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  • 1.
    Ajalloueian, F.
    et al.
    Isfahan Univ Technol, Dept Text Engn, Ctr Excellence Appl Nanotechnol, Esfahan, Iran..
    Fransson, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Tavanai, H.
    Isfahan Univ Technol, Dept Text Engn, Ctr Excellence Appl Nanotechnol, Esfahan, Iran..
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala Univ, Dept Immunol Genet & Pathol IGP, Uppsala, Sweden..
    Arpanaei, A.
    Natl Inst Genet Engn & Biotechnol, Dept Ind & Environm Biotechnol, Tehran, Iran..
    Comparing PLGA and PLGA/Chitosan Nanofibers Seeded by Msc: A Cell-scaffold Interaction Study2015In: Tissue Engineering. Part A, ISSN 1937-3341, E-ISSN 1937-335X, Vol. 21, p. S406-S407Article in journal (Other academic)
  • 2.
    Ajalloueian, Fatemeh
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fransson, Moa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Tavanai, Hossein
    Massuni, Mohammad
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    LeBlanc, Katarina
    Arpanaei, Ayyoob
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Investigation of Human Mesenchymal Stromal Cells Cultured on PLGA orPLGA/Chitosan Electrospun Nanofibers2015In: Journal of Bioprocessing & Biotechniques, ISSN 2155-9821, Vol. 5, no 6, article id 230Article in journal (Refereed)
    Abstract [en]

    We compared the viability, proliferation, and differentiation of human Mesenchymal Stromal Cells (MSC)after culture on poly(lactic-co-glycolic acid) (PLGA) and PLGA/chitosan (PLGA/CH) hybrid scaffolds. We appliedconventional and emulsion electrospinning techniques, respectively, for the fabrication of the PLGA and PLGA/CH scaffolds. Electrospinning under optimum conditions resulted in an average fiber diameter of 166 ± 33 nmfor the PLGA/CH and 680 ± 175 nm for the PLGA scaffold. The difference between the tensile strength of thePLGA and PLGA/CH nanofibers was not significant, but PLGA/CH showed a significantly lower tensile modulusand elongation at break. However, it should be noted that the extensibility of the PLGA/CH was higher than thatof the nanofibrous scaffolds of pure chitosan. As expected, a higher degree of hydrophilicity was seen with PLGA/CH, as compared to PLGA alone. The biocompatibility of the PLGA and PLGA/CH scaffolds was compared usingMTS assay as well as analysis by scanning electron microscopy and confocal microscopy. The results showed thatboth scaffold types supported the viability and proliferation of human MSC, with significantly higher rates on PLGA/CH nanofibers. Nonetheless, an analysis of gene expression of MSC grown on either PLGA or PLGA/CH showed asimilar differentiation pattern towards bone, nerve and adipose tissues.

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  • 3.
    Asif, Sana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sedigh, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Nordström, Johan
    Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Brandhorst, Heide
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jorns, Carl
    Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Magnusson, Peetra U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nowak, Greg
    Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Theisinger, Sonja
    Novaliq GmbH, Heidelberg, Germany.
    Hoeger, Simone
    Department of Nephrology, Endocrinology and Rheumatology, University Medical Center Mannheim, Mannheim, Germany.
    Wennberg, Lars
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Oxygen-charged HTK-F6H8 emulsion reduces ischemia: reperfusion injury in kidneys from brain-dead pigs2012In: Journal of Surgical Research, ISSN 0022-4804, E-ISSN 1095-8673, Vol. 178, no 2, p. 959-967Article in journal (Refereed)
    Abstract [en]

    Background:

    Prolonged cold ischemia is frequently associated with a greater risk of delayed graft function and enhanced graft failure. We hypothesized that media, combining a high oxygen-dissolving capacity with specific qualities of organ preservation solutions, would be more efficient in reducing immediate ischemia-reperfusion injury from organs stored long term compared with standard preservation media.

    Methods:

    Kidneys retrieved from brain-dead pigs were flushed using either cold histidine-tryptophan-ketoglutarate (HTK) or oxygen-precharged emulsion composed of 75% HTK and 25% perfluorohexyloctane. After 18 h of cold ischemia the kidneys were transplanted into allogeneic recipients and assessed for adenosine triphosphate content, morphology, and expression of genes related to hypoxia, environmental stress, inflammation, and apoptosis.

