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1. Learning to Reconstruct Confocal Microscopy Stacks from Single Light Field Images

Author

Page, Josue, Saltarin, Federico, Belyaev, Yury, Lyck, Ruth, and Favaro, Paolo

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Computer Vision and Pattern Recognition, Physics - Optics
Abstract

We present a novel deep learning approach to reconstruct confocal microscopy stacks from single light field images. To perform the reconstruction, we introduce the LFMNet, a novel neural network architecture inspired by the U-Net design. It is able to reconstruct with high-accuracy a 112x112x57.6$\mu m^3$ volume (1287x1287x64 voxels) in 50ms given a single light field image of 1287x1287 pixels, thus dramatically reducing 720-fold the time for confocal scanning of assays at the same volumetric resolution and 64-fold the required storage. To prove the applicability in life sciences, our approach is evaluated both quantitatively and qualitatively on mouse brain slices with fluorescently labelled blood vessels. Because of the drastic reduction in scan time and storage space, our setup and method are directly applicable to real-time in vivo 3D microscopy. We provide analysis of the optical design, of the network architecture and of our training procedure to optimally reconstruct volumes for a given target depth range. To train our network, we built a data set of 362 light field images of mouse brain blood vessels and the corresponding aligned set of 3D confocal scans, which we use as ground truth. The data set will be made available for research purposes., Comment: 22 pages, 12 figures

Published
2020

3. Compromised Blood-Brain Barrier Junctions Enhance Melanoma Cell Intercalation and Extravasation

Author

Saltarin, Federico, primary, Wegmüller, Adrian, additional, Bejarano, Leire, additional, Ildiz, Ece Su, additional, Zwicky, Pascale, additional, Vianin, Andréj, additional, Spadin, Florentin, additional, Soukup, Klara, additional, Wischnewski, Vladimir, additional, Engelhardt, Britta, additional, Deutsch, Urban, additional, J. Marques, Ines, additional, Frenz, Martin, additional, Joyce, Johanna A., additional, and Lyck, Ruth, additional

Published
2023
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5. Dual role of ALCAM in neuroinflammation and blood—brain barrier homeostasis

Author

Lécuyer, Marc-André, Saint-Laurent, Olivia, Bourbonnière, Lyne, Larouche, Sandra, Larochelle, Catherine, Michel, Laure, Charabati, Marc, Abadier, Michael, Zandee, Stephanie, Jahromi, Neda Haghayegh, Gowing, Elizabeth, Pittet, Camille, Lyck, Ruth, Engelhardt, Britta, and Prat, Alexandre

Published
2017

10. Claudin-3-deficient C57BL/6J mice display intact brain barriers

Author

Castro Dias, Mariana, Coisne, Caroline, Lazarevic, Ivana, Baden, Pascale, Hata, Masaki, Iwamoto, Noriko, Francisco, David Miguel Ferreira, Vanlandewijck, Michael, He, Liqun, Baier, Felix A., Stroka, Deborah, Bruggmann, Rémy, Lyck, Ruth, Enzmann, Gaby, Deutsch, Urban, Betsholtz, Christer, Furuse, Mikio, Tsukita, Shoichiro, and Engelhardt, Britta

Published
2019
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20. PECAM-1 Stabilizes Blood-Brain Barrier Integrity and Favors Paracellular T-Cell Diapedesis Across the Blood-Brain Barrier During Neuroinflammation

Author

Wimmer, Isabella, Tietz, Silvia, Nishihara, Hideaki, Deutsch, Urban, Sallusto, Federica, Gosselet, Fabien, Lyck, Ruth, Muller, William A., Lassmann, Hans, Engelhardt, Britta, Theodor Kocher Institut, University of Bern, Theodor Kocher Institute, Medizinische Universität Wien = Medical University of Vienna, Institute for Research in Biomedicine, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Laboratoire de la Barrière Hémato-Encéphalique (LBHE), Université d'Artois (UA), Northwestern University [Chicago, Ill. USA], and University of Vienna [Vienna]

Subjects
blood-brain barrier, endothelial junctions, PECAM-1, T-cell diapedesis, vascular permeability, multiple sclerosis, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, cardiovascular system, 570 Life sciences, biology, 610 Medicine & health
Abstract

