Exocrine contamination impairs implantation of pancreatic islets transplanted beneath the kidney capsule

Gray, Derek W. R.; Sutton, Robert; McShane, Paul; Peters, Michael J.; Morris, Peter J.

doi:10.1016/0022-4804(88)90193-x

Cited by 96 publications

(54 citation statements)

References 21 publications

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“…Second, even for the model involving the transplantation of human islet into nude mice, islet purity and insulin content are both critical for proper graft function [28]. 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].…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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“…Despite having a 10-fold-increased implant mass, animals with 1,500 to 2,500 IE grafts had only ϳ50% more total insulin content as compared with 150 -300 IE grafts. This observation is likely related to the relatively high packed-cell volume required for higher islet equivalent grafts, which must be transplanted at several subcapsular sites and places the islets in close proximity to contaminating exocrine tissue, which likely causes enzymatic islet lysis and necrosis and thus an apoptosis-independent loss of functional ␤-cell mass in these grafts (30,31). While the effect of EP1013 in vitro pretreatment in the absence of continued posttransplant dosing was not explored in this study, the fact that human islet grafts required up to 3 weeks to reverse diabetes supports the necessity for posttransplant caspase inhibitor therapy, since a marginal implant mass will not function maximally until it has fully engrafted (32).…”

Section: Discussionmentioning

confidence: 99%

The Caspase Selective Inhibitor EP1013 Augments Human Islet Graft Function and Longevity in Marginal Mass Islet Transplantation in Mice

Emamaullee

Davis²,

Pawlick³

et al. 2008

Diabetes

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OBJECTIVE—Clinical islet transplantation can provide insulin independence in patients with type 1 diabetes, but chronic graft failure has been observed. This has been attributed in part to loss of ≥60% of the transplanted islets in the peritransplant period, resulting in a marginal implant mass. Strategies designed to maximize survival of the initial islet mass are likely to have major impact in enhancing long-term clinical outcomes. EP1013 (N-benzyloxycabonyl-Val Asp-fluoromethyl ketone [zVD-FMK]), is a broad-spectrum caspase selective inhibitor with no observed toxicity in rodents. RESEARCH DESIGN AND METHODS—The therapeutic benefit of EP1013 was examined in a syngeneic rodent islet transplant model using deceased donor human islets to determine whether the amount of tissue required to restore euglycemia in diabetic animals could be reduced. RESULTS—EP1013 (combined pretransplant islet culture for 2 h and in vivo treatment for days 0–5 posttransplant) significantly improved marginal islet mass function following syngeneic islet transplantation in mice, even at lower doses, compared with previous studies using the pan-caspase inhibitor N-benzyloxycabonyl-Val Ala-Asp-fluoromethyl ketone (zVAD-FMK). EP1013 supplementation in vitro improved human islet yields following prolonged culture and reversed diabetes following implantation of a marginal human islet mass (80–90% reduction) into mice. CONCLUSIONS—Our data suggest that EP1013 therapy will markedly reduce the islet mass required in clinical islet transplantation, improving insulin independence rates following single-donor infusion.

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“…Not only are islets mantled, therefore completely surrounded by exocrine cells, but the numbers of exocrine cells that surround the islets are so large that the size of each aggregate may raise problems in view of the intravascular infusion in clinical transplantation. Diffusion of nutrients in larger islet aggregates both in culture and after transplantation is far from ideal, affecting cell survival and exocrine contamination of the islet preparation, and contributes to impairment of islet engraftment [34,35]. Possible reasons for an inefficient separation of the islets from the neighbouring tissues are consistent with anatomical and physiological aspects.…”

Section: Discussionmentioning

confidence: 99%

Suitability of human juvenile pancreatic islets for clinical use

et al. 2006

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Aims/hypothesis The limited availability of deceased donor pancreases suitable for pancreas and islet transplantation calls for a broader utilisation of donor tissue for transplantation purposes. Young donors, representing, fortunately, a minor but significant pool of individuals, have been largely under-employed, mainly because of anatomical and functional incompatibilities with potential recipients. For islet transplantation, the isolation of pancreatic islets from young donors rarely occurs, because of technical problems. As a result of the peculiar characteristics of young donor pancreases, the standard isolation procedure does not allow efficient separation of the islets from the surrounding exocrine tissue, and favours the generation of mantled islets. Nonetheless, young donor islets offer high qualitative and clinically appealing characteristics. Subjects and methods We standardised a modified methodology to obtain purified and mantle-free human islets from young donors. This method principally involves efficient delivery of isolation enzyme with reduced mechanical disruption of the pancreas combined with additional filtration steps. Results We were able to obtain purified and mantle-free human islets from donors as young as 6 months of age with good morphological and functional properties. The good qualitative characteristics of the islets, evidenced in vitro, were proven in vivo, as they were qualitatively superior to islets of older donors in transplantation studies. Conclusions/interpretation This study justifies the utilisation of islets derived from young donors for islet transplantation.

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Exocrine contamination impairs implantation of pancreatic islets transplanted beneath the kidney capsule

Cited by 96 publications

References 21 publications

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

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

The Caspase Selective Inhibitor EP1013 Augments Human Islet Graft Function and Longevity in Marginal Mass Islet Transplantation in Mice

Suitability of human juvenile pancreatic islets for clinical use

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