    Results:

    Compared with HTK-flushed kidneys, organs preserved using oxygen-precharged HTK-perfluorohexyloctane emulsion had increased elevated adenosine triphosphate content and a significantly lower gene expression of hypoxia inducible factor-1 alpha, vascular endothelial growth factor, interleukin-1 alpha, tumor necrosis factor-alpha, interferon-alpha, JNK-1, p38, cytochrome-c, Bax, caspase-8, and caspase-3 at all time points assessed. In contrast, the mRNA expression of Bcl-2 was significantly increased.

    Conclusions:

    The present study has demonstrated that in brain-dead pigs the perfusion of kidneys with oxygen-precharged HTK-perfluorohexyloctane emulsion results in significantly reduced inflammation, hypoxic injury, and apoptosis and cellular integrity and energy content are well maintained. Histologic examination revealed less tubular, vascular, and glomerular changes in the emulsion-perfused tissue compared with the HTK-perfused counterparts. The concept of perfusing organs with oxygen-precharged emulsion based on organ preservation media represents an efficient alternative for improved organ preservation.

  • 4.
    Babiker, Adil A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Magnusson, Peetra U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Mapping pro- and antiangiogenic factors on the surface of prostasomes of normal and malignant cell origin2010In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 70, no 8, p. 834-847Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Angiogenesis is the formation of new blood vessels by capillary sprouting from pre-existing vessels. Tumor growth is angiogenesis-dependent and the formation of new blood vessels is associated with the increased expression of angiogenic factors. Prostasomes are secretory granules produced, stored and released by the glandular epithelial cells of the prostate. We investigated the expression of selected angiogenic and anti-angiogenic factors on the surface of prostasomes of different origins as well as the direct effect of prostasomes on angiogenesis. METHODS: VEGF, endothelin-1, endostatin, and thrombospondin-1 were determined on prostasomes from seminal fluid and human prostate cancer cell lines (DU145,PC-3,LNCaP) using different immunochemical techniques. Human dermal microvascular endothelial cells were incubated with seminal and DU145 cell-prostasomes and with radioactive thymidine. The effect of prostasomes on angiogenesis was judged by measuring the uptake of labeled thymidine. The presence of any deleterious effects of prostasomes on the endothelial cells was investigated using thymidine assay and confocal laser microscopy. RESULTS: VEGF and endothelin-1 were determined on malignant cell-prostasomes (no difference between cell lines) but not determined on seminal prostasomes. The same applies for the expression of endostatin but with much higher expression on malignant cell-prostasomes with obvious differences between them. Seminal and DU145 cell-prostasomes were found to have anti-angiogenic effect which was more expressed by DU145 cell-prostasomes. No deleterious effect of prostasomes on endothelial function was detected using either thymidine assay or microscopy. CONCLUSIONS: Prostasomes contain pro- and anti-angiogenic factors that function to counteract each other unless the impact from one side exceeds the other to bring about dysequilibrium.

  • 5. Berg, Aase
    et al.
    Otterdal, Karl
    Patel, Sam
    Gonca, Miguel
    David, Catarina
    Dalen, Ingvild
    Nymo, Stig
    Nilsson, Margareta
    Nordling, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ueland, Thor
    Prato, Mauro
    Giribaldi, Giuliana
    Mollnes, Tom Eirik
    Aukrust, Pål
    Langeland, Nina
    Nilsson, Per
    Complement Activation Correlates With Disease Severity and Contributes to Cytokine Responses in Plasmodium falciparum Malaria2015In: The Internet Journal of Infectious Diseases, ISSN 1528-8366, Vol. 212, no 11, p. 1835-1840Article in journal (Refereed)
    Abstract [en]

    The impact of complement activation and its possible relation to cytokine responses during malaria pathology was investigated in plasma samples from patients with confirmed Plasmodium falciparum malaria and in human whole-blood specimens stimulated with malaria-relevant agents ex vivo. Complement was significantly activated in the malaria cohort, compared with healthy controls, and was positively correlated with disease severity and with certain cytokines, in particular interleukin 8 (IL-8)/CXCL8. This was confirmed in ex vivo-stimulated blood specimens, in which complement inhibition significantly reduced IL-8/CXCL8 release. P. falciparum malaria is associated with systemic complement activation and complement-dependent release of inflammatory cytokines, of which IL-8/CXCL8 is particularly prominent.

