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  • 1.
    Abu-Siniyeh, Ahmed
    et al.
    Univ New S Wales, Sch Med Sci, ARC Ctr Adv Mol Imaging, Sydney, NSW 2052, Australia.;Univ New S Wales, Australian Ctr NanoMed, Sydney, NSW 2052, Australia..
    Owen, Dylan M.
    Kings Coll London, Dept Phys, London WC2R 2LS, England.;Kings Coll London, Randall Div Cell & Mol Biophys, London WC2R 2LS, England..
    Benzing, Carola
    Univ New S Wales, Sch Med Sci, ARC Ctr Adv Mol Imaging, Sydney, NSW 2052, Australia.;Univ New S Wales, Australian Ctr NanoMed, Sydney, NSW 2052, Australia..
    Rinkwitz, Silke
    Becker, Thomas S.
    Univ Sydney, Brain & Mind Res Inst, Sydney Med Sch, Sydney, NSW 2006, Australia.;Univ Sydney, Dept Hlth Sci, Sydney, NSW 2006, Australia..
    Majumdar, Arindam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Gaus, Katharina
    Univ New S Wales, Sch Med Sci, ARC Ctr Adv Mol Imaging, Sydney, NSW 2052, Australia.;Univ New S Wales, Australian Ctr NanoMed, Sydney, NSW 2052, Australia..
    The aPKC/Par3/Par6 Polarity Complex and Membrane Order Are Functionally Interdependent in Epithelia During Vertebrate Organogenesis2016Inngår i: Traffic: the International Journal of Intracellular Transport, ISSN 1398-9219, E-ISSN 1600-0854, Vol. 17, nr 1, s. 66-79Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The differential distribution of lipids between apical and basolateral membranes is necessary for many epithelial cell functions, but how this characteristic membrane organization is integrated within the polarity network during ductal organ development is poorly understood. Here we quantified membrane order in the gut, kidney and liver ductal epithelia in zebrafish larvae at 3-11 days post fertilization (dpf) with Laurdan 2-photon microscopy. We then applied a combination of Laurdan imaging, antisense knock-down and analysis of polarity markers to understand the relationship between membrane order and apical-basal polarity. We found a reciprocal relationship between membrane order and the cell polarity network. Reducing membrane condensation by exogenously added oxysterol or depletion of cholesterol reduced apical targeting of the polarity protein, aPKC. Conversely, using morpholino knock down in zebrafish, we found that membrane order was dependent upon the Crb3 and Par3 polarity protein expression in ductal epithelia. Hence our data suggest that the biophysical property of membrane lipid packing is a regulatory element in apical basal polarity.

  • 2.
    Ali, Muhammad Akhtar
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Younis, Shady
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Wallerman, Ola
    Gupta, Rajesh
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Andersson, Leif
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Sjoblöm, Tobias
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells2015Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 25, s. 7743-7748Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The transcription factor ZBED6 (zinc finger, BED-type containing 6) is a repressor of IGF2 whose action impacts development, cell proliferation, and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Ablation of ZBED6 affected the cell cycle and led to increased growth rate in RKO cells but reduced growth in HCT116 cells. This striking difference was reflected in the transcriptome analyses, which revealed enrichment of cell-cycle-related processes among differentially expressed genes in both cell lines, but the direction of change often differed between the cell lines. ChIP sequencing analyses displayed enrichment of ZBED6 binding at genes up-regulated in ZBED6-knockout clones, consistent with the view that ZBED6 modulates gene expression primarily by repressing transcription. Ten differentially expressed genes were identified as putative direct gene targets, and their down-regulation by ZBED6 was validated experimentally. Eight of these genes were linked to the Wnt, Hippo, TGF-beta, EGF receptor, or PI3K pathways, all involved in colorectal cancer development. The results of this study show that the effect of ZBED6 on tumor development depends on the genetic background and the transcriptional state of its target genes.

  • 3.
    Ando, Koji
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Natl Cerebral & Cardiovasc Ctr, Dept Cell Biol, Res Inst, Suita, Osaka, Japan.
    Wang, Weili
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld , Australia.
    Peng, Di
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Chiba, Ayano
    Natl Cerebral & Cardiovasc Ctr, Dept Cell Biol, Res Inst, Suita, Osaka , Japan.
    Lagendijk, Anne K.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Australia.
    Barske, Lindsey
    Univ Southern Calif, Eli & Edythe Broad CIRM Ctr Regenerat Med & Stem, Dept Stem Cell Biol & Regenerat Med, Keck Sch Med, Los Angeles, CA USA.
    Crump, J. Gage
    Univ Southern Calif, Eli & Edythe Broad CIRM Ctr Regenerat Med & Stem, Dept Stem Cell Biol & Regenerat Med, Keck Sch Med, Los Angeles, CA USA.
    Stainier, Didier Y. R.
    Max Planck Inst Heart & Lung Res, Dept Dev Genet, Bad Nauheim, Germany.
    Lendahl, Urban
    Karolinska Inst, Dept Cell & Mol Biol, Biomedicum, Stockholm, Sweden; Karolinska Inst, Dept Med, ICMC, Huddinge, Sweden.
    Koltowska, Katarzyna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Australia.
    Hogan, Benjamin M.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Australia.
    Fukuhara, Shigetomo
    Natl Cerebral & Cardiovasc Ctr, Dept Cell Biol, Res Inst, Suita, Osaka, Japan; Nippon Med Sch, Inst Adv Med Sci, Dept Mol Pathophysiol, Musashi Kosugi Hosp, Kawasaki, Kanagawa, Japan.
    Mochizuki, Naoki
    Natl Cerebral & Cardiovasc Ctr, Dept Cell Biol, Res Inst, Suita, Osaka, Japan; Natl Cerebral & Cardiovasc Ctr, AMED CREST, Dept Cell Biol, Suita, Osaka, Japan.
    Betsholtz, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Karolinska Inst, Dept Med, ICMC, Huddinge, Sweden.
    Peri-arterial specification of vascular mural cells from naive mesenchyme requires Notch signaling2019Inngår i: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 146, nr 2, artikkel-id UNSP dev165589Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mural cells (MCs) are essential for blood vessel stability and function; however, the mechanisms that regulate MC development remain incompletely understood, in particular those involved in MC specification. Here, we investigated the first steps of MC formation in zebrafish using transgenic reporters. Using pdgfrb and abcc9 reporters, we show that the onset of expression of abcc9, a pericyte marker in adult mice and zebrafish, occurs almost coincidentally with an increment in pdgfrb expression in peri-arterial mesenchymal cells, suggesting that these transcriptional changes mark the specification of MC lineage cells from naive pdgfrb(low) mesenchymal cells. The emergence of peri-arterial pdgfrb(high) MCs required Notch signaling. We found that pdgfrb-positive cells express notch2 in addition to notch3, and although depletion of notch2 or notch3 failed to block MC emergence, embryos depleted of both notch2 and notch3 lost mesoderm- as well as neural crest-derived pdgfrb(high) MCs. Using reporters that read out Notch signaling and Notch2 receptor cleavage, we show that Notch activation in the mesenchyme precedes specification into pdgfrb(high) MCs. Taken together, these results show that Notch signaling is necessary for peri-arterial MC specification.

  • 4.
    Andrae, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Betsholtz, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Gouveia, Maria Leonor Seguardo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    PDGFR alpha signaling is required for alveolar development in the mouse lung2017Inngår i: Mechanisms of Development, ISSN 0925-4773, E-ISSN 1872-6356, Vol. 145, s. S147-S147Artikkel i tidsskrift (Annet vitenskapelig)
  • 5.
    Andrae, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Gouveia, Leonor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Gallini, Radiosa
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    He, Liqun
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Fredriksson, Linda
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Nilsson, Ingrid
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Johansson, Bengt R.
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Electron Microscopy Unit, S-40530 Gothenburg, Sweden..
    Eriksson, Ulf
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Betsholtz, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    A role for PDGF-C/PDGFR alpha signaling in the formation of the meningeal basement membranes surrounding the cerebral cortex2016Inngår i: BIOLOGY OPEN, ISSN 2046-6390, Vol. 5, nr 4, s. 461-474Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Platelet-derived growth factor-C (PDGF-C) is one of three known ligands for the tyrosine kinase receptor PDGFR alpha. Analysis of Pdgfc null mice has demonstrated roles for PDGF-C in palate closure and the formation of cerebral ventricles, but redundancy with other PDGFR alpha ligands might obscure additional functions. In search of further developmental roles for PDGF-C, we generated mice that were double mutants for Pdgfc(-/-) and Pdgfra(GFP/+). These mice display a range of severe phenotypes including spina bifida, lung emphysema, abnormal meninges and neuronal over-migration in the cerebral cortex. We focused our analysis on the central nervous system (CNS), where PDGF-C was identified as a critical factor for the formation of meninges and assembly of the glia limitans basement membrane. We also present expression data on Pdgfa, Pdgfc and Pdgfra in the cerebral cortex and microarray data on cerebral meninges.

