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1.
Int Urol Nephrol ; 50(6): 1151-1161, 2018 Jun.
Article in English | MEDLINE | ID: mdl-29728994

ABSTRACT

BACKGROUND: Long-term exposure of conventional peritoneal dialysis (PD) fluid is associated with structural membrane alterations and technique failure. Previously, it has been shown that infiltrating IL-17-secreting CD4+T cells and pro-fibrotic M2 macrophages play a critical role in the PD-induced pathogenesis. Although more biocompatible PD solutions are recognized to better preserve the peritoneal membrane integrity, the impact of these fluids on the composition of the peritoneal cell infiltrate is unknown. MATERIALS AND METHODS: In a uremic PD mouse model, we compared the effects of daily instillation of standard lactate (LS) or bicarbonate/lactate-buffered solutions (BLS) and respective controls on peritoneal fibrosis, vascularisation, and inflammation. RESULTS: Daily exposure of LS fluid during a period of 8 weeks resulted in a peritoneal increase of αSMA and collagen accompanied with new vessel formation compared to the BLS group. Effluent from LS-treated mouse showed a higher percentage of CD4+ IL-17+ cell population while BLS exposure resulted in an increased macrophage population. Significantly enhanced inflammatory cytokines such as TGFß1, TNFα, INFγ, and MIP-1ß were detected in the effluent of BLS-exposed mice when compared to other groups. Further, immunohistochemistry of macrophage subset infiltrates in the BLS group confirmed a higher ratio of pro-inflammatory M1 macrophages over the pro-fibrotic M2 subset compared to LS. CONCLUSION: Development of the peritoneal fibrosis and angiogenesis was prevented in the BLS-exposed mice, which may underlie its improved biocompatibility. Peritoneal recruitment of M1 macrophages and lower number of CD4+ IL-17+ cells might explain the peritoneal integrity preservation observed in BLS-exposed mouse.


Subject(s)
Bicarbonates/analysis , Dialysis Solutions/chemistry , Lactic Acid/analysis , Peritoneal Dialysis , Peritoneum/metabolism , Peritoneum/pathology , Actins/metabolism , Animals , Bicarbonates/administration & dosage , Buffers , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/metabolism , Chemokine CCL4/metabolism , Collagen/metabolism , Disease Models, Animal , Female , Interferon-gamma/metabolism , Interleukin-17/analysis , Lactic Acid/administration & dosage , Macrophages , Macrophages, Peritoneal , Mice , Transforming Growth Factor beta/metabolism , Tumor Necrosis Factor-alpha/metabolism , Uremia/therapy
2.
Stem Cell Res ; 13(3 Pt A): 367-78, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25290189

ABSTRACT

Adipose tissue-derived stromal cells (ASC) form a rich source of autologous cells for use in regenerative medicine. In vitro induction of an endothelial phenotype may improve performance of ASCs in cardiovascular repair. Here, we report on an in vitro strategy using direct reprogramming of ASCs by means of ectopic expression of the endothelial-specific transcription factor SRY (sex determining region Y)-box18 (SOX18). SOX18 induces ASCs to express a set of genes involved in vascular patterning: MMP7, KDR, EFNB2, SEMA3G and CXCR4. Accordingly, SOX18 transduced ASCs reorganize under conditions of shear stress, display VEGF-induced chemotaxis and form tubular structures in 3D matrices in an MMP7-dependent manner. These in vitro findings provide insight into molecular and cellular processes downstream of SOX18 and show that reprogramming using SOX18 is sufficient to induce several endothelial-like features in ASCs.