  • 6.
    Bongoni, Anjan K.
    et al.
    St Vincents Hosp Melbourne, Immunol Res Ctr, Fitzroy, Vic, Australia..
    Salvaris, Evelyn
    St Vincents Hosp Melbourne, Immunol Res Ctr, Fitzroy, Vic, Australia..
    Nordling, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Klymiuk, Nikolai
    Ludwig Maximilians Univ Munchen, Inst Mol Anim Breeding & Biotechnol, Munich, Germany..
    Wolf, Eckhard
    Ludwig Maximilians Univ Munchen, Inst Mol Anim Breeding & Biotechnol, Munich, Germany..
    Ayares, David L.
    Revivicor Inc, Blacksburg, VA USA..
    Rieben, Robert
    Univ Bern, Dept Clin Res, Bern, Switzerland..
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Cowan, Peter J.
    St Vincents Hosp Melbourne, Immunol Res Ctr, Fitzroy, Vic, Australia.;Univ Melbourne, Dept Med, Melbourne, Vic, Australia..
    Surface modification of pig endothelial cells with a branched heparin conjugate improves their compatibility with human blood2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 4450Article in journal (Refereed)
    Abstract [en]

    Corline Heparin Conjugate (CHC), a compound of multiple unfractionated heparin chains, coats cells with a glycocalyx-like layer and may inhibit (xeno) transplant-associated activation of the plasma cascade systems. Here, we investigated the use of CHC to protect WT and genetically modified (GTKO. hCD46. hTBM) pig aortic endothelial cells (PAEC) in two pig-to-human in vitro xenotransplantation settings. Model 1: incubation of untreated or hTNFa-treated PAEC with 10% human plasma induced complement C3b/c and C5b-9 deposition, cellular activation and coagulation activation in WT and GTKO. hCD46. hTBM PAEC. Coating of untreated or hTNFa-treated PAEC with CHC (100 mu g/ml) protected against human plasma-induced endothelial activation and damage. Model 2: PAEC were grown on microcarrier beads, coated with CHC, and incubated with non-anticoagulated whole human blood. Genetically modified PAEC significantly prolonged clotting time of human blood (115.0 +/- 16.1 min, p < 0.001) compared to WT PAEC (34.0 +/- 8.2 min). Surface CHC significantly improved the human blood compatibility of PAEC, as shown by increased clotting time (WT: 84.3 +/- 11.3 min, p < 0.001; GTKO. hCD46. hTBM: 146.2 +/- 20.4 min, p < 0.05) and reduced platelet adhesion, complement activation, coagulation activation and inhibition of fibrinolysis. The combination of CHC coating and genetic modification provided the greatest compatibility with human blood, suggesting that pre-transplant perfusion of genetically modified porcine organs with CHC may benefit post-transplant xenograft function.

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  • 7.
    Cabric, Sanja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Sanchez, Javier
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Johansson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Magnusson, Peetra U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Anchoring of vascular endothelial growth factor to surface-immobilized heparin on pancreatic islets: implications for stimulating islet angiogenesis2010In: Tissue engineering. Part A, ISSN 1937-3341, Vol. 16, no 3, p. 961-970Article in journal (Refereed)
    Abstract [en]

    In pancreatic islet transplantation, early revascularization is necessary for long-term graft function. We have shown in in vitro and in vivo models that modification with surface-attached heparin protects the islets from acute attack by the innate immune system of the blood following intraportal islet transplantation. In this study, we have investigated the ability of an immobilized conjugate composed of heparin to bind the angiogenic growth factor vascular endothelial growth factor-A (VEGF-A) as a means of attracting endothelial cells (ECs) to induce angiogenesis and revascularization. We analyzed the capacity of VEGF-A to bind to immobilized heparin and how this affected the proliferation and adherence of ECs to both artificial glass surfaces and islets. Quartz crystal microbalance with dissipation monitoring and slot-blot demonstrated the binding of VEGF-A to heparin-coated surfaces upon which ECs showed protein-dependent proliferation. Also, ECs cultured on heparin-coated glass surfaces exhibited effects upon focal contacts. Heparinized islets combined with VEGF-A demonstrated unaffected insulin release. Further, covering islets with heparin also increased the adhesion of ECs to the islet surface. Immobilized heparin on the islet surface may be a useful anchor molecule for achieving complete coverage of islets with angiogenic growth factors, ultimately improving islet revascularization and engraftment in pancreatic islet transplantation.

