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Publications (10 of 43) Show all publications
Malinyerno, M., Maderna, C., Abu Taha, A., Corada, M., Orsenigo, F., Valentino, M., . . . Dejana, E. (2019). Endothelial cell clonal expansion in the development of cerebral cavernous malformations. Nature Communications, 10, Article ID 2761.
Open this publication in new window or tab >>Endothelial cell clonal expansion in the development of cerebral cavernous malformations
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2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 2761Article in journal (Refereed) Published
Abstract [en]

Cerebral cavernous malformation (CCM) is a neurovascular familial or sporadic disease that is characterised by capillary-venous cavernomas, and is due to loss-of-function mutations to any one of three CCM genes. Familial CCM follows a two-hit mechanism similar to that of tumour suppressor genes, while in sporadic cavernomas only a small fraction of endothelial cells shows mutated CCM genes. We reported that in mouse models and in human patients, endothelial cells lining the lesions have different features from the surrounding endothelium, as they express mesenchymal/stem-cell markers. Here we show that cavernomas originate from clonal expansion of few Ccm3-null endothelial cells that express mesenchymal/stem-cell markers. These cells then attract surrounding wild-type endothelial cells, inducing them to express mesenchymal/stem-cell markers and to contribute to cavernoma growth. These characteristics of Ccm3-null cells are reminiscent of the tumour-initiating cells that are responsible for tumour growth. Our data support the concept that CCM has benign tumour characteristics.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-390826 (URN)10.1038/s41467-019-10707-x (DOI)000472598000002 ()31235698 (PubMedID)
Funder
Swedish Research Council, 2013-9279Knut and Alice Wallenberg FoundationEU, European Research Council, 742922
Available from: 2019-08-14 Created: 2019-08-14 Last updated: 2019-08-14Bibliographically approved
Corada, M., Orsenigo, F., Bhat, G. P., Conze, L. L., Breviario, F., Cunha, S. I., . . . Dejana, E. (2019). Fine-Tuning of Sox17 and Canonical Wnt Coordinates the Permeability Properties of the Blood-Brain Barrier. Circulation Research, 124(4), 511-525
Open this publication in new window or tab >>Fine-Tuning of Sox17 and Canonical Wnt Coordinates the Permeability Properties of the Blood-Brain Barrier
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2019 (English)In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 124, no 4, p. 511-525Article in journal (Refereed) Published
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.

Keywords
blood-brain barrier, endothelial cells, permeability, stroke, Wnt/beta-catenin
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-378993 (URN)10.1161/CIRCRESAHA.118.313316 (DOI)000458887600025 ()30591003 (PubMedID)
Funder
EU, European Research Council, 742922Swedish Research CouncilKnut and Alice Wallenberg FoundationGerman Research Foundation (DFG), FOR2325
Available from: 2019-03-19 Created: 2019-03-19 Last updated: 2019-03-19Bibliographically approved
Sedigh, A., Nordling, S., Carlsson, F., Larsson, E., Norlin, B., Lubenow, N., . . . Lorant, T. (2019). Perfusion of Porcine Kidneys With Macromolecular Heparin Reduces Early Ischemia Reperfusion Injury. Transplantation, 103(2), 420-427
Open this publication in new window or tab >>Perfusion of Porcine Kidneys With Macromolecular Heparin Reduces Early Ischemia Reperfusion Injury
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2019 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 103, no 2, p. 420-427Article in journal (Refereed) Published
Abstract [en]

Background: Previously, we have been able to demonstrate the possibility of coating the inner surface of the renal arteries in porcine kidneys with a heparin conjugate during hypothermic machine perfusion (HMP). The purpose of this study was to assess the efficacy of this treatment in reducing early ischemia-reperfusion injury.

Method: Brain death was induced in male landrace pigs by stepwise volume expansion of an epidural balloon catheter until negative cerebral perfusion pressure (CPP) was obtained. Both kidneys (matched pairs; n = 6 + 6) were preserved for 20 hours byHMP during which 50mg heparin conjugate was added to one of the HMP systems (treated group). A customized ex vivo normothermic oxygenated perfusion (NP) system with added exogenous creatinine was used to evaluate early kidney function. Blood, urine and histological samples were collected during the subsequent 3 hours of NP.

Results: Kidney weight was lower at the end of NP (P = 0.017) in the treated group compared with control kidneys. The rate of decline in creatinine level was faster (P = 0.024), total urinary volume was higher (P = 0.031), and the level of urine neutrophil gelatinase-associated lipocalin (NGAL) was lower (P = 0.031) in the treated group. Histologically, less tubular changes were seen (P = 0.046). During NP intrarenal resistance remained lower (P < 0.0001) in the treated group.