International audience; Breakdown of the blood-brain barrier (BBB) and increased immune cell trafficking into the central nervous system (CNS) are hallmarks of the pathogenesis of multiple sclerosis (MS). Platelet endothelial cell adhesion molecule-1 (PECAM-1; CD31) is expressed on cells of the vascular compartment and regulates vascular integrity and immune cell trafficking. Involvement of PECAM-1 in MS pathogenesis has been suggested by the detection of increased levels of soluble PECAM-1 (sPECAM-1) in the serum and CSF of MS patients. Here, we report profound upregulation of cell-bound PECAM-1 in initial (pre-phagocytic) white matter as well as active cortical gray matter MS lesions. Using a human in vitro BBB model we observed that PECAM-1 is not essential for the transmigration of human CD4+ T-cell subsets (Th1, Th1*, Th2, and Th17) across the BBB. Employing an additional in vitro BBB model based on primary mouse brain microvascular endothelial cells (pMBMECs) we show that the lack of endothelial PECAM-1 impairs BBB properties as shown by reduced transendothelial electrical resistance (TEER) and increases permeability for small molecular tracers. Investigating T-cell migration across the BBB under physiological flow by in vitro live cell imaging revealed that absence of PECAM-1 in pMBMECs did not influence arrest, polarization, and crawling of effector/memory CD4+ T cells on the pMBMECs. Absence of endothelial PECAM-1 also did not affect the number of T cells able to cross the pMBMEC monolayer under flow, but surprisingly favored transcellular over paracellular T-cell diapedesis. Taken together, our data demonstrate that PECAM-1 is critically involved in regulating BBB permeability and although not required for T-cell diapedesis itself, its presence or absence influences the cellular route of T-cell diapedesis across the BBB. Upregulated expression of cell-bound PECAM-1 in human MS lesions may thus reflect vascular repair mechanisms aiming to restore BBB integrity and paracellular T-cell migration across the BBB as it occurs during CNS immune surveillance.

Published
2019
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23. Live cell imaging techniques to study T cell trafficking across the blood-brain barrier in vitro and in vivo

Author

Coisne Caroline, Lyck Ruth, and Engelhardt Britta

Subjects
BBB, Immune cell trafficking, Live cell imaging, CD4 T cells, CD8 T cells, α4-integrins, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background The central nervous system (CNS) is an immunologically privileged site to which access for circulating immune cells is tightly controlled by the endothelial blood–brain barrier (BBB) located in CNS microvessels. Under physiological conditions immune cell migration across the BBB is low. However, in neuroinflammatory diseases such as multiple sclerosis, many immune cells can cross the BBB and cause neurological symptoms. Extravasation of circulating immune cells is a multi-step process that is regulated by the sequential interaction of different adhesion and signaling molecules on the immune cells and on the endothelium. The specialized barrier characteristics of the BBB, therefore, imply the existence of unique mechanisms for immune cell migration across the BBB. Methods and design An in vitro mouse BBB model maintaining physiological barrier characteristics in a flow chamber and combined with high magnification live cell imaging, has been established. This model enables the molecular mechanisms involved in the multi-step extravasation of T cells across the in vitro BBB, to be defined with high-throughput analyses. Subsequently these mechanisms have been verified in vivo using a limited number of experimental animals and a spinal cord window surgical technique. The window enables live observation of the dynamic interaction between T cells and spinal cord microvessels under physiological and pathological conditions using real time epifluorescence intravital imaging. These in vitro and in vivo live cell imaging methods have shown that the BBB endothelium possesses unique and specialized mechanisms involved in the multi-step T cell migration across this endothelial barrier under physiological flow. The initial T cell interaction with the endothelium is either mediated by T cell capture or by T cell rolling. Arrest follows, and then T cells polarize and especially CD4+ T cells crawl over long distances against the direction of flow to find the rare sites permissive for diapedesis through the endothelium. Discussion The sequential use of in vitro and in vivo live cell imaging of T cells interacting with the BBB allows us to delineate the kinetics and molecular determinants involved in multistep extravasation of encephalitogenic T cells across the BBB.