  • 8.
    Corada, Monica
    et al.
    FIRC Inst Mol Oncol Fdn IFOM, Milan, Italy.
    Orsenigo, Fabrizio
    FIRC Inst Mol Oncol Fdn IFOM, Milan, Italy.
    Bhat, Ganesh Parameshwar
    Osped San Raffaele, Mol Neurobiol Lab, Div Neurosci, Milan, Italy.
    Conze, Lei Liu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Breviario, Ferruccio
    FIRC Inst Mol Oncol Fdn IFOM, Milan, Italy.
    Cunha, Sara I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Beznoussenko, Galina V.
    FIRC Inst Mol Oncol Fdn IFOM, Milan, Italy.
    Mironov, Alexander A.
    FIRC Inst Mol Oncol Fdn IFOM, Milan, Italy.
    Bacigaluppi, Marco
    Osped San Raffaele, Neuroimmunol Unit, Div Neurosci, Inst Expt Neurol, Milan, Italy.
    Martino, Gianvito
    Osped San Raffaele, Neuroimmunol Unit, Div Neurosci, Inst Expt Neurol, Milan, Italy.
    Pitulescu, Mara E.
    Univ Munster, Max Planck Inst Mol Biomed, Dept Tissue Morphogenesis, Munster, Germany; Univ Munster, Fac Med, Munster, Germany.
    Adams, Ralf H.
    Univ Munster, Max Planck Inst Mol Biomed, Dept Tissue Morphogenesis, Munster, Germany; Univ Munster, Fac Med, Munster, Germany.
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol Fdn IFOM, Milan, Italy; Univ Milan, Dept Oncol & Hematooncol, Milan, Italy.
    Fine-Tuning of Sox17 and Canonical Wnt Coordinates the Permeability Properties of the Blood-Brain Barrier2019In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 124, no 4, p. 511-525Article in journal (Refereed)
    Abstract [en]

    Rationale: The microvasculature of the central nervous system includes the blood-brain barrier (BBB), which regulates the permeability to nutrients and restricts the passage of toxic agents and inflammatory cells. Canonical Wnt/β-catenin signaling is responsible for the early phases of brain vascularization and BBB differentiation. However, this signal declines after birth, and other signaling pathways able to maintain barrier integrity at postnatal stage are still unknown.

    Objective: Sox17 (SRY [sex-determining region Y]-box 17) constitutes a major downstream target of Wnt/β-catenin in endothelial cells and regulates arterial differentiation. In the present article, we asked whether Sox17 may act downstream of Wnt/β-catenin in inducing BBB differentiation and maintenance.

    Methods and Results: Using reporter mice and nuclear staining of Sox17 and β-catenin, we report that although β-catenin signaling declines after birth, Sox17 activation increases and remains high in the adult. Endothelial-specific inactivation of Sox17 leads to increase of permeability of the brain microcirculation. The severity of this effect depends on the degree of BBB maturation: it is strong in the embryo and progressively declines after birth. In search of Sox17 mechanism of action, RNA sequencing analysis of gene expression of brain endothelial cells has identified members of the Wnt/β-catenin signaling pathway as downstream targets of Sox17. Consistently, we found that Sox17 is a positive inducer of Wnt/β-catenin signaling, and it acts in concert with this pathway to induce and maintain BBB properties. In vivo, inhibition of the β-catenin destruction complex or expression of a degradation-resistant β-catenin mutant, prevent the increase in permeability and retina vascular malformations observed in the absence of Sox17.

    Conclusions: Our data highlight a novel role for Sox17 in the induction and maintenance of the BBB, and they underline the strict reciprocal tuning of this transcription factor and Wnt/β-catenin pathway. Modulation of Sox17 activity may be relevant to control BBB permeability in pathological conditions.