Conclusions: Perfusion of porcine kidneys with heparin conjugate during HMP reduces preservation injury and improves organ function shortly after reperfusion. No increased risk of bleeding was seen in this setup. This protective strategy may potentially improve the quality of transplanted kidneys in the clinical setting.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2019
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-377674 (URN)10.1097/TP.0000000000002469 (DOI)000457576600035 ()30299374 (PubMedID)
Funder
VINNOVA
Available from: 2019-02-25 Created: 2019-02-25 Last updated: 2019-02-25Bibliographically approved
Nordling, S., Brännström, J., Carlsson, F., Lu, B., Salvaris, E., Wanders, A., . . . Magnusson, P. U. (2018). Enhanced protection of the renal vascular endothelium improves early outcome in kidney transplantation: Preclinical investigations in pig and mouse. Scientific Reports, 8, Article ID 5220.
Open this publication in new window or tab >>Enhanced protection of the renal vascular endothelium improves early outcome in kidney transplantation: Preclinical investigations in pig and mouse
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 5220Article in journal (Refereed) Published
Abstract [en]

Ischemia reperfusion injury is one of the major complications responsible for delayed graft function in kidney transplantation. Applications to reduce reperfusion injury are essential due to the widespread use of kidneys from deceased organ donors where the risk for delayed graft function is especially prominent. We have recently shown that coating of inflamed or damaged endothelial cells with a unique heparin conjugate reduces thrombosis and leukocyte recruitment. In this study we evaluated the binding capacity of the heparin conjugate to cultured human endothelial cells, to kidneys from brain-dead porcine donors, and to murine kidneys during static cold storage. The heparin conjugate was able to stably bind cultured endothelial cells with high avidity, and to the renal vasculature of explanted kidneys from pigs and mice. Treatment of murine kidneys prior to transplantation reduced platelet deposition and leukocyte infiltration 24 hours post-transplantation, and significantly improved graft function. The present study thus shows the benefits of enhanced protection of the renal vasculature during cold storage, whereby increasing the antithrombotic and anti-adhesive properties of the vascular endothelium yields improved renal function early after transplantation.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Surgery Urology and Nephrology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-354353 (URN)10.1038/s41598-018-21463-1 (DOI)000428235200024 ()29581529 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 602699VINNOVA
Available from: 2018-08-08 Created: 2018-08-08 Last updated: 2018-08-08Bibliographically approved
Cunha, S. I., Magnusson, P., Dejana, E. & Lampugnani, M. G. (2017). Deregulated TGF-beta/BMP Signaling in Vascular Malformations. Circulation Research, 121(8), 981-999
Open this publication in new window or tab >>Deregulated TGF-beta/BMP Signaling in Vascular Malformations
2017 (English)In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 121, no 8, p. 981-999Article, review/survey (Refereed) Published
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.

Keywords
cell differentiation, mutation, signal transduction, transforming growth factors, vascular malformations
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-346839 (URN)10.1161/CIRCRESAHA.117.309930 (DOI)000412807600019 ()28963191 (PubMedID)
Available from: 2018-03-28 Created: 2018-03-28 Last updated: 2018-03-28Bibliographically approved
Bongoni, A. K., Salvaris, E., Nordling, S., Klymiuk, N., Wolf, E., Ayares, D. L., . . . Cowan, P. J. (2017). Surface modification of pig endothelial cells with a branched heparin conjugate improves their compatibility with human blood. Scientific Reports, 7, Article ID 4450.
Open this publication in new window or tab >>Surface modification of pig endothelial cells with a branched heparin conjugate improves their compatibility with human blood
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 4450Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-330718 (URN)10.1038/s41598-017-04898-w (DOI)000404451300056 ()28667310 (PubMedID)
Available from: 2017-10-10 Created: 2017-10-10 Last updated: 2017-10-10Bibliographically approved
Nilsson Ekdahl, K., Teramura, Y., Hamad, O. A., Asif, S., Dührkop, C., Fromell, K., . . . Nilsson, B. (2016). Dangerous liaisons: complement, coagulation, and kallikrein/kinin cross-talk act as a linchpin in the events leading to thromboinflammation. Immunological Reviews, 274(1), 245-269
Open this publication in new window or tab >>Dangerous liaisons: complement, coagulation, and kallikrein/kinin cross-talk act as a linchpin in the events leading to thromboinflammation
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2016 (English)In: Immunological Reviews, ISSN 0105-2896, E-ISSN 1600-065X, Vol. 274, no 1, p. 245-269Article in journal (Refereed) Published
Abstract [en]

Innate immunity is fundamental to our defense against microorganisms. Physiologically, the intravascular innate immune system acts as a purging system that identifies and removes foreign substances leading to thromboinflammatory responses, tissue remodeling, and repair. It is also a key contributor to the adverse effects observed in many diseases and therapies involving biomaterials and therapeutic cells/organs. The intravascular innate immune system consists of the cascade systems of the blood (the complement, contact, coagulation, and fibrinolytic systems), the blood cells (polymorphonuclear cells, monocytes, platelets), and the endothelial cell lining of the vessels. Activation of the intravascular innate immune system in vivo leads to thromboinflammation that can be activated by several of the system's pathways and that initiates repair after tissue damage and leads to adverse reactions in several disorders and treatment modalities. In this review, we summarize the current knowledge in the field and discuss the obstacles that exist in order to study the cross-talk between the components of the intravascular innate immune system. These include the use of purified in vitro systems, animal models and various types of anticoagulants. In order to avoid some of these obstacles we have developed specialized human whole blood models that allow investigation of the cross-talk between the various cascade systems and the blood cells. We in particular stress that platelets are involved in these interactions and that the lectin pathway of the complement system is an emerging part of innate immunity that interacts with the contact/coagulation system. Understanding the resulting thromboinflammation will allow development of new therapeutic modalities.