  • 6.
    Angiolini, Francesca
    et al.
    IRCCS, European Inst Oncol, Program Gynecol Oncol, IEO,Unit Gynecol Oncol Res, Milan, Italy;GSK Vaccines Srl, Siena, Italy.
    Belloni, Elisa
    CNR, Ist Genet Mol, Pavia, Italy.
    Giordano, Marco
    IRCCS, European Inst Oncol, Program Gynecol Oncol, IEO,Unit Gynecol Oncol Res, Milan, Italy.
    Campioni, Matteo
    Univ Pavia, Dept Biol & Biotechnol, Armenise Harvard Lab Struct Biol, Pavia, Italy.
    Forneris, Federico
    Univ Pavia, Dept Biol & Biotechnol, Armenise Harvard Lab Struct Biol, Pavia, Italy.
    Paola, Paronetto Maria
    Univ Roma Foro Italico, Dept Movement Human & Hlth Sci, Rome, Italy.
    Lupia, Michela
    IRCCS, European Inst Oncol, Program Gynecol Oncol, IEO,Unit Gynecol Oncol Res, Milan, Italy.
    Brandas, Chiara
    CNR, Ist Genet Mol, Pavia, Italy.
    Pradella, Davide
    CNR, Ist Genet Mol, Pavia, Italy;Univ Pavia, Pavia, Italy.
    Di Matteo, Anna
    CNR, Ist Genet Mol, Pavia, Italy.
    Giampietro, Costanza
    FIRC Inst Mol Oncol, Milan, Italy;Swiss Fed Inst Technol, Dept Mech & Proc Engn, Lab Thermodynam Emerging Technol, Zurich, Switzerland.
    Jodice, Giovanna
    IRCCS, Mol Med Program, IEO, European Inst Oncol, Milan, Italy.
    Luise, Chiara
    IRCCS, Mol Med Program, IEO, European Inst Oncol, Milan, Italy.
    Bertalot, Giovanni
    IRCCS, Mol Med Program, IEO, European Inst Oncol, Milan, Italy.
    Freddi, Stefano
    IRCCS, Mol Med Program, IEO, European Inst Oncol, Milan, Italy.
    Malinverno, Matteo
    FIRC Inst Mol Oncol, Milan, Italy.
    Irimia, Manuel
    Barcelona Inst Sci & Technol, Ctr Genom Regulat, Barcelona, Spain;Univ Pompeu Fabra, Barcelona, Spain;Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain.
    Moulton, Jon D.
    Gene Tools LLC, Philomath, OR USA.
    Summerton, James
    Gene Tools LLC, Philomath, OR USA.
    Chiapparino, Antonella
    Univ Pavia, Dept Biol & Biotechnol, Armenise Harvard Lab Struct Biol, Pavia, Italy.
    Ghilardi, Carmen
    IRCCS, Ist Ric Farmacol Mario Negri, Lab Biol & Treatment Metastasis, Milan, Italy.
    Giavazzi, Raffaella
    IRCCS, Ist Ric Farmacol Mario Negri, Lab Biol & Treatment Metastasis, Milan, Italy.
    Nyqvist, Daniel
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden.
    Gabellini, Davide
    IRCCS, San Raffaele Sci Inst, Div Genet & Cell Biol, Milan, Italy.
    Dejana, Elisabetta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. FIRC Inst Mol Oncol, Milan, Italy.
    Cavallaro, Ugo
    IRCCS, European Inst Oncol, Program Gynecol Oncol, IEO,Unit Gynecol Oncol Res, Milan, Italy.
    Ghigna, Claudia
    CNR, Ist Genet Mol, Pavia, Italy.
    A novel L1CAM isoform with angiogenic activity generated by NOVA2-mediated alternative splicing2019Inngår i: eLIFE, E-ISSN 2050-084X, Vol. 8, artikkel-id e44305Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The biological players involved in angiogenesis are only partially defined. Here, we report that endothelial cells (ECs) express a novel isoform of the cell-surface adhesion molecule L1CAM, termed L1-ΔTM. The splicing factor NOVA2, which binds directly to L1CAM pre-mRNA, is necessary and sufficient for the skipping of L1CAM transmembrane domain in ECs, leading to the release of soluble L1-ΔTM. The latter exerts high angiogenic function through both autocrine and paracrine activities. Mechanistically, L1-ΔTM-induced angiogenesis requires fibroblast growth factor receptor-1 signaling, implying a crosstalk between the two molecules. NOVA2 and L1-ΔTM are overexpressed in the vasculature of ovarian cancer, where L1-ΔTM levels correlate with tumor vascularization, supporting the involvement of NOVA2-mediated L1-ΔTM production in tumor angiogenesis. Finally, high NOVA2 expression is associated with poor outcome in ovarian cancer patients. Our results point to L1-ΔTM as a novel, EC-derived angiogenic factor which may represent a target for innovative antiangiogenic therapies.

  • 7.
    Arce, Maximiliano
    et al.
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Adv Ctr Chron Dis ACCDiS, Santiago, Chile.
    Pinto, Mauricio P.
    Pontificia Univ Catolica Chile, Fac Med, Santiago 8331150, Chile.
    Galleguillos, Macarena
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Munoz, Catalina
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Lange, Soledad
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Ramirez, Carolina
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Erices, Rafaela
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Univ Mayor, Vicerrectoria Invest, Santiago 7510041, Chile.
    Gonzalez, Pamela
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Velasquez, Ethel
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Comis Chilena Energia Nucl CCHEN, Santiago, Chile.
    Tempio, Fabian
    Univ Chile, Fac Med, Inst Biomed Sci, Santiago 8380453, Chile.
    Lopez, Mercedes N.
    Univ Chile, Fac Med, Inst Biomed Sci, Santiago 8380453, Chile;Millennium Inst Immunol & Immunotherapy, Santiago 8331150, Chile.
    Salazar-Onfray, Flavio
    Univ Chile, Fac Med, Inst Biomed Sci, Santiago 8380453, Chile;Millennium Inst Immunol & Immunotherapy, Santiago 8331150, Chile.
    Cautivo, Kelly
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Kalergis, Alexis M.
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Millennium Inst Immunol & Immunotherapy, Santiago 8331150, Chile;Biomed Res Consortium Chile, Santiago 8331010, Chile.
    Cruz, Sebastian
    Fdn Ciencia & Vida, Lab Immunoncol, Santiago, Chile.
    Lladser, Alvaro
    Millennium Inst Immunol & Immunotherapy, Santiago 8331150, Chile;Fdn Ciencia & Vida, Lab Immunoncol, Santiago, Chile.
    Lobos-Gonzalez, Lorena
    Adv Ctr Chron Dis ACCDiS, Santiago, Chile;Fdn Ciencia & Vida, Lab Immunoncol, Santiago, Chile;Univ Desarrollo, Fac Med, Regenerat Med Ctr, Clin Alemana, Santiago 7650568, Chile.
    Valenzuela, Guillermo
    Pontificia Univ Catolica Chile, Fac Med, Santiago 8331150, Chile.
    Olivares, Nixa
    Pontificia Univ Catolica Chile, Fac Med, Santiago 8331150, Chile.
    Saez, Claudia
    Pontificia Univ Catolica Chile, Fac Med, Santiago 8331150, Chile.
    Koning, Tania
    Univ Austral Chile, Fac Med, Immunol Inst, Valdivia 5110566, Chile.
    Sanchez, Fabiola A.
    Univ Austral Chile, Fac Med, Immunol Inst, Valdivia 5110566, Chile.
    Fuenzalida, Patricia
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile.
    Godoy, Alejandro
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Roswell Pk Comprehens Canc Ctr, Dept Urol, Buffalo, NY 14203 USA.
    Contreras Orellana, Pamela
    Adv Ctr Chron Dis ACCDiS, Santiago, Chile;Univ Chile, Fac Med, Lab Cellular Commun, ICBM, Santiago 8380453, Chile.
    Leyton, Lisette
    Adv Ctr Chron Dis ACCDiS, Santiago, Chile;Univ Chile, Fac Med, Lab Cellular Commun, ICBM, Santiago 8380453, Chile.
    Lugano, Roberta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Dimberg, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Quest, Andrew F. G.
    Adv Ctr Chron Dis ACCDiS, Santiago, Chile;Univ Chile, Fac Med, Lab Cellular Commun, ICBM, Santiago 8380453, Chile.
    Owen, Gareth, I
    Pontificia Univ Catolica Chile, Fac Biol Sci, Santiago 8331150, Chile;Adv Ctr Chron Dis ACCDiS, Santiago, Chile;Pontificia Univ Catolica Chile, Fac Med, Santiago 8331150, Chile;Millennium Inst Immunol & Immunotherapy, Santiago 8331150, Chile.
    Coagulation Factor Xa Promotes Solid Tumor Growth, Experimental Metastasis and Endothelial Cell Activation2019Inngår i: Cancers, ISSN 2072-6694, Vol. 11, nr 8, artikkel-id 1103Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hypercoagulable state is linked to cancer progression; however, the precise role of the coagulation cascade is poorly described. Herein, we examined the contribution of a hypercoagulative state through the administration of intravenous Coagulation Factor Xa (FXa), on the growth of solid human tumors and the experimental metastasis of the B16F10 melanoma in mouse models. FXa increased solid tumor volume and lung, liver, kidney and lymph node metastasis of tail-vein injected B16F10 cells. Concentrating on the metastasis model, upon coadministration of the anticoagulant Dalteparin, lung metastasis was significantly reduced, and no metastasis was observed in other organs. FXa did not directly alter proliferation, migration or invasion of cancer cells in vitro. Alternatively, FXa upon endothelial cells promoted cytoskeleton contraction, disrupted membrane VE-Cadherin pattern, heightened endothelial-hyperpermeability, increased inflammatory adhesion molecules and enhanced B16F10 adhesion under flow conditions. Microarray analysis of endothelial cells treated with FXa demonstrated elevated expression of inflammatory transcripts. Accordingly, FXa treatment increased immune cell infiltration in mouse lungs, an effect reduced by dalteparin. Taken together, our results suggest that FXa increases B16F10 metastasis via endothelial cell activation and enhanced cancer cell-endothelium adhesion advocating that the coagulation system is not merely a bystander in the process of cancer metastasis.

  • 8.
    Aspelund, Aleksanteri
    et al.
    Univ Helsinki, Wihuri Res Inst, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland.;Univ Helsinki, Translat Canc Biol Program, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland..
    Robciuc, Marius R.
    Univ Helsinki, Wihuri Res Inst, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland.;Univ Helsinki, Translat Canc Biol Program, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland..
    Karaman, Sinem
    Univ Helsinki, Wihuri Res Inst, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland..
    Mäkinen, Taija
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Alitalo, Kari
    Univ Helsinki, Wihuri Res Inst, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland.;Univ Helsinki, Translat Canc Biol Program, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland..
    Lymphatic System in Cardiovascular Medicine2016Inngår i: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 118, nr 3, s. 515-530Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The mammalian circulatory system comprises both the cardiovascular system and the lymphatic system. In contrast to the blood vascular circulation, the lymphatic system forms a unidirectional transit pathway from the extracellular space to the venous system. It actively regulates tissue fluid homeostasis, absorption of gastrointestinal lipids, and trafficking of antigen-presenting cells and lymphocytes to lymphoid organs and on to the systemic circulation. The cardinal manifestation of lymphatic malfunction is lymphedema. Recent research has implicated the lymphatic system in the pathogenesis of cardiovascular diseases including obesity and metabolic disease, dyslipidemia, inflammation, atherosclerosis, hypertension, and myocardial infarction. Here, we review the most recent advances in the field of lymphatic vascular biology, with a focus on cardiovascular disease.

  • 9. Aspelund, Aleksanteri
    et al.
    Tammela, Tuomas
    Antila, Salli
    Nurmi, Harri
    Leppanen, Veli-Matti
    Zarkada, Georgia
    Stanczuk, Lukas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Francois, Mathias
    Mäkinen, Taija
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Saharinen, Pipsa
    Immonen, Ilkka
    Alitalo, Kari
    Therapeutic Insights to Lymphangiogenic Growth Factors2015Inngår i: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 52, nr S1, s. 19-19Artikkel i tidsskrift (Annet vitenskapelig)
  • 10.
    Aspenström, Pontus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Activated Rho GTPases in Cancer-The Beginning of a New Paradigm2018Inngår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 19, nr 12, artikkel-id 3949Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Involvement of Rho GTPases in cancer has been a matter of debate since the identification of the first members of this branch of the Ras superfamily of small GTPases. The Rho GTPases were ascribed important roles in the cell, although these were restricted to regulation of cytoskeletal dynamics, cell morphogenesis, and cell locomotion, with initially no clear indications of direct involvement in cancer progression. This paradigm has been challenged by numerous observations that Rho-regulated pathways are often dysregulated in cancers. More recently, identification of point mutants in the Rho GTPases Rac1, RhoA, and Cdc42 in human tumors has finally given rise to a new paradigm, and we can now state with confidence that Rho GTPases serve as oncogenes in several human cancers. This article provides an expose of current knowledge of the roles of activated Rho GTPases in cancers.