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  • 9.
    Cross, Michael J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lu, Lingge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nyqvist, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Holmqvist, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    The Shb Adaptor Protein Binds to Tyrosine 766 in the FGFR-1 and Regulatesthe Ras/MEK/MAPK Pathway via FRS2 Phosphorylation in Endothelial Cells2002In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 13, no 8, p. 2881-2893Article in journal (Refereed)
    Abstract [en]

    Stimulation of fibroblast growth factor receptor-1 (FGFR-1) is known to result in phosphorylation of tyrosine 766 and the recruitment and subsequent activation of phospholipase C-γ (PLC-γ). To assess the role of tyrosine 766 in endothelial cell function, we generated endothelial cells expressing a chimeric receptor, composed of the extracellular domain of the PDGF receptor-α and the intracellular domain of FGFR-1. Mutation of tyrosine 766 to phenylalanine prevented PLC-γ activation and resulted in a reduced phosphorylation of FRS2 and reduced activation of the Ras/MEK/MAPK pathway relative to the wild-type chimeric receptor. However, FGFR-1–mediated MAPK activation was not dependent on PKC activation or intracellular calcium, both downstream mediators of PLC-γ activation. We report that the adaptor protein Shb is also able to bind tyrosine 766 in the FGFR-1, via its SH2 domain, resulting in its subsequent phosphorylation. Overexpression of an SH2 domain mutant Shb caused a dramatic reduction in FGFR-1–mediated FRS2 phosphorylation with concomitant perturbment of the Ras/MEK/MAPK pathway. Expression of the chimeric receptor mutant and the Shb SH2 domain mutant resulted in a similar reduction in FGFR-1–mediated mitogenicity. We conclude, that Shb binds to tyrosine 766 in the FGFR-1 and regulates FGF-mediated mitogenicity via FRS2 phosphorylation and the subsequent activation of the Ras/MEK/MAPK pathway.

  • 10.
    Cunha, Sara I.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Institute of Molecular Oncology, Milan, Italy (E.D., M.G.L.); Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy (M.G.L.).
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. FIRC Institute of Molecular Oncology, Milan, Italy (E.D., M.G.L.); Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy (M.G.L.).
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol, Milan, Italy..
    Lampugnani, Maria Grazia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. FIRC Inst Mol Oncol, Milan, Italy.;Ist Ric Farmacol Mario Negri, Milan, Italy..
    Deregulated TGF-beta/BMP Signaling in Vascular Malformations2017In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 121, no 8, p. 981-999Article, review/survey (Refereed)
    Abstract [en]

    Correct organization of the vascular tree requires the balanced activities of several signaling pathways that regulate tubulogenesis and vascular branching, elongation, and pruning. When this balance is lost, the vessels can be malformed and fragile, and they can lose arteriovenous differentiation. In this review, we concentrate on the transforming growth factor (TGF)-beta/bone morphogenetic protein (BMP) pathway, which is one of the most important and complex signaling systems in vascular development. Inactivation of these pathways can lead to altered vascular organization in the embryo. In addition, many vascular malformations are related to deregulation of TGF-beta/BMP signaling. Here, we focus on two of the most studied vascular malformations that are induced by deregulation of TGF-beta/BMP signaling: hereditary hemorrhagic telangiectasia (HHT) and cerebral cavernous malformation (CCM). The first of these is related to loss-of-function mutation of the TGF-beta/BMP receptor complex and the second to increased signaling sensitivity to TGF-beta/BMP. In this review, we discuss the potential therapeutic targets against these vascular malformations identified so far, as well as their basis in general mechanisms of vascular development and stability.

