The Transgenic Expression of Human CD39 on Murine Islets Inhibits Clotting of Human Blood

Dwyer, Karen M.; Mysore, Tharun; Crikis, Sandra; Robson, Simon C.; Nandurkar, Harshal; Cowan, Peter J.; d’Apice, Anthony J.F.

doi:10.1097/01.tp.0000229023.38873.c0

Cited by 65 publications

(57 citation statements)

References 21 publications

(15 reference statements)

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“…The human CD39 transgene (hCD39) is under the control of the mouse H-2Kb promoter, which promotes expression on all nucleated cells. The level of CD39 overexpression is increased on circulating cells (as demonstrated by flow cytometry) [4,14] and in solid organs (as demonstrated by immunohistochemistry) such as the heart [4], lung [4], liver [15], pancreatic islets [16], and kidneys, especially on the vasculature [17]. CD39Tg mice have the same phenotype as WT littermates and have similar body weights and breeding patterns [4].…”

Section: Methods Animalsmentioning

confidence: 95%

CD39 overexpression does not attenuate renal fibrosis in the unilateral ureteric obstructive model of chronic kidney disease

Roberts

Lü

Chia

et al. 2016

Purinergic Signalling

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Chronic kidney disease has multiple etiologies, but its single, hallmark lesion is renal fibrosis. CD39 is a key purinergic enzyme in the hydrolysis of ATP and increased CD39 activity on regulatory T cells (Treg) is protective in adriamycin-induced renal fibrosis. We examined the effect of overexpression of human CD39 on the development of renal fibrosis in the unilateral ureteric obstructive (UUO) model, a model widely used to study the molecular and cellular factors involved in renal fibrosis. Mice overexpressing human CD39 (CD39Tg) and their wild-type (WT) littermates were subjected to UUO; renal histology and messenger RNA (mRNA) levels of adenosine receptors and markers of renal fibrosis were examined up to 14 days after UUO. There were no differences between CD39Tg mice and WT mice in the development of renal fibrosis at days 3, 7, and 14 of UUO. Relative mRNA expression of the adenosine A 2A receptor and endothelin-1 were higher in CD39Tg than WT mice at day 7 post UUO, but there were no differences in markers of fibrosis. We conclude that human CD39 overexpression does not attenuate the development of renal fibrosis in the UUO model. The lack of protection by CD39 overexpression in the UUO model is multifactorial due to the different effects of adenosinergic receptors on the development of renal fibrosis.

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Section: Methods Animalsmentioning

confidence: 95%

CD39 overexpression does not attenuate renal fibrosis in the unilateral ureteric obstructive model of chronic kidney disease

Roberts

Lü

Chia

et al. 2016

Purinergic Signalling

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“…A number of proteins, such as APC (25) and CD39 (26), are also possible candidates for use. APC significantly reduced loss of functional islet mass after intraportal transplantation in diabetic mice, and islets from transgenic mice that express CD39 fail to induce coagulation in roughly one-half of the experiments when exposed to human blood.…”

Section: Discussionmentioning

confidence: 99%

Islet Surface Heparinization Prevents the Instant Blood-Mediated Inflammatory Reaction in Islet Transplantation

et al. 2007

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OBJECTIVE—In clinical islet transplantation, the instant blood-mediated inflammatory reaction (IBMIR) is a major factor contributing to the poor initial engraftment of the islets. This reaction is triggered by tissue factor and monocyte chemoattractant protein (MCP)-1, expressed by the transplanted pancreatic islets when the islets come in contact with blood in the portal vein. All currently identified systemic inhibitors of the IBMIR are associated with a significantly increased risk of bleeding or other side effects. To avoid systemic treatment, the aim of the present study was to render the islet graft blood biocompatible by applying a continuous heparin coating to the islet surface. RESEARCH DESIGN AND METHODS—A biotin/avidin technique was used to conjugate preformed heparin complexes to the surface of pancreatic islets. This endothelial-like coating was achieved by conjugating barely 40 IU heparin per full-size clinical islet transplant. RESULTS—Both in an in vitro loop model and in an allogeneic porcine model of clinical islet transplantation, this heparin coating provided protection against the IBMIR. Culturing heparinized islets for 24 h did not affect insulin release after glucose challenge, and heparin-coated islets cured diabetic mice in a manner similar to untreated islets. CONCLUSIONS—This novel pretreatment procedure prevents intraportal thrombosis and efficiently inhibits the IBMIR without increasing the bleeding risk and, unlike other pretreatment procedures (e.g., gene therapy), without inducing acute or chronic toxicity in the islets.

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“…The thromboregulatory molecule CD39 is an ectonucleotidase that degrades the platelet agonist ATP. Dwyer et al 15 isolated pancreatic islets from hCD39 transgenic mice, incubated them with human blood and analyzed their impact on IBMIR in comparison to WT islets. The results showed that expression of hCD39 on murine islets significantly delayed clotting in human blood.…”

Section: Genetic Engineering For Molecules That Control Coagulation Amentioning

confidence: 99%

Progress and prospects: genetic engineering in xenotransplantation

2008

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In this review, we summarize the work published over the last 2 years using genetic modifications of animals in the field of xenotransplantation. Genetic engineering of the donor has become a powerful tool in xenotransplantation, both for the inactivation of one particular porcine gene and for the addition of human genes with the goal of overcoming xenogeneic barriers. We summarize the work relative to the knockout of the a1,3-galactosyltransferase gene, followed by genetic engineering aimed at reducing the humoral and cellular immune response, complement activation and coagulation. Finally, we report on the genetic modification of pigs to reduce porcine endogenous retrovirus infection risk in the xenogeneic context.

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The Transgenic Expression of Human CD39 on Murine Islets Inhibits Clotting of Human Blood

Cited by 65 publications

References 21 publications

CD39 overexpression does not attenuate renal fibrosis in the unilateral ureteric obstructive model of chronic kidney disease

CD39 overexpression does not attenuate renal fibrosis in the unilateral ureteric obstructive model of chronic kidney disease

Islet Surface Heparinization Prevents the Instant Blood-Mediated Inflammatory Reaction in Islet Transplantation

Progress and prospects: genetic engineering in xenotransplantation

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