Impaired revascularization of transplanted mouse pancreatic islets is chronic and glucose-independent1

Mattsson, Göran; Jansson, Leif; Nordin, Astrid; Carlsson, Per‐Ola

doi:10.1097/01.tp.0000052592.92966.fe

Cited by 41 publications

(43 citation statements)

References 10 publications

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“…We noted that most neovessels developed in the connective tissue surrounding engrafted islets in both mock-and sirolimus-treated diabetic recipient mice. Similar results have been reported in subcapsular islet grafts in diabetic recipient mice (9,12,13). In light of these observations, we determined total vascular density collectively from microvessels within islet grafts as well as in connective tissue by morphometric analysis following anti-CD31 immunohistochemistry (Fig.…”

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confidence: 59%

Sirolimus Is Associated With Reduced Islet Engraftment and Impaired β-Cell Function

et al. 2006

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Successful islet transplantation depends on the infusion of sufficiently large quantities of islets, but only a fraction of transplanted islets can survive and become engrafted, and yet the underlying mechanism remains unclear. In this study, we examined the effect of sirolimus, a key component of the immunosuppressive regimen in clinical islet transplantation, on islet engraftment and function. To distinguish the effect of sirolimus on immune rejection from its effect on islet engraftment, we used a syngeneic model. Diabetic mice were transplanted with 250 islets under the renal capsule, followed by treatment with sirolimus or vehicle for 14 days. Thirty days posttransplantation, islet grafts were retrieved for the determination of insulin content and vascular density. Compared with mocktreated controls, diabetic recipient mice receiving sirolimus exhibited impaired blood glucose profiles and reduced glucose-stimulated insulin secretion, correlating with reduced intragraft insulin content and decreased vascular density. Islets exposed to sirolimus for 24 h in culture displayed significantly diminished glucose-stimulated insulin release, coinciding with decreased pancreas duodenum homeobox-1 and GLUT2 expression in cultured islets. Furthermore, sirolimus-treated diabetic recipient mice, as opposed to mock-treated controls, were associated with dyslipidemia. These data suggest that sirolimus, administered in the early posttransplantation phase, is a confounding factor for reduced islet engraftment and impaired ␤-cell function in transplants. Diabetes 55:2429 -2436, 2006 T he Edmonton protocol for islet transplantation depends on the infusion of ϳ10,000 IE (islet equivalents)/kg body wt, requiring multiple cadaver pancreata per diabetic recipient (1-4). Despite the implantation of such a large quantity of islets, Ͻ30% of transplanted islets can survive the procedure and gain stable engraftment, and yet the mechanism underlying the loss of a vast majority of islet mass in the early posttransplantation phase remains elusive (4,5). Unlike whole-organ transplantation, by which grafts are implanted as vascularized tissue, islets are transplanted as single islets or islet clusters that are considered avascular following collagenase digestion and isolation. Although residual endothelial cells in isolated islets may contribute to islet revascularization (6,7), adequate intraislet blood flow requires the formation of a functional microvascular network that links engrafted islets to surrounding tissues. These data suggest that microvascular perfusion to newly transplanted islets does not resume immediately after transplantation and can take up to 2 weeks before the reestablishment of a functional microvasculature in islet grafts (8,9). This delay in islet revascularization can potentially deprive islets of oxygen and nutrients, resulting in islet cell death, particularly within the core of engrafted islets. There is mounting evidence that impaired islet revascularization is an independent factor that limits the success rate...

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confidence: 59%

Sirolimus Is Associated With Reduced Islet Engraftment and Impaired β-Cell Function

et al. 2006

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“…The presence of exocrine tissue in islet preparations has been previously shown to impair islet engraftment in nude mice [26]. Impure islets have been shown to induce tissue necrosis and subsequent fibrosis at the implant site, consequently delaying the revascularization process [27]. In the approach described here, there are still pancreatic exocrine cells within the induced islet-like clusters that might affect the function of the transplanted cells.…”

Section: Discussionmentioning

confidence: 96%

In vitro derivation of functional insulin-producing cells from human embryonic stem cells

et al. 2007

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The capacity for self-renewal and differentiation of human embryonic stem (ES) cells makes them a potential source for generation of pancreatic beta cells for treating type I diabetes mellitus. Here, we report a newly developed and effective method, carried out in a serum-free system, which induced human ES cells to differentiate into insulin-producing cells. Activin A was used in the initial stage to induce definitive endoderm differentiation from human ES cells, as detected by the expression of the definitive endoderm markers Sox17 and Brachyury. Further, all-trans retinoic acid (RA) was used to promote pancreatic differentiation, as indicated by the expression of the early pancreatic transcription factors pdx1 and hlxb9. After maturation in DMEM/F12 serum-free medium with bFGF and nicotinamide, the differentiated cells expressed islet specific markers such as C-peptide, insulin, glucagon and glut2. The percentage of C-peptide-positive cells exceeded 15%. The secretion of insulin and C-peptide by these cells corresponded to the variations in glucose levels. When transplanted into renal capsules of Streptozotocin (STZ)-treated nude mice, these differentiated human ES cells survived and maintained the expression of beta cell marker genes, including C-peptide, pdx1, glucokinase, nkx6.1, IAPP, pax6 and Tcf1. Thirty percent of the transplanted nude mice exhibited apparent restoration of stable euglycemia; and the corrected phenotype was sustained for more than six weeks. Our new method provides a promising in vitro differentiation model for studying the mechanisms of human pancreas development and illustrates the potential of using human ES cells for the treatment of type I diabetes mellitus.

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“…A normoglycaemic environment, in contrast to hyperglycaemia, provides better islet transplantation results [14,17,18] for uncertain reasons that may include enhanced beta cell growth of the grafts [19], and/or avoidance of hyperglycaemia-induced increased oxygen demand with resulting hypoxia, a pro-apoptotic state of beta cells, and less-efficient vascularisation [20,21], although it seems that in the long term, vascular density is unchanged by hyperglycaemia [22]. It cannot be ruled out that nephrectomy leads to release of compensatory growth factors in the contralateral kidney where the 75-islet graft is situated, thus stimulating islet growth [23]; even so, a remarkably low number of islets was required to maintain normoglycaemia.…”

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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Impaired revascularization of transplanted mouse pancreatic islets is chronic and glucose-independent1

Abstract: The vascular density is decreased in islets implanted to cure diabetic recipients. No improvement occurs in transplanted islets after 1 month posttransplantation.

Cited by 41 publications

References 10 publications

Sirolimus Is Associated With Reduced Islet Engraftment and Impaired β-Cell Function

Sirolimus Is Associated With Reduced Islet Engraftment and Impaired β-Cell Function

In vitro derivation of functional insulin-producing cells from human embryonic stem cells

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

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