  • 11.
    Aspenström, Pontus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    The Intrinsic GDP/GTP Exchange Activities of Cdc42 and Rac1 Are A Critical Determinants for Their Specific Effects on Mobilization of the Actin Filament System2019Inngår i: CELLS, ISSN 2073-4409, Vol. 8, nr 7, artikkel-id 759Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Rho GTPases comprise a subfamily of the Ras superfamily of small GTPases. Their importance in regulation of cell morphology and cell migration is well characterized. According to the prevailing paradigm, Cdc42 regulates the formation of filopodia, Rac1 regulates the formation of lamellipodia, and RhoA triggers the assembly of focal adhesions. However, this scheme is clearly an oversimplification, as the Rho subfamily encompasses 20 members with diverse effects on a number of vital cellular processes, including cytoskeletal dynamics and cell proliferation, migration, and invasion. This article highlights the importance of the catalytic activities of the classical Rho GTPases Cdc42 and Rac1, in terms of their specific effects on the dynamic reorganization of the actin filament system. GTPase-deficient mutants of Cdc42 and Rac1 trigger the formation of broad lamellipodia and stress fibers, and fast-cycling mutations trigger filopodia formation and stress fiber dissolution. The filopodia response requires the involvement of the formin family of actin nucleation promotors. In contrast, the formation of broad lamellipodia induced by GTPase-deficient Cdc42 and Rac1 is mediated through Arp2/3-dependent actin nucleation.

  • 12.
    Baek, Sungmin
    et al.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia.
    Oh, Tae Gyu
    Univ Queensland, Inst Mol Biosci, Div Cell Biol & Mol Med, Brisbane, Qld 4073, Australia.
    Secker, Genevieve
    Univ South Australia, Ctr Canc Biol, Adelaide, SA, Australia;SA Pathol, Adelaide, SA 5000, Australia.
    Sutton, Drew L.
    Univ South Australia, Ctr Canc Biol, Adelaide, SA, Australia;SA Pathol, Adelaide, SA 5000, Australia.
    Okuda, Kazuhide S.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia.
    Paterson, Scott
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia.
    Bower, Neil I.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia.
    Toubia, John
    Univ South Australia, Ctr Canc Biol, Adelaide, SA, Australia;SA Pathol, Adelaide, SA 5000, Australia;Univ South Australia, Ctr Canc Biol, Fdn Canc Genom Facil, Australian Canc Res, Frome Rd, Adelaide, SA 5000, Australia.
    Koltowska, Katarzyna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia.
    Capon, Samuel J.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia.
    Baillie, Gregory J.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia.
    Simons, Cas
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia;Murdoch Childrens Res Inst, Parkville, Vic, Australia.
    Muscat, George E. O.
    Univ Queensland, Inst Mol Biosci, Div Cell Biol & Mol Med, Brisbane, Qld 4073, Australia.
    Lagendijk, Anne K.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia.
    Smith, Kelly A.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia.
    Harvey, Natasha L.
    Univ South Australia, Ctr Canc Biol, Adelaide, SA, Australia;SA Pathol, Adelaide, SA 5000, Australia.
    Hogan, Benjamin M.
    Univ Queensland, Inst Mol Biosci, Div Genom Dev & Dis, Brisbane, Qld 4073, Australia.
    The Alternative Splicing Regulator Nova2 Constrains Vascular Erk Signaling to Limit Specification of the Lymphatic Lineage2019Inngår i: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 49, nr 2, s. 279-292Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The correct assignment of cell fate within fields of multipotent progenitors is essential for accurate tissue diversification. The first lymphatic vessels arise from pre-existing veins after venous endothelial cells become specified as lymphatic progenitors. Prox1 specifies lymphatic fate and labels these progenitors; however, the mechanisms restricting Prox1 expression and limiting the progenitor pool remain unknown. We identified a zebrafish mutant that displayed premature, expanded, and prolonged lymphatic specification. The gene responsible encodes the regulator of alternative splicing, Nova2. In zebrafish and human endothelial cells, Nova2 selectively regulates pre-mRNA splicing for components of signaling pathways and phosphoproteins. Nova2-deficient endothelial cells display increased Mapk/Erk signaling, and Prox1 expression is dynamically controlled by Erk signaling. We identify a mechanism whereby Nova2-regulated splicing constrains Erk signaling, thus limiting lymphatic progenitor cell specification. This identifies the capacity of a factor that tunes mRNA splicing to control assignment of cell fate during vascular differentiation.

  • 13.
    Barbera, Stefano
    et al.
    Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy.
    Nardi, Federica
    Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy.
    Elia, Ines
    Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy.
    Realini, Giulia
    Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy.
    Lugano, Roberta
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Santucci, Annalisa
    Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy.
    Tosi, Gian Marco
    Univ Siena, Dept Med Surg & Neurosci, Ophthalmol Unit, Policlin Le Scotte, Viale Bracci, I-53100 Siena, Italy.
    Dimberg, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Galvagni, Federico
    Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy.
    Orlandini, Maurizio
    Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy.
    The small GTPase Rab5c is a key regulator of trafficking of the CD93/Multimerin-2/1 integrin complex in endothelial cell adhesion and migration2019Inngår i: Cell Communication and Signaling, ISSN 1478-811X, E-ISSN 1478-811X, Vol. 17, artikkel-id 55Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    In the endothelium, the single-pass membrane protein CD93, through its interaction with the extracellular matrix protein Multimerin-2, activates signaling pathways that are critical for vascular development and angiogenesis. Trafficking of adhesion molecules through endosomal compartments modulates their signaling output. However, the mechanistic basis coordinating CD93 recycling and its implications for endothelial cell (EC) function remain elusive.

    Methods

    Human umbilical vein ECs (HUVECs) and human dermal blood ECs (HDBEC) were used in this study. Fluorescence confocal microscopy was employed to follow CD93 retrieval, recycling, and protein colocalization in spreading cells. To better define CD93 trafficking, drug treatments and transfected chimeric wild type and mutant CD93 proteins were used. The scratch assay was used to evaluate cell migration. Gene silencing strategies, flow citometry, and quantification of migratory capability were used to determine the role of Rab5c during CD93 recycling to the cell surface.

    Results

    Here, we identify the recycling pathway of CD93 following EC adhesion and migration. We show that the cytoplasmic domain of CD93, by its interaction with Moesin and F-actin, is instrumental for CD93 retrieval in adhering and migrating cells and that aberrant endosomal trafficking of CD93 prevents its localization at the leading edge of migration. Moreover, the small GTPase Rab5c turns out to be a key component of the molecular machinery that is able to drive CD93 recycling to the EC surface. Finally, in the Rab5c endosomal compartment CD93 forms a complex with Multimerin-2 and active 1 integrin, which is recycled back to the basolaterally-polarized cell surface by clathrin-independent endocytosis.

    Conclusions

    Our findings, focusing on the pro-angiogenic receptor CD93, unveil the mechanisms of its polarized trafficking during EC adhesion and migration, opening novel therapeutic opportunities for angiogenic diseases.

  • 14.
    Bartlett, Christina S.
    et al.
    Northwestern Univ, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USA.;Northwestern Univ, Div Nephrol & Hypertens, Chicago, IL 60611 USA..
    Jeansson, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Quaggin, Susan E.
    Northwestern Univ, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USA.;Northwestern Univ, Div Nephrol & Hypertens, Chicago, IL 60611 USA..
    Vascular Growth Factors and Glomerular Disease2016Inngår i: ANNUAL REVIEW OF PHYSIOLOGY, VOL 78, ANNUAL REVIEWS, 2016, s. 437-461Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    The glomerulus is a highly specialized microvascular bed that filters blood to form primary urinary filtrate. It contains four cell types: fenestrated endothelial cells, specialized vascular support cells termed podocytes, perivascular mesangial cells, and parietal epithelial cells. Glomerular cell-cell communication is critical for the development and maintenance of the glomerular filtration barrier. VEGF, ANGPT, EGF, SEMA3A, TGF-beta, and CXCL12 signal in paracrine fashions between the podocytes, endothelium, and mesangium associated with the glomerular capillary bed to maintain filtration barrier function. In this review, we summarize the current understanding of these signaling pathways in the development and maintenance of the glomerulus and the progression of disease.

  • 15.
    Bentley, Katie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Harvard Med Sch, Beth Israel Deaconess Med Ctr, Computat Biol Lab, Boston, MA USA..
    Chakravartula, Shilpa
    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Computat Biol Lab, Boston, MA USA..
    The temporal basis of angiogenesis2017Inngår i: Philosophical Transactions of the Royal Society of London. Biological Sciences, ISSN 0962-8436, E-ISSN 1471-2970, Vol. 372, nr 1720, s. 1-11, artikkel-id 20150522Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The process of new blood vessel growth (angiogenesis) is highly dynamic, involving complex coordination of multiple cell types. Though the process must carefully unfold over time to generate functional, well-adapted branching networks, we seldom hear about the time-based properties of angiogenesis, despite timing being central to other areas of biology. Here, we present a novel, time-based formulation of endothelial cell behaviour during angiogenesis and discuss a flurry of our recent, integrated in silico/in vivo studies, put in context to the wider literature, which demonstrate that tissue conditions can locally adapt the timing of collective cell behaviours/decisions to grow different vascular network architectures. A growing array of seemingly unrelated 'temporal regulators' have recently been uncovered, including tissue derived factors (e.g. semaphorins or the high levels of VEGF found in cancer) and cellular processes (e.g. asymmetric cell division or filopodia extension) that act to alter the speed of cellular decisions to migrate. We will argue that 'temporal adaptation' provides a novel account of organ/disease-specific vascular morphology and reveals 'timing' as a new target for therapeutics. We therefore propose and explain a conceptual shift towards a 'temporal adaptation' perspective in vascular biology, and indeed other areas of biology where timing remains elusive. This article is part of the themed issue 'Systems morphodynamics: understanding the development of tissue hardware'.