Published
2013
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24. Claudin-3-deficient C57BL/6J mice display intact brain barriers

Author

Dias, Mariana Castro, Coisne, Caroline, Lazarevic, Ivana, Baden, Pascale, Hata, Masaki, Iwamoto, Noriko, Francisco, David Miguel Ferreira, Vanlandewijck, Michael, He, Liqun, Baier, Felix A., Stroka, Deborah, Bruggmann, Remy, Lyck, Ruth, Enzmann, Gaby, Deutsch, Urban, Betsholtz, Christer, Furuse, Mikio, Tsukita, Shoichiro, Engelhardt, Britta, Dias, Mariana Castro, Coisne, Caroline, Lazarevic, Ivana, Baden, Pascale, Hata, Masaki, Iwamoto, Noriko, Francisco, David Miguel Ferreira, Vanlandewijck, Michael, He, Liqun, Baier, Felix A., Stroka, Deborah, Bruggmann, Remy, Lyck, Ruth, Enzmann, Gaby, Deutsch, Urban, Betsholtz, Christer, Furuse, Mikio, Tsukita, Shoichiro, and Engelhardt, Britta

Abstract

The tight junction protein claudin-3 has been identified as a transcriptional target of the Wnt/beta-catenin signaling pathway regulating blood-brain barrier (BBB) maturation. In neurological disorders loss of claudin-3 immunostaining is observed at the compromised BBB and blood-cerebrospinal fluid barrier (BCSFB). Although these observations support a central role of claudin-3 in regulating brain barriers' tight junction integrity, expression of claudin-3 at the brain barriers has remained a matter of debate. This prompted us to establish claudin-3-/-C57BL/6J mice to study the role of claudin-3 in brain barrier integrity in health and neuroinflammation. Bulk and single cell RNA sequencing and direct comparative qRT-PCR analysis of brain microvascular samples from WT and claudin-3-/- mice show beyond doubt that brain endothelial cells do not express claudin-3 mRNA. Detection of claudin-3 protein at the BBB in vivo and in vitro is rather due to junctional reactivity of anti-claudin-3 antibodies to an unknown antigen still detected in claudin-3-/- brain endothelium. We confirm expression and junctional localization of claudin-3 at the BCSFB of the choroid plexus. Our study clarifies that claudin-3 is not expressed at the BBB and shows that absence of claudin-3 does not impair brain barrier function during health and neuroinflammation in C57BL/6J mice., Correction in: SCIENTIFIC REPORTS, Volume: 9, Article Number: 10702, DOI: 10.1038/s41598-019-43511-0

Published
2019
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25. The Rho regulator Myosin IXb enables nonlymphoid tissue seeding of protective CD8+ T cells

Author

Moalli, Federica, primary, Ficht, Xenia, additional, Germann, Philipp, additional, Vladymyrov, Mykhailo, additional, Stolp, Bettina, additional, de Vries, Ingrid, additional, Lyck, Ruth, additional, Balmer, Jasmin, additional, Fiocchi, Amleto, additional, Kreutzfeldt, Mario, additional, Merkler, Doron, additional, Iannacone, Matteo, additional, Ariga, Akitaka, additional, Stoffel, Michael H., additional, Sharpe, James, additional, Bähler, Martin, additional, Sixt, Michael, additional, Diz-Muñoz, Alba, additional, and Stein, Jens V., additional

Published
2018
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26. VLA-4 mediated adhesion of melanoma cells on the blood–brain barrier is the critical cue for melanoma cell intercalation and barrier disruption

Author

García-Martín, Ana B, primary, Zwicky, Pascale, additional, Gruber, Thomas, additional, Matti, Christoph, additional, Moalli, Federica, additional, Stein, Jens V, additional, Francisco, David, additional, Enzmann, Gaby, additional, Levesque, Mitchell P, additional, Hewer, Ekkehard, additional, and Lyck, Ruth, additional

Published
2018
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27. Claudin-1 induced sealing of blood-brain barrier tight junctions ameliorates chronic experimental autoimmune encephalomyelitis

Author

Pfeiffer, Friederike, Schäfer, Julia, Lyck, Ruth, Makrides, Victoria, Brunner, Sarah, Schaeren-Wiemers, Nicole, Deutsch, Urban, Engelhardt, Britta, Pfeiffer, Friederike, Schäfer, Julia, Lyck, Ruth, Makrides, Victoria, Brunner, Sarah, Schaeren-Wiemers, Nicole, Deutsch, Urban, and Engelhardt, Britta

