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

Olsson, Richard F.; Carlsson, Per‐Ola

doi:10.1007/s00125-004-1650-x

Cited by 73 publications

(58 citation statements)

References 44 publications

(51 reference statements)

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“…The improved recovery of these interactions in the islet+MSC grafts may account for some beneficial effects of the MSC co-transplant in our model. Another striking observation from our analysis of endothelial cell distribution in the grafts was the low vascular density in the non-endocrine tissue surrounding the islets in the islet+MSC grafts, when compared with islet-alone grafts, in which the surrounding non-endocrine parenchyma contained large numbers of endothelial cells, as reported previously [39][40][41]. These observations are consistent with earlier reports that transplanted islets induce increased vascularisation of the surrounding tissue to compensate for their low vascular density [42].…”

Section: Discussionsupporting

confidence: 92%

Co-transplantation of mesenchymal stem cells maintains islet organisation and morphology in mice

et al. 2011

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Aims/hypothesis Recent studies have shown that mesenchymal stem cells (MSCs) secrete several factors that improve survival and function of transplanted islets. Implantation of islets beneath the kidney capsule results in morphological changes, due to interactions of the graft with the host, thus impairing islet function. We co-transplanted MSCs with islets to determine their effects on the remodelling process and studied graft function in a mouse model of minimal islet mass. Methods Islets were syngeneically transplanted, either alone or with kidney-derived MSCs, underneath the kidney capsule of streptozotocin-induced diabetic C57Bl/6 mice. Blood glucose levels were monitored and intraperitoneal glucose tolerance tests carried out. Hormone contents of grafts and pancreas were assessed by radioimmunoassay. Graft morphology and vascularisation were evaluated by immunohistochemistry. Results MSCs improved the capacity of islet grafts to reverse hyperglycaemia, with 92% of mice co-transplanted with MSCs reverting to normoglycaemia, compared with 42% of those transplanted with islets alone. Average blood glucose concentrations were lower throughout the 1 month monitoring period in MSC co-transplanted mice. MSCs did not alter graft hormone content. Islets co-transplanted with MSCs maintained a morphology that more closely resembled that of islets in the endogenous pancreas, both in terms of size, and of endocrine and endothelial cell distribution. Vascular engraftment was superior in MSC co-transplanted mice, as shown by increased endothelial cell numbers within the endocrine tissue. Conclusions/interpretation Co-transplantation of islets with MSCs had a profound impact on the remodelling process, maintaining islet organisation and improving islet revascularisation. MSCs also improved the capacity of islets to reverse hyperglycaemia.

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Section: Discussionsupporting

confidence: 92%

Co-transplantation of mesenchymal stem cells maintains islet organisation and morphology in mice

et al. 2011

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“…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.…”

Section: Discussionmentioning

confidence: 81%

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

et al. 2006

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Aims/hypothesis: Early islet graft survival is crucial in determining the outcome after clinical islet transplantation. Exendin-4 has anti-apoptotic and beta cell proliferative properties, which could improve islet graft survival and function. The aim of these studies was to evaluate the effect of exendin-4 on graft function after islet transplantation. Materials and methods: Rat islets were transplanted under the kidney capsule of diabetic athymic mice. First, we performed a dose-finding study and found that 30 islets just failed to cure diabetic mice. In the following two studies, we transplanted 30 islets and treated the mice that had received these islets with exendin-4 i.p. (100 ng/mouse) once daily for 1 week. Blood glucose levels and body weights were used as evaluation criteria. In the short-term study evaluation was done at day 8. This study was followed by a long-term study that was evaluated at 4 weeks. In this study, islets were precultured with exendin-4 (0.1 nmol/l) in addition to the treatment given to mouse-recipients of transplanted islets. The cured mice underwent an intraperitoneal glucose tolerance test (IPGTT). Results: In the shortterm study, 63% of exendin-4-treated mice achieved graft function compared with 21% of untreated mice (p=0.033). In the long-term study, 88% of treated mice had functioning grafts compared with 22% of controls (p=0.015). Cured mice showed a normal response in the IPGTT, comparable to that of healthy mice. Exendin-4-treated mice gained significantly more weight than their untreated counterparts. Conclusions/interpretation: Islet preculture and a short course of therapy with exendin-4 improves metabolic control after rat islet transplantation in athymic mice. The beneficial effect lasts beyond the treatment period.

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“…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].…”

Section: Discussionmentioning

confidence: 99%

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

King

Lock

et al. 2005

Diabetologia

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Aims/hypothesis: Although islet transplantation in diabetes holds great promise, two or three donor pancreases are usually required to achieve normoglycaemia in human or rodent recipients. We investigated whether there were differences between fresh and cultured islets in terms of transplantation outcome. We also investigated the effects of normoglycaemia during engraftment and the effects of exendin-4, a glucagon-like peptide-1 receptor agonist, on islet transplantation. Materials and methods: Seventy-five fresh islets were transplanted to the right kidney of diabetic mice and 425 fresh islets were transplanted to the left kidney. The mice were treated with exendin-4 or vehicle for 14 days, after which the large graft was removed by left nephrectomy. In a separate set of experiments, islets cultured in the presence or absence of exendin-4 for 72 h, or fresh islets, were transplanted to diabetic mice. In both sets of experiments, blood glucose levels were monitored. Results: Compared with cultured islets, fresh islets were more effective at reversing hyperglycaemia in mice. The treatment of the recipient mice with exendin-4 did not have beneficial effects on glucose homeostasis. However, when islets are cultured, exendin-4 treatment increases the rate of reversal of hyperglycaemia, but not to the degree of fresh islets. Conclusions/ interpretation: Fresh islets are more effective than cultured islets at reversing hyperglycaemia. Exendin-4 has beneficial effects on islet transplantation.

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

Cited by 73 publications

References 44 publications

Co-transplantation of mesenchymal stem cells maintains islet organisation and morphology in mice

Co-transplantation of mesenchymal stem cells maintains islet organisation and morphology in mice

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

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

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