Fate of αGal +/+ pancreatic islet grafts after transplantation into αGal knockout mice

Chandra, Abhilash P.; Salvaris, Evelyn; Walters, Stacey N.; Murray‐Segal, Lisa; Gock, Hilton; Lehnert, Anne M.; Wong, J.Y.C.; Cowan, Peter J.; d’Apice, Anthony J.F.; O’Connell, Philip J.

doi:10.1111/j.1399-3089.2004.00138.x

Cited by 10 publications

(11 citation statements)

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“…One limitation of this approach in the experimental setting is that evaluation of composite EC-MSC islet grafts in small animal models are not easily performed because of several significant species-specific differences in important areas such as angiogenesis, tissue repair, and innate immunity (31). Also, severely immunodeficient mice (SCID, nu/nu, and Rag) trigger strong innate immune responses that mainly target the vasculature of a transplanted organ due to the phylogenetic disparity between the two species, i.e., human-to-mouse is a discordant xenotransplantation model triggering activation of neutrophils, natural killer cells, macrophages, the complement and coagulation systems, and naturally occurring xenoreactive antibodies (32)(33)(34)(35)(36)(37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Formation of Composite Endothelial Cell–Mesenchymal Stem Cell Islets

et al. 2008

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OBJECTIVE-Mesenchymal stem cells (MSCs) contribute to endothelial cell (EC) migration by producing proteases, thereby paving the way into the tissues for ECs. MSCs were added to our previously described composite EC islets as a potential means to improve their capacity for islet angiogenesis.RESEARCH DESIGN AND METHODS-Human islets were coated with primary human bone marrow-derived MSCs and dermal microvascular ECs. The capacity of ECs, with or without MSCs, to adhere to and grow into human islets was analyzed. The survival and functionality of these composite islets were evaluated in a dynamic perifusion assay, and their capacity for angiogenesis in vitro was assessed in a three-dimensional fibrin gel assay.RESULTS-ECs proliferated after culture in MSC-conditioned medium, and MSCs improved the EC coverage threefold compared with EC islets alone. Islet survival in vitro and the functionality of the composite islets after culture were equal to those of control islets. The EC-MSC islets showed a twofold increase in total sprout formation compared with EC islets, and vascular sprouts emanating from the EC-MSC-islet surface showed migration of ECs into the islets and also into the surrounding matrix, either alone or in concert with MSCs. T he islets of Langerhans are micro-organs, with afferent and efferent blood vessels connecting the capillary network of the islets to the circulation system (1). Intra-islet endothelial cells (ECs) are fenestrated, and the density of the capillary network in the islets is ϳ10 times higher than that of the surrounding exocrine tissue (2,3). During the process of islet isolation before transplantation, the ECs in the islets lose their external vascular support; this situation contributes to their dedifferentiation, apoptosis, and necrosis during subsequent in vitro culture (4). CONCLUSIONS-ECThe formation of new capillaries during revascularization is a complex process that involves digestion of the vascular wall by proteases and the migration, proliferation, and differentiation of ECs (5). When blood vessels are assembled, ECs produce platelet-derived growth factor, which attracts supportive cells, including mesenchymal stem cells (MSCs) that can differentiate into pericytes (6).We hypothesized that adding MSCs to our previously described composite EC islets (7) might improve the adherence of the ECs to the islets and subsequent vascularization because MSCs contribute to EC migration by producing proteases, thereby paving the way into the surrounding tissue for the immature EC sprouts (8). MSCs have also been shown to upregulate the expression of angiopoietin and vascular endothelial growth factor (VEGF) in ECs, contributing to an increase in angiogenesis and stabilization of the vasculature (9). Moreover, MSCs have been shown to possess important immune-modulating properties (10), and they do not trigger adaptive immune reactions, which could make them ideal in islet transplantation setting (11,12).The present study describes a gentle and reproducible technique for forming EC-MSC i...

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Section: Discussionmentioning

confidence: 99%

Formation of Composite Endothelial Cell–Mesenchymal Stem Cell Islets

et al. 2008

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“…from porcine cornea and islet cells [4,6]. In fact, transplantation of Gal +/+ porcine islet cells into a-galactosyltransferase geneknockout (GTKO) mice showed good survival, suggesting that the low Gal expression influenced graft survival [7]. The feasibility of the porcine Abstract: Background: To investigate aGal (Gala1-3Galb1-4GlcNAc-R) expression of the porcine cornea in vitro, in vivo and after xenotransplantation.…”

Section: Introductionmentioning

confidence: 99%

Galα(1‐3)Gal expression of the cornea in vitro, in vivo and in xenotransplantation

Lee

Kim

et al. 2007

Xenotransplantation

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“…In order to determine the importance of T-cell passive cell death in the induction of tolerance to pancreatic islets in an allograft model, hBcl-2Ϯ mice and hBcl-2 Ϫ/Ϫ mice were transplanted with 600 Balb/c pancreatic islets (9). MR1 monoclonal antibodies (mAb) (10) was administered as a single 250 g intraperineal (i.p.)…”

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confidence: 99%

Blockade of the Passive Cell Death Pathway Does Not Prevent Tolerance Induction to Islet Grafts

Lehnert¹,

Murray‐Segal²,

Cowan³

et al. 2007

Transplantation

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Fate of αGal +/+ pancreatic islet grafts after transplantation into αGal knockout mice

Abstract: The results suggest that the level of alphaGal expression plays an important role in graft survival. Therefore, its removal is important in the development of a pig islet donor for future clinical therapy.

Cited by 10 publications

References 40 publications

Formation of Composite Endothelial Cell–Mesenchymal Stem Cell Islets

Formation of Composite Endothelial Cell–Mesenchymal Stem Cell Islets

Galα(1‐3)Gal expression of the cornea in vitro, in vivo and in xenotransplantation

Blockade of the Passive Cell Death Pathway Does Not Prevent Tolerance Induction to Islet Grafts

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