Human multipotent adult progenitor cells enhance islet function and revascularisation when co-transplanted as a composite pellet in a mouse model of diabetes

AIMS/HYPOTHESIS: Hypoxia in the initial days after islet transplantation leads to considerable loss of islet mass and contributes to disappointing outcomes in the clinical setting. The aim of the present study was to investigate whether co-transplantation of human non-endothelial bone marrow-derived multipotent adult progenitor cells (MAPCs), which are non-immunogenic and can secrete angiogenic growth factors during the initial days after implantation, could improve islet engraftment and survival.METHODS: Islets (150) were co-transplanted, with or without human MAPCs (2.5 × 105) as separate or composite pellets, under the kidney capsule of syngeneic alloxan-induced diabetic C57BL/6 mice. Blood glucose levels were frequently monitored and IPGTTs were carried out. Grafts and serum were harvested at 2 and 5 weeks after transplantation to assess outcome.RESULTS: Human MAPCs produced high amounts of angiogenic growth factors, including vascular endothelial growth factor, in vitro and in vivo, as demonstrated by the induction of neo-angiogenesis in the chorioallantoic membrane assay. Islet-human MAPC co-transplantation as a composite pellet significantly improved the outcome of islet transplantation as measured by the initial glycaemic control, diabetes reversal rate, glucose tolerance and serum C-peptide concentration compared with the outcome following transplantation of islets alone. Histologically, a higher blood vessel area and density in addition to a higher vessel/islet ratio were detected in recipients of islet-human MAPC composites.CONCLUSIONS/INTERPRETATION: The present data suggest that co-transplantation of mouse pancreatic islets with human MAPCs, which secrete high amounts of angiogenic growth factors, enhance islet graft revascularisation and subsequently improve islet graft function

Glucagon-Like Peptide-1 Protects Human Islets against Cytokine-Mediated β-Cell Dysfunction and Death: A Proteomic Study of the Pathways Involved

Glucagon-like peptide-1 (GLP-1) has been shown to protect pancreatic β-cells against cytokine-induced dysfunction and destruction. The mechanisms through which GLP-1 exerts its effects are complex and still poorly understood. The aim of this study was to analyze the protein expression profiles of human islets of Langerhans treated with cytokines (IL-1β and IFN-γ) in the presence or absence of GLP-1 by 2D difference gel electrophoresis and subsequent protein interaction network analysis to understand the molecular pathways involved in GLP-1-mediated β-cell protection. Co-incubation of cytokine-treated human islets with GLP-1 resulted in a marked protection of β-cells against cytokine-induced apoptosis and significantly attenuated cytokine-mediated inhibition of glucose-stimulated insulin secretion. The cytoprotective effects of GLP-1 coincided with substantial alterations in the protein expression profile of cytokine-treated human islets, illustrating a counteracting effect on proteins from different functional classes such as actin cytoskeleton, chaperones, metabolic proteins, and islet regenerating proteins. In summary, GLP-1 alters in an integrated manner protein networks in cytokine-exposed human islets while protecting them against cytokine-mediated cell death and dysfunction. These data illustrate the beneficial effects of GLP-1 on human islets under immune attack, leading to a better understanding of the underlying mechanisms involved, a prerequisite for improving therapies for diabetic patients.status: publishe

Understanding non-governmental organizations in world politics: the promise and pitfalls of the early ‘science of internationalism’

The years immediately preceding the First World War witnessed the development of a significant body of literature claiming to establish a ‘science of internationalism’. This article draws attention to the importance of this literature, especially in relation to understanding the roles of non-governmental organizations in world politics. It elaborates the ways in which this literature sheds light on issues that have become central to twenty-first century debates, including the characteristics, influence, and legitimacy of non-governmental organizations in international relations. Amongst the principal authors discussed in the article are Paul Otlet, Henri La Fontaine and Alfred Fried, whose role in the development of international theory has previously received insufficient attention. The article concludes with evaluation of potential lessons to be drawn from the experience of the early twentieth century ‘science of internationalism’

Prevention of primary non-function of islet xenografts in autoimmune diabetic NOD mice by anti-inflammatory agents

El libro Libertad e igualdad en el Caribe colombiano de la profesora Aline Helg, muestra la pretensión en Colombia de instaurar una nación blanca. Inicialmente con la aceptación de una nación mestiza en aras de blanqueamiento y cómo en este contexto, las comunidades negras se desdibujaron e invisibilizaron; términos utilizados por la autora para abordar el fenómeno en el Caribe colombiano entre 1770 a 1835. Buena parte de la tesis acerca de la invisibilización afro en la región, sugiere la autora, fue la ausencia de una identidad negra, que les permitiera tener una acción política colectiva, donde lo racial fuera central, como sí sucedió en Haití

Pancreatic Duct Cells in Human Islet Cell Preparations Are a Source of Angiogenic Cytokines Interleukin-8 and Vascular Endothelial Growth Factor

OBJECTIVE—Engraftment and function of human islet cell implants is considered to be dependent on their rapid and adequate revascularization. Studies with rodent islet grafts have shown that vascular endothelial growth factor (VEGF) expression by β-cells can promote this process. The present work examines whether human islet preparations produce VEGF as well as interleukin (IL)-8, another angiogenic protein, and assesses the role of contaminating duct cells in VEGF and IL-8–mediated angiogenesis