  • 11.
    Duprez, Ida Rasmusson
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Johansson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Magnusson, Peetra U
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Preparatory studies of composite mesenchymal stem cell islets for application in intraportal islet transplantation2011In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 116, no 1, p. 8-17Article in journal (Refereed)
    Abstract [en]

    Abstract Background. Low engraftment and adverse immune reactions hamper the success rate of clinical islet transplantation. In this study, we investigated the capacity of human mesenchymal stem cells (MSCs) to adhere to human islets of Langerhans and their effects in immune modulation and during blood interactions in vitro. Methods. Composite MSC-islets were formed by suspension co-culture, and the phenotype was evaluated by confocal microscopy. Islet function was assessed by dynamic insulin release in response to glucose in vitro. Mixed lymphocyte-islet reactions (MLIR) and the tubing blood loop model were utilized as in vitro tools to analyse the effect of MSCs on the innate and adaptive immune reactions triggered by the islets. Results. MSCs rapidly adhered to islets and spread out to cover the islet surface. Insulin expression and secretion were sustained with the MSC coating. MSC-coated islets showed unaffected reactions with blood in vitro in comparison to control islets. Furthermore, MSCs suppressed lymphocyte proliferation induced by islet cells in MLIR. Conclusion. We conclude that it is possible to create composite MSC-islets to enable delivery of the MSCs by utilizing the adhesive capacity of the MSCs. This could have beneficial immunosuppressive effects in optimizing pancreatic islet transplantation.

  • 12.
    Edin, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Boström, Marja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Magnusson, Peetra U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Differentiation of human neural progenitor cell-derived spiral ganglion-like neurons: a time-lapse video study2014In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 134, no 5, p. 441-447Article in journal (Refereed)
    Abstract [en]

    Conclusions: Human neural progenitor cells can differentiate into spiral ganglion-like cells when exposed to inner ear-associated growth factors. The phenotype bears resemblance to human sphere-derived neurons. Objective: To establish an in vitro model for the human auditory nerve to replace and complement in vivo animal experiments and ultimately human in vivo transplantation. Methods: Human neural progenitors were differentiated under conditions developed for in vitro survival of human primary spiral ganglion culture with media containing growth factors associated with inner ear development. Differentiation was documented using time-lapse video microscopy. Time-dependent marker expression was evaluated using immunocytochemistry with fluorescence and laser confocal microscopy. Results: Within 14 days of differentiation, neural progenitors adopted neural phenotype and expressed spiral ganglion-associated markers.

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  • 13.
    Edin, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Li, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Atturo, Francesca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Magnusson, Peetra U
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    3-D gel culture and time-lapse video microscopy of the human vestibular nerve2014In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 134, no 12, p. 1211-1218Article in journal (Refereed)
    Abstract [en]

    UNLABELLED: Abstract Conclusions: Human inner ear neurons have an innate regenerative capacity and can be cultured in vitro in a 3-D gel. The culture technique is valuable for experimental investigations of human inner ear neuron signaling and regeneration.

    OBJECTIVES: To establish a new in vitro model to study human inner ear nerve signaling and regeneration.

    METHODS: Human superior vestibular ganglion (SVG) was harvested during translabyrinthine surgery for removal of vestibular schwannoma. After dissection tissue explants were embedded and cultured in a laminin-based 3-D matrix (Matrigel™). 3-D growth cone (GC) expansion was analyzed using time-lapse video microscopy (TLVM). Neural marker expression was appraised using immunocytochemistry with fluorescence and laser confocal microscopy.

    RESULTS: Tissue explants from adult human SVG could be cultured in 3-D in a gel, indicating an innate potential for regeneration. Cultured GCs were found to expand dynamically in the gel. Growth cone expansion and axonal Schwann cell alignment were documented using TLVM. Neurons were identified morphologically and through immunohistochemical staining.

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  • 14.
    Fransson, Moa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Brännström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Duprez, Ida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Le Blanc, Katarina
    Karolinska Inst, Dept Clin Immunol & Transfus Med, Huddinge, Sweden; Karolinska Univ Hosp, Hematol Ctr, Huddinge, Sweden.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Mesenchymal stromal cells supportendothelial cell interactions in anintramuscular islet transplantation model2015In: Regenerative Medicine Research, ISSN 2050-490X, Vol. 3, article id UNSP 1Article in journal (Refereed)
    Abstract [en]

    Background:

    Mesenchymal stromal cells (MSC) have been under investigation for a number of therapies andhave lately been in focus as immunosuppressive actors in the field of transplantation. Herein we haveextended our previously published in vitro model of MSC-islets in an experimental setting of islettransplantation to the abdominal muscle.Human islets coated with luciferase-GFP transduced human MSC were transplanted to the abdomen muscletissue of NOD-scid ILR2γnull mice and cellular interactions were investigated by confocal microscopy.