  • 16.
    Betsholtz, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Karolinska Inst, AZ ICMC, Huddinge, Sweden.
    Cell-cell signaling in blood vessel development and function2018Inngår i: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, Vol. 10, nr 3, artikkel-id UNSP e8610Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    The blood vasculature is an organ pervading all other organs (almost). During vascular development, cell-cell signaling by extracellular ligands and cell surface receptors ensure that new vessels sprout into non-vascularized regions and simultaneously acquire organ-specific specializations and adaptations that match the local physiological needs. The vessels thereby specialize in their permeability, molecular transport between blood and tissue, and ability to regulate blood flow on demand. Over the past decades, we have learnt about the generic cell-cell signaling mechanisms governing angiogenic sprouting, mural cell recruitment, and vascular remodeling, and we have obtained the first insights into signals that induce and maintain vascular organotypicity. However, intra-organ vascular diversity and arterio-venous hierarchies complicate the molecular characterization of the vasculature's cellular building blocks. Single-cell RNA sequencing provides a way forward, as it allows elucidation at a genome-wide and quantitative level of the transcriptional diversity occurring within the same cell types at different anatomical positions and levels of arterio-venous hierarchy in the organs. In this Louis-Jeantet Prize Winner: Commentary, I give a brief overview of vascular development and how recent advances in the field pave the way for more systematic efforts to explore vascular functions in health and disease.

  • 17.
    Betsholtz, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Lipid transport and human brain development2015Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, nr 7, s. 699-701Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    How the human brain rapidly builds up its lipid content during brain growth and maintains its lipids in adulthood has remained elusive. Two new studies show that inactivating mutations in MFSD2A, known to be expressed specifically at the blood-brain barrier, lead to microcephaly, thereby offering a simple and surprising solution to an old enigma.

  • 18.
    Betsholtz, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Transcriptional control of endothelial energy2016Inngår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 529, nr 7585, s. 160-161Artikkel i tidsskrift (Annet vitenskapelig)
  • 19. Bianchi, Roberta
    et al.
    Teijeira, Alvaro
    Proulx, Steven T.
    Christiansen, Ailsa J.
    Seidel, Catharina D.
    Ruelicke, Thomas
    Mäkinen, Taija
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Haegerling, Rene
    Halin, Cornelia
    Detmar, Michael
    A Transgenic Prox1-Cre-tdTomato Reporter Mouse for Lymphatic Vessel Research2015Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 4, artikkel-id e0122976Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The lymphatic vascular system plays an active role in immune cell trafficking, inflammation and cancer spread. In order to provide an in vivo tool to improve our understanding of lymphatic vessel function in physiological and pathological conditions, we generated and characterized a tdTomato reporter mouse and crossed it with a mouse line expressing Cre recombinase under the control of the lymphatic specific promoter Prox1 in an inducible fashion. We found that the tdTomato fluorescent signal recapitulates the expression pattern of Prox1 in lymphatic vessels and other known Prox1-expressing organs. Importantly, tdTomato co-localized with the lymphatic markers Prox1, LYVE-1 and podoplanin as assessed by whole-mount immunofluorescence and FACS analysis. The tdTomato reporter was brighter than a previously established red fluorescent reporter line. We confirmed the applicability of this animal model to intravital microscopy of dendritic cell migration into and within lymphatic vessels, and to fluorescence-activated single cell analysis of lymphatic endothelial cells. Additionally, we were able to describe the early morphological changes of the lymphatic vasculature upon induction of skin inflammation. The Prox1-Cre-tdTomato reporter mouse thus shows great potential for lymphatic research.

  • 20.
    Bovay, Esther
    et al.
    CHU Vaudois, Dept Oncol, Epalinges, Switzerland;Univ Lausanne, Epalinges, Switzerland.
    Sabine, Amelie
    CHU Vaudois, Dept Oncol, Epalinges, Switzerland;Univ Lausanne, Epalinges, Switzerland.
    Prat-Luri, Borja
    CHU Vaudois, Dept Oncol, Epalinges, Switzerland;Univ Lausanne, Epalinges, Switzerland.
    Kim, Sudong
    Seoul Natl Univ, Sch Mech & Aerosp Engn, Seoul, South Korea.
    Son, Kyungmin
    Seoul Natl Univ, Sch Mech & Aerosp Engn, Seoul, South Korea.
    Willrodt, Ann-Helen
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland.
    Olsson, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Halin, Cornelia
    Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland.
    Kiefer, Friedemann
    Max Planck Inst Mol Biomed, Munster, Germany;Univ Munster, European Inst Mol Imaging, Munster, Germany.
    Betsholtz, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Karolinska Inst, Integrated Cardio Metab Ctr, Dept Med Huddinge, Stockholm, Sweden.
    Li Jeon, Noo
    Seoul Natl Univ, Sch Mech & Aerosp Engn, Seoul, South Korea.
    Luther, Sanjiv A.
    Univ Lausanne, Dept Biochem, Epalinges, Switzerland.
    Petrova, Tatiana, V
    CHU Vaudois, Dept Oncol, Epalinges, Switzerland;Univ Lausanne, Epalinges, Switzerland;Ludwig Inst Canc Res, Epalinges, Switzerland;Ecole Polytech Fed Lausanne, Swiss Inst Expt Canc Res, Lausanne, Switzerland;CHU Vaudois, Div Expt Pathol, Lausanne, Switzerland.
    Multiple roles of lymphatic vessels in peripheral lymph node development2018Inngår i: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 215, nr 11, s. 2760-2777Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mammalian lymphatic system consists of strategically located lymph nodes (LNs) embedded into a lymphatic vascular network. Mechanisms underlying development of this highly organized system are not fully understood. Using highresolution imaging, we show that lymphoid tissue inducer (LTi) cells initially transmigrate from veins at LN development sites using gaps in venous mural coverage. This process is independent of lymphatic vasculature, but lymphatic vessels are indispensable for the transport of LTi cells that egress from blood capillaries elsewhere and serve as an essential LN expansion reservoir. At later stages, lymphatic collecting vessels ensure efficient LTi cell transport and formation of the LN capsule and subcapsular sinus. Perinodal lymphatics also promote local interstitial flow, which cooperates with lymphotoxin-beta signaling to amplify stromal CXCL13 production and thereby promote LTi cell retention. Our data unify previous models of LN development by showing that lymphatics intervene at multiple points to assist LN expansion and identify a new role for mechanical forces in LN development.

  • 21. Bravi, Luca
    et al.
    Rudini, Noemi
    Cuttano, Roberto
    Giampietro, Costanza
    Maddaluno, Luigi
    Ferrarini, Luca
    Adams, Ralf H.
    Corada, Monica
    Boulday, Gwenola
    Tournier-Lasserve, Elizabeth
    Dejana, Elisabetta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Lampugnani, Maria Grazia
    Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice2015Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 27, s. 8421-8426Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences. At present, the only recommended treatment of CCM is surgical. Because surgery is often not applicable, pharmacological treatment would be highly desirable. We describe here a murine model of the disease that develops after endothelial-cell-selective ablation of the CCM3 gene. We report an early, cell-autonomous, Wnt-receptor-independent stimulation of beta-catenin transcription activity in CCM3-deficient endothelial cells both in vitro and in vivo and a triggering of a beta-catenin-driven transcription program that leads to endothelial-tomesenchymal transition. TGF-beta/BMP signaling is then required for the progression of the disease. We also found that the anti-inflammatory drugs sulindac sulfide and sulindac sulfone, which attenuate beta-catenin transcription activity, reduce vascular malformations in endothelial CCM3-deficient mice. This study opens previously unidentified perspectives for an effective pharmacological therapy of intracranial vascular cavernomas.

  • 22.
    Caolo, V.
    et al.
    Katholieke Univ Leuven, Cardiovasc Sci, Leuven, Belgium..
    Peacock, H. M.
    Katholieke Univ Leuven, Cardiovasc Sci, Leuven, Belgium..
    Kasaai, B.
    Katholieke Univ Leuven, Cardiovasc Sci, Leuven, Belgium..
    Swennen, G.
    Maastricht Univ, CARIM, Maastricht, Netherlands..
    Gordon, Emma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Claesson-Welsh, Lena
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Verhamme, P.
    Katholieke Univ Leuven, Cardiovasc Sci, Leuven, Belgium..
    Jones, E. A. V.
    Katholieke Univ Leuven, Cardiovasc Sci, Leuven, Belgium..
    Shear stress, notch and VE-cadherin: the molecular mechanism of vascular fusion2018Inngår i: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 114, s. S13-S13Artikkel i tidsskrift (Annet vitenskapelig)
  • 23.
    Caolo, Vincenza
    et al.
    Katholieke Univ Leuven, Ctr Mol & Vasc Biol, Dept Cardiovasc Sci, Leuven, Belgium.
    Peacock, Hanna M.
    Katholieke Univ Leuven, Ctr Mol & Vasc Biol, Dept Cardiovasc Sci, Leuven, Belgium.
    Kasaai, Bahar
    Katholieke Univ Leuven, Ctr Mol & Vasc Biol, Dept Cardiovasc Sci, Leuven, Belgium.
    Swennen, Geertje
    Maastricht Univ, CARIM, Dept Physiol, Maastricht, Netherlands.
    Gordon, Emma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Claesson-Welsh, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Post, Mark J.
    Maastricht Univ, CARIM, Dept Physiol, Maastricht, Netherlands.
    Verhamme, Peter
    Katholieke Univ Leuven, Ctr Mol & Vasc Biol, Dept Cardiovasc Sci, Leuven, Belgium.
    Jones, Elizabeth A. V.
    Katholieke Univ Leuven, Ctr Mol & Vasc Biol, Dept Cardiovasc Sci, Leuven, Belgium.
    Shear Stress and VE-Cadherin: The Molecular Mechanism of Vascular Fusion2018Inngår i: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 38, nr 9, s. 2174-2183Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Vascular fusion represents an important mechanism of vessel enlargement during development; however, its significance in postnatal vessel enlargement is still unknown. During fusion, 2 adjoining vessels merge to share 1 larger lumen. The aim of this research was to identify the molecular mechanism responsible for vascular fusion.

    Approach and Results: We previously showed that both low shear stress and DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester) treatment in the embryo result in a hyperfused vascular plexus and that increasing shear stress levels could prevent DAPT-induced fusion. We, therefore, investigated vascular endothelial-cadherin (VEC) phosphorylation because this is a common downstream target of low shear stress and DAPT treatment. VEC phosphorylation increases after DAPT treatment and decreased shear stress. The increased phosphorylation occurred independent of the cleavage of the Notch intracellular domain. Increasing shear stress rescues hyperfusion by DAPT treatment by causing the association of the phosphatase vascular endothelial-protein tyrosine phosphatase with VEC, counteracting VEC phosphorylation. Finally, Src (proto-oncogene tyrosine-protein kinase Src) inhibition prevents VEC phosphorylation in endothelial cells and can rescue hyperfusion induced by low shear stress and DAPT treatment. Moesin, a VEC target that was previously reported to mediate endothelial cell rearrangement during lumenization, relocalizes to cell membranes in vascular beds undergoing hyperfusion.