Keywords
coagulation, complement system, contact activation/kallikrein system, innate immunity, platelets, thromboinflammation
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-373992 (URN)10.1111/imr.12471 (DOI)000387059600017 ()27782319 (PubMedID)
Funder
Swedish Research Council, 2013‐65X‐05647‐34‐4EU, FP7, Seventh Framework Programme, 602699The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)Novo Nordisk
Available from: 2019-01-17 Created: 2019-01-17 Last updated: 2019-01-21Bibliographically approved
Liu, W., Edin, F., Blom, H., Magnusson, P., Schrott-Fischer, A., Glueckert, R., . . . Rask-Andersen, H. (2016). Super-resolution structured illumination fluorescence microscopy of the lateral wall of the cochlea: the Connexin26/30 proteins are separately expressed in man. Cell and Tissue Research, 365(1), 13-27
Open this publication in new window or tab >>Super-resolution structured illumination fluorescence microscopy of the lateral wall of the cochlea: the Connexin26/30 proteins are separately expressed in man
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2016 (English)In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 365, no 1, p. 13-27Article in journal (Refereed) Published
Abstract [en]

Globally 360 million people have disabling hearing loss and, of these, 32 million are children. Human hearing relies on 15,000 hair cells that transduce mechanical vibrations to electrical signals in the auditory nerve. The process is powered by the endo-cochlear potential, which is produced by a vascularized epithelium that actively transports ions in conjunction with a gap junction (GJ) system. This "battery" is located "off-site" in the lateral wall of the cochlea. The GJ syncytium contains the GJ protein genes beta 2 (GJB2/connexin26 (Cx26)) and 6 (GJB6/connexin30 (Cx30)), which are commonly involved in hereditary deafness. Because the molecular arrangement of these proteins is obscure, we analyze GJ protein expression (Cx26/30) in human cochleae by using super-resolution structured illumination microscopy. At this resolution, the Cx26 and Cx30 proteins were visible as separate plaques, rather than being co-localized in heterotypic channels, as previously suggested. The Cx26 and Cx30 proteins thus seem not to be co-expressed but to form closely associated assemblies of GJ plaques. These results could assist in the development of strategies to treat genetic hearing loss in the future.

Keywords
Human cochlea, Connexin (as elsewhere) 26/30, Structured illumination microscopy
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-299834 (URN)10.1007/s00441-016-2359-0 (DOI)000378877600003 ()26941236 (PubMedID)
Available from: 2016-07-29 Created: 2016-07-28 Last updated: 2018-05-18Bibliographically approved
Ajalloueian, F., Fransson, M., Tavanai, H., Hilborn, J., Magnusson, P. & Arpanaei, A. (2015). Comparing PLGA and PLGA/Chitosan Nanofibers Seeded by Msc: A Cell-scaffold Interaction Study. Paper presented at 4th TERMIS World Congress, SEP 08-11, 2015, Boston, MA. Tissue Engineering. Part A, 21, S406-S407
Open this publication in new window or tab >>Comparing PLGA and PLGA/Chitosan Nanofibers Seeded by Msc: A Cell-scaffold Interaction Study
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2015 (English)In: Tissue Engineering. Part A, ISSN 1937-3341, E-ISSN 1937-335X, Vol. 21, p. S406-S407Article in journal, Meeting abstract (Other academic) Published
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-265958 (URN)000360205202690 ()
Conference
4th TERMIS World Congress, SEP 08-11, 2015, Boston, MA
Available from: 2015-11-04 Created: 2015-11-04 Last updated: 2018-05-18Bibliographically approved
Berg, A., Otterdal, K., Patel, S., Gonca, M., David, C., Dalen, I., . . . Nilsson, P. (2015). Complement Activation Correlates With Disease Severity and Contributes to Cytokine Responses in Plasmodium falciparum Malaria. The Internet Journal of Infectious Diseases, 212(11), 1835-1840
Open this publication in new window or tab >>Complement Activation Correlates With Disease Severity and Contributes to Cytokine Responses in Plasmodium falciparum Malaria
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2015 (English)In: The Internet Journal of Infectious Diseases, ISSN 1528-8366, Vol. 212, no 11, p. 1835-1840Article in journal (Refereed) Published
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.

Keywords
C5a/C5aR1; IL-8/CXCL8; Plasmodium falciparum; complement activation; cytokines; heme; hemozoin; inflammation; malaria
National Category
Medical and Health Sciences Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-276987 (URN)10.1093/infdis/jiv283 (DOI)000368669500019 ()25980034 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme
Available from: 2016-02-16 Created: 2016-02-16 Last updated: 2018-01-10Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-1142-854X

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