    Results:

    The MSC reduced fibrotic encapsulation and facilitated endothelial cell interactions. In particular, weshow a decreased fraction of αSMA expressing fibrotic tissue surrounding the graft in presence of MSC-isletscompared to islets solely distributed into the muscle tissue. Also, in the presence of MSC, human isletendothelial cells migrated from the center of the graft out into the surrounding tissue forming chimeric bloodvessels with recipient endothelial cells. Further, in the graft periphery, MSC were seen interacting with infiltratingmacrophages.

    Conclusions:

    Here, in our experimental in vivo model of composite human islets and luciferase-GFP-transducedhuman MSC, we enable the visualization of close interactions between the MSC and the surrounding tissue. In thismodel of transplantation the MSC contribute to reduced fibrosis and increased islet endothelial cell migration.Furthermore, the MSC interact with the recipient vasculature and infiltrating macrophages.

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  • 15.
    Fransson, Moa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Piras, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Nilsson, Berith
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lu, Binfeng
    Harris, Robert A
    Magnusson, Peetra U
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Loskog, Angelica Si
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery2012In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 9, p. 112-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). In the murine experimental autoimmune encephalomyelitis (EAE) model of MS, T regulatory (Treg) cell therapy has proved to be beneficial, but generation of stable CNS-targeting Tregs needs further development. Here, we propose gene engineering to achieve CNS-targeting Tregs from naive CD4 cells and demonstrate their efficacy in the EAE model.

    METHODS

    CD4+T cells were modified utilizing a lentiviral vector system to express a chimeric antigen receptor (CAR) targeting myelin oligodendrocyte glycoprotein (MOG) in trans with the murine FoxP3 gene that drives Treg differentiation. The cells were evaluated in vitro for suppressive capacity and in C57BL/6 mice to treat EAE. Cells were administered by intranasal (i.n.) cell delivery.

    RESULTS

    The engineered Tregs demonstrated suppressive capacity in vitro and could efficiently access various regions in the brain via i.n cell delivery. Clinical score 3 EAE mice were treated and the engineered Tregs suppressed ongoing encephalomyelitis as demonstrated by reduced disease symptoms as well as decreased IL-12 and IFNgamma mRNAs in brain tissue. Immunohistochemical markers for myelination (MBP) and reactive astrogliosis (GFAP) confirmed recovery in mice treated with engineered Tregs compared to controls. Symptomfree mice were echallenged with a second EAE-inducing inoculum but remained healthy, demonstrating the sustained effect of engineered Tregs.

    CONCLUSION

    CNS-targeting Tregs delivered i.n. localized to the CNS and efficiently suppressed ongoing inflammation leading to diminished disease symptoms.

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  • 16.
    Fransson, Moa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Piras, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wang, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Duprez, Ida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Harris, Robert A
    Leblanc, Katarina
    Magnusson, Peetra U
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Loskog, Angelica S I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Intranasal Delivery of CNS-Retargeted Human Mesenchymal Stromal Cells Prolongs Treatment Efficacy of Experimental Autoimmune Encephalomyelitis2014In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 142, no 3, p. 431-441Article in journal (Refereed)
    Abstract [en]

    Treatment with mesenchymal stromal cells (MSC) is currently of interest for a number of diseases including multiple sclerosis (MS). MSCs is well known to target inflamed tissues however, in a therapeutic scenery, systemic administration will lead to few cells reaching the brain. We hypothesized that MSCs may target the brain upon intranasal (i.n) administration and persist in CNS tissue if expressing a CNS-targeting receptor. To demonstrate proof of concept, MSCs were genetically engineered to express a myelin oligodendrocyte glycoprotein (MOG)-specific receptor. Engineered MSCs retained their immunosuppressive capacity, infiltrated into the brain upon i.n. cell administration, and were able to significantly reduce disease symptoms of experimental autoimmune encephalomyelitis (EAE). The mice treated with CNS-targeting MSCs were resistant to further EAE induction whereas non-targeted MSC did not give such persistent effects. Histological analysis revealed increased brain restoration in engineered MSC-treated mice. In conclusion, MSCs can be genetically engineered to target the brain and prolong therapeutic efficacy in an EAE model.