    Conclusions: This study provides the first evidence that VEC phosphorylation, induced by DAPT treatment and low shear stress, is involved in the process of fusion during vascular remodeling.

  • 24.
    Carthy, Jon M.
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning. Imperial Coll London, Fac Med, Div Brain Sci, London, England..
    Stoeter, Martin
    Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
    Bellomo, Claudia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Vanlandewijck, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Heldin, Angelos
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Moren, Anita
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Kardassis, Dimitris
    Univ Crete, Sch Med, Dept Biochem, Iraklion 71003, Crete, Greece..
    Gahman, Timothy C.
    Ludwig Inst Canc Res, Small Mol Discovery Program, La Jolla, CA 92093 USA..
    Shiau, Andrew K.
    Ludwig Inst Canc Res, Small Mol Discovery Program, La Jolla, CA 92093 USA..
    Bickle, Marc
    Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
    Zerial, Marino
    Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
    Heldin, Carl-Henrik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Moustakas, Aristidis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myofibroblast differentiation2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 29868Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Plasticity in epithelial tissues relates to processes of embryonic development, tissue fibrosis and cancer progression. Pharmacological modulation of epithelial transitions during disease progression may thus be clinically useful. Using human keratinocytes and a robotic high-content imaging platform, we screened for chemical compounds that reverse transforming growth factor beta (TGF-beta)-induced epithelial-mesenchymal transition. In addition to TGF-beta receptor kinase inhibitors, we identified small molecule epithelial plasticity modulators including a naturally occurring hydroxysterol agonist of the liver X receptors (LXRs), members of the nuclear receptor transcription factor family. Endogenous and synthetic LXR agonists tested in diverse cell models blocked alpha-smooth muscle actin expression, myofibroblast differentiation and function. Agonist-dependent LXR activity or LXR overexpression in the absence of ligand counteracted TGF-beta-mediated myofibroblast terminal differentiation and collagen contraction. The protective effect of LXR agonists against TGF-beta-induced pro-fibrotic activity raises the possibility that anti-lipidogenic therapy may be relevant in fibrotic disorders and advanced cancer.

  • 25.
    Carvalho, Alexandra T. P.
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Gouveia, Leonor
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Kanna, Charan Raju
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Warmlander, Sebastian K. T. S.
    Platts, Jamie A.
    Kamerlin, Lynn Shina Caroline
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Struktur- och molekylärbiologi.
    Understanding the structural and dynamic consequences of DNA epigenetic modifications: Computational insights into cytosine methylation and hydroxymethylation2014Inngår i: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 9, nr 12, s. 1604-1612Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We report a series of molecular dynamics (MD) simulations of up to a microsecond combined simulation time designed to probe epigenetically modified DNA sequences. More specifically, by monitoring the effects of methylation and hydroxymethylation of cytosine in different DNA sequences, we show, for the first time, that DNA epigenetic modifications change the molecule's dynamical landscape, increasing the propensity of DNA toward different values of twist and/or roll/tilt angles (in relation to the unmodified DNA) at the modification sites. Moreover, both the extent and position of different modifications have significant effects on the amount of structural variation observed. We propose that these conformational differences, which are dependent on the sequence environment, can provide specificity for protein binding.

  • 26.
    Castro, Marco
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Laviña, Bàrbara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Ando, Koji
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Alvarez-Aznar, Alberto
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Abu Taha, Abdallah
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Brakebusch, Cord
    Biotech Research and Innovation Center, University of Copenhagen, Denmark;ICMC (Integrated Cardio Metabolic Centre), Karolinska Institutet/AstraZeneca/Integrated Cardio Metabolic Centre, Huddinge, Stockholm, Sweden.
    Dejana, Elisabetta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. FOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
    Betsholtz, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. AstraZeneca/Karolinska Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet.
    Gängel, Konstantin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    CDC42 deletion elicits cerebral vascular malformations via increased MEKK3-dependent KLF4 expression2019Inngår i: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 124, nr 8, s. 1240-1252Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Rationale: Aberrant formation of blood vessels precedes a broad spectrum of vascular complications; however, the cellular and molecular events governing vascular malformations are not yet fully understood. Objective: Here, we investigated the role of CDC42 (cell division cycle 42) during vascular morphogenesis and its relative importance for the development of cerebrovascular malformations. Methods and Results: To avoid secondary systemic effects often associated with embryonic gene deletion, we generated an endothelial-specific and inducible knockout approach to study postnatal vascularization of the mouse brain. Postnatal endothelial-specific deletion of Cdc42 elicits cerebrovascular malformations reminiscent of cerebral cavernous malformations (CCMs). At the cellular level, loss of CDC42 function in brain endothelial cells (ECs) impairs their sprouting, branching morphogenesis, axial polarity, and normal dispersion within the brain tissue. Disruption of CDC42 does not alter EC proliferation, but malformations occur where EC proliferation is the most pronounced during brain development-the postnatal cerebellum-indicating that a high, naturally occurring EC proliferation provides a permissive state for the appearance of these malformations. Mechanistically, CDC42 depletion in ECs elicited increased MEKK3 (mitogen-activated protein kinase kinase kinase 3)-MEK5 (mitogen-activated protein kinase kinase 5)-ERK5 (extracellular signal-regulated kinase 5) signaling and consequent detrimental overexpression of KLF (Kruppel-like factor) 2 and KLF4, recapitulating the hallmark mechanism for CCM pathogenesis. Through genetic approaches, we demonstrate that the coinactivation of Klf4 reduces the severity of vascular malformations in Cdc42 mutant mice. Moreover, we show that CDC42 interacts with CCMs and that CCM3 promotes CDC42 activity in ECs. Conclusions: We show that endothelial-specific deletion of Cdc42 elicits CCM-like cerebrovascular malformations and that CDC42 is engaged in the CCM signaling network to restrain the MEKK3-MEK5-ERK5-KLF2/4 pathway.

  • 27.
    Cedervall, Jessica
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Dimberg, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Olsson, Anna-Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Tumor-Induced Local and Systemic Impact on Blood Vessel Function2015Inngår i: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, artikkel-id 418290Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Endothelial dysfunction plays a role in several processes that contribute to cancer-associated mortality. The vessel wall serves as a barrier for metastatic tumor cells, and the integrity and activation status of the endothelium serves as an important defense mechanism against metastasis. In addition, leukocytes, such as cytotoxic T-cells, have to travel across the vessel wall to enter the tumor tissue where they contribute to killing of cancer cells. Tumor cells can alter the characteristics of the endothelium by recruitment of leukocytes such as neutrophils andmacrophages, which further stimulate inflammation and promote tumorigenesis. Recent findings also suggest that leukocyte-mediated effects on vascular function are not limited to the primary tumor or tissues that represent metastatic sites. Peripheral organs, such as kidney and heart, also display impaired vascular function in tumor-bearing individuals, potentially contributing to organ failure. Here, we discuss how vascular function is altered in malignant tissue and distant organs in individuals with cancer and how leukocytes function as potent mediators of these tumor-induced effects.

  • 28.
    Cedervall, Jessica
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Dimberg, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Olsson, Anna-Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Tumor-induced neutrophil extracellular traps-drivers of systemic inflammation and vascular dysfunction2016Inngår i: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 5, nr 3, artikkel-id e1098803Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Neutrophil extracellular traps (NETs) are part of the innate immune defense against microbes, but their contribution to several non-infectious inflammatory conditions has recently been unraveled. We demonstrate that NETs accumulate in the peripheral circulation in tumor-bearing mice, causing systemic inflammation and vascular dysfuntion in organs not affected by tumor cells.

  • 29.
    Cedervall, Jessica
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Saupe, Falk
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Zhang, Yanyu
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Ärnlöv, Johan
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Divis Family Med, Huddinge, Sweden.
    Larsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Dimberg, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Olsson, Anna-Karin
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice.2017Inngår i: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 6, nr 8, artikkel-id e1320009Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Renal insufficiency is a frequent cancer-associated problem affecting more than half of all cancer patients at the time of diagnosis. To minimize nephrotoxic effects the dosage of anticancer drugs are reduced in these patients, leading to sub-optimal treatment efficacy. Despite the severity of this cancer-associated pathology, the molecular mechanisms, as well as therapeutic options, are still largely lacking. We here show that formation of intravascular tumor-induced neutrophil extracellular traps (NETs) is a cause of kidney injury in tumor-bearing mice. Analysis of clinical biomarkers for kidney function revealed impaired creatinine clearance and elevated total protein levels in urine from tumor-bearing mice. Electron microscopy analysis of the kidneys from mice with cancer showed reversible pathological signs such as mesangial hypercellularity, while permanent damage such as fibrosis or necrosis was not observed. Removal of NETs by treatment with DNase I, or pharmacological inhibition of the enzyme peptidylarginine deiminase 4 (PAD4), was sufficient to restore renal function in mice with cancer. Tumor-induced systemic inflammation and impaired perfusion of peripheral vessels could be reverted by the PAD4 inhibitor. In conclusion, the current study identifies NETosis as a previously unknown cause of cancer-associated renal dysfunction and describes a novel promising approach to prevent renal failure in individuals with cancer.

  • 30.
    Cedervall, Jessica
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Zhang, Yanyu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Huang, Hua
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Zhang, Lei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Femel, Julia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Dimberg, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Olsson, Anna-Karin
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals2015Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, nr 13, s. 2653-2662Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cancer produces a variety of collateral effects in patients beyond the malignancy itself, including threats to distal organ functions. However, the basis for such effects, associated with either primary or metastatic tumors, are generally poorly understood. In this study, we show how heart and kidney vascular function is impaired by neutrophils that accumulate in those tissues as a result of tumor formation in two different transgenic mouse models of cancer (RIP1-Tag2 model of insulinoma and MMTV-PyMT model of breast cancer). Neutrophil depletion by systemic administration of an anti-Gr1 antibody improved vascular perfusion and prevented vascular leakage in kidney vessels. We also observed the accumulation of platelet-neutrophil complexes, a signature of neutrophil extracellular traps (NET), in the kidneys of tumor-bearing mice that were completely absent from healthy nontumor-bearing littermates. NET accumulation in the vasculature was associated with upregulation of the proinflammatory adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the proinflammatory cytokines IL1 beta, IL6, and the chemokine CXCL1. Administering DNase I to dissolve NETs, which have a high DNA content, restored perfusion in the kidney and heart to levels seen in nontumor-bearing mice, and also prevented vessel leakage in the blood vasculature of these organs. Taken together, our findings strongly suggest that NETs mediate the negative collateral effects of tumors on distal organs, acting to impair vascular function, and to heighten inflammation at these sites.