Subject(s)
Adipose Tissue/cytology , Endothelial Cells/metabolism , SOXF Transcription Factors/metabolism , Stromal Cells/metabolism , Cell Differentiation , Cell Movement/drug effects , Cells, Cultured , Cellular Reprogramming , Chemotaxis/drug effects , Endothelial Cells/cytology , Genetic Vectors/genetics , Genetic Vectors/metabolism , Human Umbilical Vein Endothelial Cells , Humans , Matrix Metalloproteinase 7/metabolism , Microtubules/chemistry , Microtubules/metabolism , SOXF Transcription Factors/genetics , Shear Strength , Stromal Cells/cytology , Vascular Endothelial Growth Factor A/pharmacology
3.
J Exp Med ; 211(7): 1465-83, 2014 Jun 30.
Article in English | MEDLINE | ID: mdl-24935259

ABSTRACT

Myelin oligodendrocyte glycoprotein (MOG), a constituent of central nervous system myelin, is an important autoantigen in the neuroinflammatory disease multiple sclerosis (MS). However, its function remains unknown. Here, we show that, in healthy human myelin, MOG is decorated with fucosylated N-glycans that support recognition by the C-type lectin receptor (CLR) DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) on microglia and DCs. The interaction of MOG with DC-SIGN in the context of simultaneous TLR4 activation resulted in enhanced IL-10 secretion and decreased T cell proliferation in a DC-SIGN-, glycosylation-, and Raf1-dependent manner. Exposure of oligodendrocytes to proinflammatory factors resulted in the down-regulation of fucosyltransferase expression, reflected by altered glycosylation at the MS lesion site. Indeed, removal of fucose on myelin reduced DC-SIGN-dependent homeostatic control, and resulted in inflammasome activation, increased T cell proliferation, and differentiation toward a Th17-prone phenotype. These data demonstrate a new role for myelin glycosylation in the control of immune homeostasis in the healthy human brain through the MOG-DC-SIGN homeostatic regulatory axis, which is comprised by inflammatory insults that affect glycosylation. This phenomenon should be considered as a basis to restore immune tolerance in MS.


Subject(s)
Brain/immunology , Cell Adhesion Molecules/immunology , Immune Tolerance/physiology , Inflammasomes/immunology , Lectins, C-Type/immunology , Myelin-Oligodendrocyte Glycoprotein/immunology , Receptors, Cell Surface/immunology , Th17 Cells/immunology , Animals , Brain/cytology , CHO Cells , Cell Adhesion Molecules/genetics , Cell Proliferation , Cricetinae , Cricetulus , Female , Humans , Inflammasomes/genetics , Inflammation Mediators/immunology , Interleukin-10/genetics , Interleukin-10/immunology , Lectins, C-Type/genetics , Male , Myelin-Oligodendrocyte Glycoprotein/genetics , Proto-Oncogene Proteins c-raf/genetics , Proto-Oncogene Proteins c-raf/immunology , Receptors, Cell Surface/genetics , Th17 Cells/cytology , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/immunology
4.
Eur Surg Res ; 41(4): 346-52, 2008.
Article in English | MEDLINE | ID: mdl-18841021

ABSTRACT

BACKGROUND: Abdominal wall repair can be performed with synthetic or biological materials. Biological materials may reduce the risk of infections and fibrosis. The aim of this study was to evaluate two acellular human dermis products. MATERIALS AND METHODS: A rat model was used to compare the two materials. One was prepared using low concentrations of NaOH; the other material was SureDerm, which is commercially available. Full thickness defects were prepared in the abdominal wall and closed with the materials. Rats were sacrificed at 1 or 4 months after operation and the numbers of adhesions to the bowels were scored. Samples were taken for histological analysis and to measure the breaking strength. RESULTS: In both groups a good functional integration of the implants with the abdominal wall was observed. There was no adhesion formation with the bowels in the group with the NaOH prototype. In the SureDerm group, 4 out of 7 rats showed only small adhesions at 4 months after operation. Breaking strength of the healed tissue was significantly higher in the NaOH prototype group at 4 months after operation (p < 0.0026). CONCLUSIONS: The results indicate that both human acellular dermis products may be used in clinical trials for closure of abdominal wall defects.


Subject(s)
Abdominal Wall/surgery , Dermis/transplantation , Animals , Male , Prostheses and Implants , Rats , Rats, Wistar , Surgical Mesh , Tensile Strength , Tissue Adhesions/etiology
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