  • 17.
    Johansson, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Rasmusson, Ida
    Niclou, Simone P.
    Forslund, Naomi
    Gustavsson, Linda
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Magnusson, Peetra U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Formation of composite endothelial cell-mesenchymal stem cell islets: a novel approach to promote islet revascularization2008In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 57, no 9, p. 2393-2401Article in journal (Refereed)
    Abstract [en]

     

    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. CONCLUSIONS: EC proliferation, sprout formation, and ingrowth of ECs into the islets were enhanced by MSCs. The use of composite EC-MSC islets may have beneficial effects on revascularization and immune regulation. The technique presented allows for pretreatment of donor islets with recipient-derived ECs and MSCs as a means of improving islet engraftment.

     

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  • 18.
    Johansson, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lau, Joey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sandberg, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Borg, L.A. Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Endothelial cell signalling supports pancreatic beta cellfunction in the rat2009In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 52, no 11, p. 2385-2394Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis The proximity of endothelial cells andbeta cells in islets by necessity means that they are exposedto each other’s products. Whereas islet endothelial cellsrequire signals from beta cells to function properly,endothelin-1, thrombospondin-1 and laminins, amongothers, have been identified as endothelial-derived molecules,although their full effects on beta cells have not beenexplored. We tested the hypothesis that islet endothelialderivedproducts affect beta cell function.Methods Endothelial cells from rat islets were proliferatedand purified. Endothelium-conditioned culture medium(ECCM) was obtained by maintaining the endothelial cellsin culture medium. Islet function was evaluated followingexposure of cultured islets to standard culture medium orECCM. Changes in mRNA levels for key beta cellmetabolic enzymes were also measured in islets afterECCM exposure.Results Glucose-stimulated insulin release and islet insulincontent were markedly enhanced by exposure to ECCM.This was at least partly explained by improved mitochondrialfunction, as assessed by glucose oxidation and anupregulation of the mitochondrial gene for glycerol-3-phosphate dehydrogenase (mGpdh [also known as Gpd2]),combined with upregulation of the rate-limiting enzyme inthe glycolysis, glucokinase, in the islets. The intracellulardegradation of insulin was also decreased in the islets. Isletendothelial cells produced laminins, and the positive effectsof islet endothelial cells were prevented by addition of aneutralising antibody to the β1-chain of laminin. Additionof exogenous laminin stimulated islet function.Conclusions/interpretation This study provides proof ofprinciple that endothelial cells can affect the function of betacells in their vicinity and that this is at least partially mediatedby laminins.

  • 19. Kourtzelis, Iannis
    et al.
    Magnusson, Peetra U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Kotlabova, Klara
    Lambris, John D.
    Chavakis, Triantafyllos
    Regulation of Instant Blood Mediated Infl ammatoryReaction (IBMIR) in Pancreatic Islet Xeno-Transplantation: Points for Therapeutic Interventions2015In: Immune Responses to Biosurfaces: Mechanisms and Therapeutic Interventions / [ed] John D. Lambris, Kristina N. Ekdahl, Daniel Ricklin, Bo Nilsson, Cham: Springer, 2015, p. 171-188Chapter in book (Refereed)
    Abstract [en]

    Xeno-transplantation of pancreatic islets represents a promising therapeuticalternative for the treatment of type 1 diabetes mellitus. However, potentinnate immune responses induced shortly after the transplantation of donor islets tothe recipient, comprising the Instant Blood Mediated Immune Reaction (IBMIR),exert detrimental actions on islet graft function. The coagulation and complementcascades together with the leukocyte and platelet populations are the major playersin IBMIR. This innate immune attack affects dramatically islet integrity and leadsto signifi cant loss of function of the xenograft. In the present review, we focus on themechanisms contributing to IBMIR components and address therapeutic interventionapproaches to limit IBMIR by administering inhibitors in circulation, by coatingthe islet surface with inhibitors or by generating transgenic donor animals; theseapproaches could result in improved xenograft survival.

  • 20.
    Kourtzelis, Ioannis