  • 31.
    Chiang, Ivy Kim-Ni
    et al.
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Fritzsche, Martin
    Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford OX3 7DQ, England..
    Pichol-Thievend, Cathy
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Neal, Alice
    Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford OX3 7DQ, England..
    Holmes, Kelly
    Univ Cambridge, Li Ka Shing Ctr, Canc Res UK, Robinson Way, Cambridge CB2 0RE, England..
    Lagendijk, Anne
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Overman, Jeroen
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    D'Angelo, Donatella
    Univ Milan, Dipartimento Biosci, Via Celoria 26, I-20133 Milan, Italy..
    Omini, Alice
    Univ Milan, Dipartimento Biosci, Via Celoria 26, I-20133 Milan, Italy..
    Hermkens, Dorien
    Univ Munster, D-48149 Munster, Germany.;Westfalische Wilhelms Univ Munster WWU, Inst Cardiovasc Organogenesis & Regenerat, Fac Med, Mendelstr 7, D-48149 Munster, Germany.;CiM Cluster Excellence, Munster, Germany..
    Lesieur, Emmanuelle
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Liu, Ke
    Univ Liverpool, Inst Aging & Chron Dis, Liverpool L69 3GA, Merseyside, England..
    Ratnayaka, Indrika
    Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford OX3 7DQ, England..
    Corada, Monica
    FIRC Inst Mol Oncol, IFOM, I-1620139 Milan, Italy..
    Bou-Gharios, George
    Univ Liverpool, Inst Aging & Chron Dis, Liverpool L69 3GA, Merseyside, England..
    Carroll, Jason
    Univ Cambridge, Li Ka Shing Ctr, Canc Res UK, Robinson Way, Cambridge CB2 0RE, England..
    Dejana, Elisabetta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. FIRC Inst Mol Oncol, IFOM, I-1620139 Milan, Italy.
    Schulte-Merker, Stefan
    Univ Munster, D-48149 Munster, Germany.;Westfalische Wilhelms Univ Munster WWU, Inst Cardiovasc Organogenesis & Regenerat, Fac Med, Mendelstr 7, D-48149 Munster, Germany.;CiM Cluster Excellence, Munster, Germany..
    Hogan, Benjamin
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Beltrame, Monica
    Univ Milan, Dipartimento Biosci, Via Celoria 26, I-20133 Milan, Italy..
    De Val, Sarah
    Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford OX3 7DQ, England..
    Francois, Mathias
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development2017Inngår i: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 144, nr 14, s. 2629-2639Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Arterial specification and differentiation are influenced by a number of regulatory pathways. While it is known that the Vegfa-Notch cascade plays a central role, the transcriptional hierarchy controlling arterial specification has not been fully delineated. To elucidate the direct transcriptional regulators of Notch receptor expression in arterial endothelial cells, we used histone signatures, DNaseI hypersensitivity and ChIP-seq data to identify enhancers for the human NOTCH1 and zebrafish notch1b genes. These enhancerswere able to direct arterial endothelial cell-restricted expression in transgenic models. Genetic disruption of SoxF binding sites established a clear requirement for members of this group of transcription factors (SOX7, SOX17 and SOX18) to drive the activity of these enhancers in vivo. Endogenous deletion of the notch1b enhancer led to a significant loss of arterial connections to the dorsal aorta in Notch pathway-deficient zebrafish. Loss of SoxF function revealed that these factors are necessary for NOTCH1 and notch1b enhancer activity and for correct endogenous transcription of these genes. These findings position SoxF transcription factors directly upstream of Notch receptor expression during the acquisition of arterial identity in vertebrates.

  • 32.
    Cho, Hyunsoo
    et al.
    Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Daejeon, South Korea.
    Kim, Jaeryung
    Inst for Basic Sci Korea, Ctr Vasc Res, Daejeon, South Korea.
    Ahn, Ji Hoon
    Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Daejeon, South Korea.
    Hong, Young-Kwon
    Univ Southern Calif, Keck Sch Med, Dept Surg, Los Angeles, CA 90033 USA;Univ Southern Calif, Keck Sch Med, Dept Biochem & Mol Biol, Los Angeles, CA 90033 USA.
    Mäkinen, Taija
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Lim, Dae-Sik
    Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Daejeon, South Korea.
    Koh, Gou Young
    Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Daejeon, South Korea;Inst for Basic Sci Korea, Ctr Vasc Res, Daejeon, South Korea.
    YAP and TAZ Negatively Regulate Prox1 During Developmental and Pathologic Lymphangiogenesis2019Inngår i: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 124, nr 2, s. 225-242Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Rationale: The Hippo pathway governs cellular differentiation, morphogenesis, and homeostasis, but how it regulates these processes in lymphatic vessels is unknown. Objective: We aimed to reveal the role of the final effectors of the Hippo pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), in lymphatic endothelial cell (LEC) differentiation, morphogenesis, and homeostasis. Methods and Results: During mouse embryonic development, LEC-specific depletion of Yap/Taz disturbed both plexus patterning and valve initiation with upregulated Prox1 (prospero homeobox 1). Conversely, LEC-specific YAP/TAZ hyperactivation impaired lymphatic specification and restricted lymphatic sprouting with profoundly downregulated Prox1. Notably, lymphatic YAP/TAZ depletion or hyperactivation aggravated or attenuated pathological lymphangiogenesis in mouse cornea. Mechanistically, VEGF (vascular endothelial growth factor)-C activated canonical Hippo signaling pathway in LECs. Indeed, repression of PROX1 transcription by YAP/TAZ hyperactivation was mediated by recruitment of NuRD (nucleosome remodeling and histone deacetylase) complex and endogenous binding activity of TEAD (TEA domain family members) to the PROX1 promoter. Furthermore, YAP/TAZ hyperactivation enhanced MYC signaling and inhibited CDKN1C, leading to cell cycle dysregulation and aberrant proliferation. Conclusions: We find that YAP and TAZ play promoting roles in remodeling lymphatic plexus patterning and postnatal lymphatic valve maintenance by negatively regulating Prox1 expression. We further show that YAP and TAZ act as plastic regulators of lymphatic identity and define the Hippo signaling-mediated PROX1 transcriptional programing as a novel dynamic checkpoint underlying LEC plasticity and pathophysiology.

  • 33.
    Chohan, Muhammad O.
    et al.
    Univ New Mexico, Ctr Comprehens Canc, Albuquerque, NM 87131 USA;Univ New Mexico, Sch Med, Dept Neurosurg, Albuquerque, NM 87131 USA.
    Marchio, Serena
    Univ New Mexico, Ctr Comprehens Canc, Albuquerque, NM 87131 USA;Univ New Mexico, Sch Med, Dept Neurosurg, Albuquerque, NM 87131 USA;Univ Torino, Dept Oncol, Sch Med, Turin, Italy;Ist Ricovero Cura & Carattere Sci, Fdn Piemonte Oncol, Candiolo Canc Inst, Turin, Italy.
    Morrison, Leslie A.
    Univ New Mexico, Sch Med, Dept Neurol, Albuquerque, NM 87131 USA.
    Sidman, Richard L.
    Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA.
    Cavenee, Webster K.
    Univ Calif San Diego, Ludwig Inst Canc Res, San Diego, CA 92103 USA.
    Dejana, Elisabetta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Fdn Italiana Ric Canc, Inst Mol Oncol Fdn, Milan, Italy;Mario Negri Inst Pharmacol Res, Milan, Italy;Milano Univ, Sch Sci, Dept Biosci, Milan, Italy;Milano Univ, Sch Med, Dept Oncol, Milan, Italy.
    Yonas, Howard
    Univ New Mexico, Sch Med, Dept Neurosurg, Albuquerque, NM 87131 USA.
    Pasqualini, Renata
    Univ Hosp, Rutgers Canc Inst New Jersey, 205 S Orange Ave, Newark, NJ 07103 USA;Rutgers New Jersey Med Sch, Dept Radiat Oncol, Div Canc Biol, Newark, NJ USA.
    Arap, Wadih
    Univ Hosp, Rutgers Canc Inst New Jersey, 205 S Orange Ave, Newark, NJ 07103 USA;Rutgers New Jersey Med Sch, Dept Med, Div Hematol Oncol, Newark, NJ USA.
    Emerging Pharmacologic Targets in Cerebral Cavernous Malformation and Potential Strategies to Alter the Natural History of a Difficult Disease: A Review2019Inngår i: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 76, nr 4, s. 492-500Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    IMPORTANCE: Cerebral cavernous malformations (CCMs) are vascular lesions of the brain that may lead to hemorrhage, seizures, and neurologic deficits. Most are linked to loss-of-function mutations in 1 of 3 genes, namely CCM1 (originally called KRIT1), CCM2 (MGC4607), or CCM3 (PDCD10), that can either occur as sporadic events or are inherited in an autosomal dominant pattern with incomplete penetrance. Familial forms originate from germline mutations, often have multiple intracranial lesions that grow in size and number over time, and cause an earlier and more severe presentation. Despite active preclinical research on a few pharmacologic agents, clinical translation has been slow. Open surgery and, in some cases, stereotactic radiosurgery remain the only effective treatments, but these options are limited by lesion accessibility and are associated with nonnegligible rates of morbidity and mortality.

    OBSERVATIONS: We discuss the limits of CCM management and introduce findings from in vitro and in vivo studies that provide insight into CCM pathogenesis and indicate molecular mechanisms as potential therapeutic targets. These studies report dysregulated cellular pathways shared between CCM, cardiovascular diseases, and cancer. They also suggest the potential effectiveness of proper drug repurposing in association with, or as an alternative to, targeted interventions.

    CONCLUSIONS AND RELEVANCE: We propose methods to exploit specific molecular pathways to design patient-tailored therapeutic approaches in CCM, with the aim to alter its natural progression. In this scenario, the lack of effective pharmacologic options remains a critical barrier that poses an unfulfilled and urgent medical need.

  • 34.
    Claesson-Welsh, Lena
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Alk1 (Activin Receptor-Like Kinase 1) and Vascular Hyperpermeability in Diabetic Retinopathy: More Is Less2018Inngår i: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 38, nr 8, s. 1673-1675Artikkel i tidsskrift (Annet vitenskapelig)
  • 35.
    Claesson-Welsh, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    New Frontiers in VEGF/VEGFR Biology2015Inngår i: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 52, s. 79-79Artikkel i tidsskrift (Annet vitenskapelig)
  • 36.
    Claesson-Welsh, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    On the physiology of vascular permeability2015Inngår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, s. 19-19Artikkel i tidsskrift (Annet vitenskapelig)
  • 37.
    Claesson-Welsh, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Vascular permeability - the essentials2015Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, nr 3, s. 135-143Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The vasculature, composed of vessels of different morphology and function, distributes blood to all tissues and maintains physiological tissue homeostasis. In pathologies, the vasculature is often affected by, and engaged in, the disease process. This may result in excessive formation of new, unstable, and hyperpermeable vessels with poor blood flow, which further promotes hypoxia and disease propagation. Chronic vessel permeability may also facilitate metastatic spread of cancer. Thus, there is a strong incentive to learn more about an important aspect of vessel biology in health and disease: the regulation of vessel permeability. The current review aims to summarize current insights into different mechanisms of vascular permeability, its regulatory factors, and the consequences for disease.