Characterization of the Autocrine/Paracrine Function of Vitamin D in Human Gingival Fibroblasts and Periodontal Ligament Cells

Background: We previously demonstrated that 25-hydroxyvitamin D-3, the precursor of 1 alpha,25-dihydroxyvitamin D-3, is abundant around periodontal soft tissues. Here we investigate whether 25-hydroxyvitamin D-3 is converted to 1 alpha,25-dihydroxyvitamin D-3 in periodontal soft tissue cells and explore the possibility of an autocrine/paracrine function of 1 alpha,25-dihydroxyvitamin D-3 in periodontal soft tissue cells. Methodology/Principal Findings: We established primary cultures of human gingival fibroblasts and human periodontal ligament cells from 5 individual donors. We demonstrated that 1 alpha-hydroxylase was expressed in human gingival fibroblasts and periodontal ligament cells, as was cubilin. After incubation with the 1 alpha-hydroxylase substrate 25-hydroxyvitamin D-3, human gingival fibroblasts and periodontal ligament cells generated detectable 1 alpha,25-dihydroxyvitamin D-3 that resulted in an up-regulation of CYP24A1 and RANKL mRNA. A specific knockdown of 1 alpha-hydroxylase in human gingival fibroblasts and periodontal ligament cells using siRNA resulted in a significant reduction in both 1 alpha, 25-dihydroxyvitamin D-3 production and mRNA expression of CYP24A1 and RANKL. The classical renal regulators of 1 alpha-hydroxylase (parathyroid hormone, calcium and 1 alpha,25-dihydroxyvitamin D-3) and Porphyromonas gingivalis lipopolysaccharide did not influence 1 alpha-hydroxylase expression significantly, however, interleukin-1 beta and sodium butyrate strongly induced 1 alpha-hydroxylase expression in human gingival fibroblasts and periodontal ligament cells. Conclusions/Significance: In this study, the expression, activity and functionality of 1 alpha-hydroxylase were detected in human gingival fibroblasts and periodontal ligament cells, raising the possibility that vitamin D acts in an autocrine/paracrine manner in these cells.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000305781700070&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701Multidisciplinary SciencesSCI(E)PubMed13ARTICLE6e39878

Dietary Vitamin D3 Supplements Reduce Demyelination in the Cuprizone Model

Vitamin D is emerging as a probably important environmental risk factor in multiple sclerosis, affecting both susceptibility and disease progression. It is not known to what extent this effect is due to a modulation of peripheral lymphocyte function, or to intrathecal effects of vitamin D. We investigated the effect of dietary vitamin D3 content on de/remyelination in the cuprizone model, which is a well established toxic model of demyelination, with no associated lymphocyte infiltration. The mice received diets either deficient of (<50 IU/kg), or supplemented with low (500 IU/kg), high (6200 IU/kg) or very high (12500 IU/kg) amounts of vit D3. Cuprizone (0.2%) was added to the diet for six weeks, starting two weeks after onset of the experimental diets. Mouse brain tissue was histopathologically evaluated for myelin and oligodendrocyte loss, microglia/macrophage activation, and lymphocyte infiltration after six weeks of cuprizone exposure, and two weeks after discontinuation of cuprizone exposure. High and very high doses of vitamin D3 significantly reduced the extent of white matter demyelination (p = 0.004) and attenuated microglia activation (p = 0.001). No differences in the density of oligodendrocytes were observed between the diet groups. Two weeks after discontinuation of cuprizone exposure, remyelination was only detectable in the white matter of mice receiving diets deficient of or with low vitamin D3 content. In conclusion, high dietary doses of vitamin D3 reduce the extent of demyelination, and attenuate microglia activation and macrophage infiltration in a toxic model of demyelination, independent of lymphocyte infiltration

The Involvement of IL-17A in the Murine Response to Sub-Lethal Inhalational Infection with Francisella tularensis

Background: Francisella tularensis is an intercellular bacterium often causing fatal disease when inhaled. Previous reports have underlined the role of cell-mediated immunity and IFNc in the host response to Francisella tularensis infection. Methodology/Principal Findings: Here we provide evidence for the involvement of IL-17A in host defense to inhalational tularemia, using a mouse model of intranasal infection with the Live Vaccine Strain (LVS). We demonstrate the kinetics of IL-17A production in lavage fluids of infected lungs and identify the IL-17A-producing lymphocytes as pulmonary cd and Th17 cells. The peak of IL-17A production appears early during sub-lethal infection, it precedes the peak of immune activation and the nadir of the disease, and then subsides subsequently. Exogenous airway administration of IL-17A or of IL-23 had a limited yet consistent effect of delaying the onset of death from a lethal dose of LVS, implying that IL-17A may be involved in restraining the infection. The protective role for IL-17A was directly demonstrated by in vivo neutralization of IL-17A. Administration of anti IL-17A antibodies concomitantly to a sub-lethal airway infection with 0.16LD50 resulted in a fatal disease. Conclusion: In summary, these data characterize the involvement and underline the protective key role of the IL-17A axis in the lungs from inhalational tularemia