survival, islet insulin content, and ␤-cell mass declined 1-3 days after transplantation. This is the period when the islet graft is avascular, since islet isolation severs arterial and venous connections; until revascularized, transplanted islets are dependent on diffusion of nutrients and oxygen fr...

Exendin-4 treatment improves metabolic control after rat islet transplantation to athymic mice with streptozotocin-induced diabetes

“…However, rat islets are larger than mice islets [19] and the viability may have been better because of our shorter culture time. Longer culture has been shown to increase islet hypoxia and central necrosis of islets [20], and may also affect the viability of the intra-islet endothelial cells, which are important for the revascularisation of grafts [21]. In spite of some differences in results, both studies support the idea that exendin-4 has beneficial effects on islet transplant outcome.…”

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

“…It could be argued that the remaining microvessels in freshly isolated islets serve as channels for the migration of new vessels, which may induce the process of revascularisation. Remaining endothelial cells may also attract and become incorporated within the newly formed microvessels [16,17]. Furthermore, it should be noted that macrophages residing within the pancreatic islets are known to disappear during culture [9].…”

“…The newly formed blood vessels were earlier considered to originate from recipient blood ves-sels [15]. 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].…”

Islet transplantation outcomes in mice are better with fresh islets and exendin-4 treatment

“…Another possible explanation of the success of transplanting freshly isolated islets may the intactness of their capillary network. The potential importance of donor endothelium in the revascularisation process has recently been shown [26]. Indeed, it has been noted that grafts from fresh islets have higher oxygen contents than those from cultured islets, even 1 month after transplantation [27].…”