  • 38.
    Claesson-Welsh, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    VEGF receptor signal transduction - A brief update2016Inngår i: Vascular pharmacology, ISSN 1537-1891, E-ISSN 1879-3649, Vol. 86, s. 14-17Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Vascular endothelial growth factor (VEGF) signal transduction through receptor tyrosine lcinases VEGF receptor 1, -2 and -3 is of crucial importance for monocytes/macrophages, blood vascular endothelial and lymphatic endothelial cells both in physiology and in a number of pathologies notably cancer. This brief review summarizes the current status of VEGF receptor signaling with emphasis on in vivo data.

  • 39.
    Claesson-Welsh, Lena
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    What is normal?: Apelin and VEGFA, drivers of tumor vessel abnormality2019Inngår i: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, Vol. 11, nr 8, artikkel-id e10892Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    In this issue of EMBO Molecular Medicine, Uribesalgo and coworkers show that high Apelin expression correlates with poor survival in advanced breast (MMTV-NeuT) and lung (KRAS(G12D)) murine tumor models as well as in breast and lung cancer in humans. Combining Apelin inhibition (genetically or using an inactive Apelin agonist) with anti-angiogenic therapy using different small molecular weight kinase inhibitors (sunitinib, axitinib) led to marked delay in breast cancer growth in mice. The vasculature in Apelin-targeted cancer showed normalized features including improved perfusion and reduced leakage. These important data provide a strong incentive to target Apelin in human cancer treatment.

  • 40.
    Claesson-Welsh, Lena
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Royal Swedish Acad Sci, POB 50005, SE-10405 Stockholm, Sweden..
    Hansson, Goran K.
    Royal Swedish Acad Sci, POB 50005, SE-10405 Stockholm, Sweden..
    Tracheobronchial transplantation: The Royal Swedish Academy of Sciences' concerns2016Inngår i: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 387, nr 10022, s. 942-942Artikkel i tidsskrift (Fagfellevurdert)
  • 41. Collu, Giovanna M.
    et al.
    Jenny, Andreas
    Albert Einstein Coll Med, Dept Dev & Mol Biol, New York, NY USA;Albert Einstein Coll Med, Dept Genet, New York, NY USA.
    Gängel, Konstantin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Mirkovic, Ivana
    Chin, Meiling
    Transon Asia Inc, Dayuan, Taoyuan County, Taiwan.
    Weber, Ursula
    Smith, Michael J.
    Mlodzik, Marek
    Icahn Sch Med Mt Sinai, Dept Cell Dev & Regenerat Biol, New York, NY 10029 USA.
    Prickle is phosphorylated by Nemo and targeted for degradation to maintain Prickle/Spiny-legs isoform balance during planar cell polarity establishment2018Inngår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 14, nr 5, artikkel-id e1007391Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Planar cell polarity (PCP) instructs tissue patterning in a wide range of organisms from fruit flies to humans. PCP signaling coordinates cell behavior across tissues and is integrated by cells to couple cell fate identity with position in a developing tissue. In the fly eye, PCP signaling is required for the specification of R3 and R4 photoreceptors based upon their positioning relative to the dorso-ventral axis. The 'core' PCP pathway involves the asymmetric localization of two distinct membrane-bound complexes, one containing Frizzled (Fz, required in R3) and the other Van Gogh (Vang, required in R4). Inhibitory interactions between the cytosolic components of each complex reinforce asymmetric localization. Prickle (Pk) and Spiny-legs (Pk-Sple) are two antagonistic isoforms of the prickle (pk) gene and are cytoplasmic components of the Vang complex. The balance between their levels is critical for tissue patterning, with Pk-Sple being the major functional isoform in the eye. Here we uncover a post-translational role for Nemo kinase in limiting the amount of the minor isoform Pk. We identified Pk as a Nemo substrate in a genome-wide in vitro band-shift screen. In vivo, nemo genetically interacts with pk(pk) but not pk(sple) and enhances PCP defects in the eye and leg. Nemo phosphorylation limits Pk levels and is required specifically in the R4 photoreceptor like the major isoform, Pk-Sple. Genetic interaction and biochemical data suggest that Nemo phosphorylation of Pk leads to its proteasomal degradation via the Cullin1/SkpA/Slmb complex. dTAK and Homeodomain interacting protein kinase (Hipk) may also act together with Nemo to target Pk for degradation, consistent with similar observations in mammalian studies. Our results therefore demonstrate a mechanism to maintain low levels of the minor Pk isoform, allowing PCP complexes to form correctly and specify cell fate.

  • 42.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Breviario, Ferruccio
    FIRC Inst Mol Oncol Fdn IFOM, Milan, Italy.
    Cunha, Sara I.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Claesson-Welsh, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Dejana, Elisabetta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. 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 Barrier2019Inngår i: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 124, nr 4, s. 511-525Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 43.
    Costa, Guilherme
    et al.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England..
    Harrington, Kyle I.
    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Computat Biol Lab, Boston, MA 02215 USA..
    Lovegrove, Holly E.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England..
    Page, Donna J.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England..
    Chakravartula, Shilpa
    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Computat Biol Lab, Boston, MA 02215 USA..
    Bentley, Katie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Harvard Med Sch, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Computat Biol Lab, Boston, MA 02215 USA..
    Herbert, Shane P.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England..
    Asymmetric division coordinates collective cell migration in angiogenesis2016Inngår i: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 18, nr 12, s. 1292-+Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The asymmetric division of stem or progenitor cells generates daughters with distinct fates and regulates cell diversity during tissue morphogenesis. However, roles for asymmetric division in other more dynamic morphogenetic processes, such as cell migration, have not previously been described. Here we combine zebrafish in vivo experimental and computational approaches to reveal that heterogeneity introduced by asymmetric division generates multicellular polarity that drives coordinated collective cell migration in angiogenesis. We find that asymmetric positioning of the mitotic spindle during endothelial tip cell division generates daughters of distinct size with discrete 'tip' or 'stalk' thresholds of pro-migratory Vegfr signalling. Consequently, post-mitotic Vegfr asymmetry drives Dll4/Notch-independent self-organization of daughters into leading tip or trailing stalk cells, and disruption of asymmetry randomizes daughter tip/stalk selection. Thus, asymmetric division seamlessly integrates cell proliferation with collective migration, and, as such, may facilitate growth of other collectively migrating tissues during development, regeneration and cancer invasion.

  • 44.
    Cruys, Bert
    et al.
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Wong, Brian W.
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Kuchnio, Anna
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Verdegem, Dries
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Cantelmo, Anna Rita
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Conradi, Lena-Christin
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Vandekeere, Saar
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Bouche, Ann
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Cornelissen, Ivo
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Vinckier, Stefan
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Merks, Roeland M. H.
    Ctr Wiskunde & Informat, Life Sci Grp, Sci Pk 123, NL-1098 XG Amsterdam, Netherlands.;Leiden Univ, Math Inst, Niels Bohrweg 1, NL-2333 CA Leiden, Netherlands..
    Dejana, Elisabetta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. FIRC Inst Mol Oncol, Via Adamello 16, I-20139 Milan, Italy.;Univ Milan, Dept Oncol & Hematooncol, I-20139 Milan, Italy..
    Gerhardt, Holger
    Katholieke Univ Leuven, Vasc Patterning Lab, Dept Oncol, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Vasc Patterning Lab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;Max Delbruck Ctr Mol Med, Integrat Vasc Biol Lab, Robert Rossle Str 10, D-13125 Berlin, Germany..
    Dewerchin, Mieke
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Bentley, Katie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Harvard Med Sch, Dept Pathol, Computat Biol Lab, Beth Israel Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA..
    Carmeliet, Peter
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Glycolytic regulation of cell rearrangement in angiogenesis2016Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, artikkel-id 12240Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    During vessel sprouting, endothelial cells (ECs) dynamically rearrange positions in the sprout to compete for the tip position. We recently identified a key role for the glycolytic activator PFKFB3 in vessel sprouting by regulating cytoskeleton remodelling, migration and tip cell competitiveness. It is, however, unknown how glycolysis regulates EC rearrangement during vessel sprouting. Here we report that computational simulations, validated by experimentation, predict that glycolytic production of ATP drives EC rearrangement by promoting filopodia formation and reducing intercellular adhesion. Notably, the simulations correctly predicted that blocking PFKFB3 normalizes the disturbed EC rearrangement in high VEGF conditions, as occurs during pathological angiogenesis. This interdisciplinary study integrates EC metabolism in vessel sprouting, yielding mechanistic insight in the control of vessel sprouting by glycolysis, and suggesting anti-glycolytic therapy for vessel normalization in cancer and non-malignant diseases.

  • 45.
    Cunha, Sara I.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Jia, Min
    Karolinska Inst, Dept Biosci & Nutr, S-14157 Stockholm, Sweden.
    Souchelnytskyi, Serhiy
    Qatar Univ, Coll Med, Bldg H12,Al Jamiaa St, Doha 2713, Qatar.
    Exposure to EGF and 17 beta-estradiol irreversibly affects the proliferation and transformation of MCF7 cells but is not sufficient to promote tumor growth in a xenograft mouse model upon withdrawal of exposure2018Inngår i: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 42, nr 3, s. 1615-1624Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Epidermal growth factor (EGF) and estrogen are potent regulators of breast tumorigenesis. Their short-term actions on human breast epithelial cells have been investigated extensively. However, the consequence of a long-term exposure to EGF and estrogen remains to be fully elucidated. The present study examined the effects of long-term exposure to EGF and 17 beta-estradiol on the proliferation, transformation, expression of markers of stemness, and tumorigenesis of MCF7 human breast adenocarcinoma cells. Exposure to EGF and/or 17 beta-estradiol irreversibly enhanced the proliferation rate of MCF7 cells, even following withdrawal. However, in a mouse xenograft experiment, no significant difference in tumor volume was observed between tumors derived from cells exposed to EGF, 17 beta-estradiol or EGF + 17 beta-estradiol. Immunohistochemistry performed on tumors derived from 17 beta-estradiol-exposed cells revealed reduced cell proliferation and vessel scores, according to the results obtained using Ki67 and von Willebrand factor staining, respectively. The EGF-and/or 17 beta-estradiol-treated cells exhibited an increased ratio of cluster of differentiation (CD) 44(+)/CD24(-) cells and enhanced ability to form mammospheres. Furthermore, the long-term exposure of MCF7 cells to EGF and 17 beta-estradiol altered their responsiveness to short-term stimulatory or inhibitory treatments with EGF, 17 beta-estradiol, transforming growth factor-beta 1 (TGF beta 1), Iressa and SB431542. Therefore, the findings indicated that sustained exposure of MCF7 cells to EGF and/or 17 beta-estradiol resulted in enhanced cell proliferation and mammosphere formation, an increased ratio of CD 44(+)/CD24 cells, and altered responses to short-term treatments with EGF, 17 beta-estradiol, TGF beta 1, and drugs inhibiting these signaling pathways. However, this sustained exposure was not sufficient to affect tumor take or volume in a xenograft mouse model.

  • 46.
    Cunha, Sara I.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. 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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. 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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. FIRC Inst Mol Oncol, Milan, Italy..
    Lampugnani, Maria Grazia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. FIRC Inst Mol Oncol, Milan, Italy.;Ist Ric Farmacol Mario Negri, Milan, Italy..
    Deregulated TGF-beta/BMP Signaling in Vascular Malformations2017Inngår i: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 121, nr 8, s. 981-999Artikkel, forskningsoversikt (Fagfellevurdert)
    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.

  • 47.
    Cuttano, Roberto
    et al.
    IFOM, Milan, Italy..
    Rudini, Noemi
    IFOM, Milan, Italy..
    Bravi, Luca
    IFOM, Milan, Italy..
    Corada, Monica
    IFOM, Milan, Italy..
    Giampietro, Costanza
    IFOM, Milan, Italy.;Univ Milan, Dept Biosci, Milan, Italy..
    Papa, Eleanna
    IFOM, Milan, Italy..
    Morini, Marco Francesco
    IFOM, Milan, Italy..
    Maddaluno, Luigi
    IFOM, Milan, Italy..
    Baeyens, Nicolas
    Yale Cardiovasc Res Ctr, New Haven, CT USA..
    Adams, Ralf H.
    Univ Munster, Max Planck Inst Mol Biomed, Fac Med, Dept Tissue Morphogenesis, D-48149 Munster, Germany..
    Jain, Mukesh K.
    Case Cardiovasc Res Inst, Cleveland, OH USA.;Harrington Heart & Vasc Inst, Cleveland, OH USA.;Univ Hosp Case Med Ctr, Dept Med, Cleveland, OH USA.;Case Western Reserve Univ, Sch Med, Univ Hosp Case Med Ctr, Cleveland, OH USA..
    Owens, Gary K.
    Univ Virginia, Sch Med, Robert M Berne Cardiovasc Res Ctr, Charlottesville, VA 22908 USA..
    Schwartz, Martin
    Yale Cardiovasc Res Ctr, New Haven, CT USA..
    Lampugnani, Maria Grazia
    IFOM, Milan, Italy.;Mario Negri Inst Pharmacol Res, Milan, Italy..
    Dejana, Elisabetta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. IFOM, Milan, Italy.;Univ Milan, Dept Oncol & Oncohematol, Milan, Italy..
    KLF4 is a key determinant in the development and progression of cerebral cavernous malformations2016Inngår i: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, Vol. 8, nr 1, s. 6-24Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cerebral cavernous malformations (CCMs) are vascular malformations located within the central nervous system often resulting in cerebral hemorrhage. Pharmacological treatment is needed, since current therapy is limited to neurosurgery. Familial CCM is caused by loss-of-function mutations in any of Ccm1, Ccm2, and Ccm3 genes. CCM cavernomas are lined by endothelial cells (ECs) undergoing endothelial-to-mesenchymal transition (EndMT). This switch in phenotype is due to the activation of the transforming growth factor beta/bone morphogenetic protein (TGFb/BMP) signaling. However, the mechanism linking Ccm gene inactivation and TGFb/ BMP-dependent EndMT remains undefined. Here, we report that Ccm1 ablation leads to the activation of a MEKK3-MEK5-ERK5MEF2 signaling axis that induces a strong increase in Kruppel-like factor 4 (KLF4) in ECs in vivo. KLF4 transcriptional activity is responsible for the EndMT occurring in CCM1-null ECs. KLF4 promotes TGFb/BMP signaling through the production of BMP6. Importantly, in endothelial-specific Ccm1 and Klf4 double knockout mice, we observe a strong reduction in the development of CCM and mouse mortality. Our data unveil KLF4 as a therapeutic target for CCM.

  • 48. Dang, Thanh Chung
    et al.
    Ishii, Yoko
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Pathol, Toyama 9300194, Japan;Univ Nagano, Fac Hlth & Human Dev, Dept Hlth Sci, Nagano 3808525, Japan.
    Nguyen, Van De
    Yamamoto, Seiji
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Pathol, Toyama 9300194, Japan.
    Hamashima, Takeru
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Pathol, Toyama 9300194, Japan.
    Okuno, Noriko
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Pathol, Toyama 9300194, Japan.
    Nguyen, Quang Linh
    Sang, Yang
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Pathol, Toyama 9300194, Japan.
    Ohkawa, Noriaki
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Biochem, Toyama 9300194, Japan;JST, CREST, Toyama 9300194, Japan.
    Saitoh, Yoshito
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Biochem, Toyama 9300194, Japan;JST, CREST, Toyama 9300194, Japan.
    Shehata, Mohammad
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Biochem, Toyama 9300194, Japan;JST, CREST, Toyama 9300194, Japan.
    Takakura, Nobuyuki
    Osaka Univ, Res Inst Microbial Dis, Dept Signal Transduct, Suita, Osaka 5650871, Japan.
    Fujimori, Toshihiko
    Natl Inst Basic Biol, Div Embryol, Okazaki, Aichi 4448787, Japan.
    Inokuchi, Kaoru
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Biochem, Toyama 9300194, Japan;JST, CREST, Toyama 9300194, Japan.
    Mori, Hisashi
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Mol Neurosci, Toyama 9300194, Japan.
    Andrae, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Betsholtz, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Karolinska Inst, Integrated Cardio Metab Ctr, S-14157 Huddinge, Sweden.
    Sasahara, Masakiyo
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Pathol, Toyama 9300194, Japan.
    Powerful Homeostatic Control of Oligodendroglial Lineage by PDGFR alpha in Adult Brain2019Inngår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 27, nr 4, s. 1073-1089Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Oligodendrocyte progenitor cells (OPCs) are widely distributed cells of ramified morphology in adult brain that express PDGFR alpha and NG2. They retain mitotic activities in adulthood and contribute to oligodendrogenesis and myelin turnover; however, the regulatory mechanisms of their cell dynamics in adult brain largely remain unknown. Here, we found that global Pdgfra inactivation in adult mice rapidly led to elimination of OPCs due to synchronous maturation toward oligodendrocytes. Surprisingly, OPC densities were robustly reconstituted by the active expansion of Nestin(+) immature cells activated in meninges and brain parenchyma, as well as a few OPCs that escaped from Pdgfra inactivation. The multipotent immature cells were induced in the meninges of Pdgfra-inactivated mice, but not of control mice. Our findings revealed powerful homeostatic control of adult OPCs, engaging dual cellular sources of adult OPC formation. These properties of the adult oligodendrocyte lineage and the alternative OPC source may be exploited in regenerative medicine.

  • 49.
    De La Fuente, Alerie Guzman
    et al.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Lange, Simona
    Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria..
    Silva, Maria Elena
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England.;Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Univ Austral Chile, Fac Med, Inst Anat Histol & Pathol, Lab Stem Cells & Neuroregenerat, Valdivia, Chile.;Univ Austral Chile, Ctr Interdisciplinary Studies Nervous Syst CISNe, Valdivia, Chile.;Univ Austral Chile, Inst Pharm, Fac Sci, Valdivia, Chile..
    Gonzalez, Ginez A.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Tempfer, Herbert
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Tendon & Bone Regenerat, A-5020 Salzburg, Austria.;Austrian Cluster Tissue Regenerat, Vienna, Austria..
    van Wijngaarden, Peter
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England.;Univ Melbourne, Dept Surg, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia,Ophthalmol, Melbourne, Vic, Australia..
    Zhao, Chao
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Di Canio, Ludovica
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Trost, Andrea
    Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Ophthalmol Optometry & Res Program Expt Ophthalmo, A-5020 Salzburg, Austria..
    Bieler, Lara
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    Zaunmair, Pia
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    Rotheneichner, Peter
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    O'Sullivan, Anna
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    Couillard-Despres, Sebastien
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    Errea, Oihana
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Mäe, Maarja A.
    Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Andrae, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    He, Liqun
    Tianjin Med Univ, Key Lab Post Neuroinjury Neuro Repair & Regenerat, Tianjin Neurol Inst, Dept Neurosurg,Gen Hosp,Minist Educ & Tianjin Cit, Tianjin 300052, Peoples R China..
    Keller, Annika
    Zurich Univ, Zurich Univ Hosp, Div Neurosurg, CH-8091 Zurich, Switzerland..
    Batiz, Luis F.
    Univ Austral Chile, Fac Med, Inst Anat Histol & Pathol, Lab Stem Cells & Neuroregenerat, Valdivia, Chile.;Univ Los Andes, Fac Med, CIB, Santiago, Chile..
    Betsholtz, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Aigner, Ludwig
    Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Austrian Cluster Tissue Regenerat, Vienna, Austria..
    Franklin, Robin J. M.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Rivera, Francisco J.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England.;Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Univ Austral Chile, Fac Med, Inst Anat Histol & Pathol, Lab Stem Cells & Neuroregenerat, Valdivia, Chile.;Univ Austral Chile, Ctr Interdisciplinary Studies Nervous Syst CISNe, Valdivia, Chile..
    Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination2017Inngår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 20, nr 8, s. 1755-1764Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The role of the neurovascular niche in CNS myelin regeneration is incompletely understood. Here, we show that, upon demyelination, CNS-resident pericytes (PCs) proliferate, and parenchymal non-vessel-associated PC-like cells (PLCs) rapidly develop. During remyelination, mature oligodendrocytes were found in close proximity to PCs. In Pdgfb(ret/ret) mice, which have reduced PC numbers, oligodendrocyte progenitor cell (OPC) differentiation was delayed, although remyelination proceeded to completion. PC-conditioned medium accelerated and enhanced OPC differentiation in vitro and increased the rate of remyelination in an ex vivo cerebellar slice model of demyelination. We identified Lama2 as a PC-derived factor that promotes OPC differentiation. Thus, the functional role of PCs is not restricted to vascular homeostasis but includes the modulation of adult CNS progenitor cells involved in regeneration.

  • 50.
    Dejana, Elisabetta
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. FIRC Inst Mol Oncol, Milan, Italy; niv Milan, Dept Oncol & Hematooncol, Milan, Italy.
    Betsholtz, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden.
    Oligodendrocytes follow blood vessel trails in the brain Brain microvasculature is a scaffold for neuroglial migration2016Inngår i: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 351, nr 6271, s. 341-342Artikkel i tidsskrift (Fagfellevurdert)
12345 1 - 50 of 232
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