Abstract

In experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS), loss of the blood-brain barrier (BBB) tight junction (TJ) protein claudin-3 correlates with immune cell infiltration into the CNS and BBB leakiness. Here we show that sealing BBB TJs by ectopic tetracycline-regulated expression of the TJ protein claudin-1 in Tie-2 tTA//TRE-claudin-1 double transgenic C57BL/6 mice had no influence on immune cell trafficking across the BBB during EAE and furthermore did not influence the onset and severity of the first clinical disease episode. However, expression of claudin-1 did significantly reduce BBB leakiness for both blood borne tracers and endogenous plasma proteins specifically around vessels expressing claudin-1. In addition, mice expressing claudin-1 exhibited a reduced disease burden during the chronic phase of EAE as compared to control littermates. Our study identifies BBB TJs as the critical structure regulating BBB permeability but not immune cell trafficking into CNS during EAE, and indicates BBB dysfunction is a potential key event contributing to disease burden in the chronic phase of EAE. Our observations suggest that stabilizing BBB barrier function by therapeutic targeting of TJs may be beneficial in treating MS, especially when anti-inflammatory treatments have failed

Published
2018

28. Identifizierung von Subklassen spezifischer Mechanismen für CD8+ versus CD4+ T-Zell Migration über die Blut-Hirn-Schranke im Rahmen von Neuroinflammation (DGPI-Forschungsstipendium 2012)

Author

Rudolph, Henriette, Kloppstein, Armelle, Blatti, Claudia, Schroten, Horst, Tenenbaum, Tobias, Lyck, Ruth, and Engelhardt, Britta

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Obwohl CD8+ T-Zellen mit der Pathogenese der Multiplen Sklerose (MS) in Zusammenhang gebracht werden, sind die molekularen Mechanismen, die ihre Migration über die Blut-Hirn-Schranke (BHS) regulieren, bisher wenig erforscht. Mit Hilfe von in vitro live cell imaging konnten wir direkt die Transmigration[zum vollständigen Text gelangen Sie über die oben angegebene URL], 24. Jahrestagung der Deutschen Gesellschaft für Pädiatrische Infektiologie (DGPI)

Published
2016
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30. The ESRP1-GPR137 axis contributes to intestinal pathogenesis

Author

Mager, Lukas Franz, primary, Koelzer, Viktor Hendrik, additional, Stuber, Regula, additional, Thoo, Lester, additional, Keller, Irene, additional, Koeck, Ivonne, additional, Langenegger, Maya, additional, Simillion, Cedric, additional, Pfister, Simona P, additional, Faderl, Martin, additional, Genitsch, Vera, additional, Tcymbarevich, Irina, additional, Juillerat, Pascal, additional, Li, Xiaohong, additional, Xia, Yu, additional, Karamitopoulou, Eva, additional, Lyck, Ruth, additional, Zlobec, Inti, additional, Hapfelmeier, Siegfried, additional, Bruggmann, Rémy, additional, McCoy, Kathy D, additional, Macpherson, Andrew J, additional, Müller, Christoph, additional, Beutler, Bruce, additional, and Krebs, Philippe, additional

Published
2017
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31. Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers

Author

Małecki, Andrzej, primary, Skipor-Lahuta, Janina, additional, Toborek, Michal, additional, Abbott, N. Joan, additional, Antonetti, David A., additional, Su, Enming Joe, additional, Lawrence, Daniel A., additional, Atış, Müge, additional, Akcan, Uğur, additional, Yılmaz, Canan Uğur, additional, Orhan, Nurcan, additional, Düzgün, Poyraz, additional, Ceylan, Umut Deniz, additional, Arıcan, Nadir, additional, Karahüseyinoğlu, Serçin, additional, Şahin, Gizem Nur, additional, Ahıshalı, Bülent, additional, Kaya, Mehmet, additional, Aydin, Sidar, additional, Klopstein, Armelle, additional, Engelhardt, Britta, additional, Baumann, Julia, additional, Tsao, Chih-Chieh, additional, Huang, Sheng-Fu, additional, Ogunshola, Omolara, additional, Boytsova, Elizaveta B., additional, Morgun, Andrey V., additional, Khilazheva, Elena D., additional, Pozhilenkova, Elena A., additional, Gorina, Yana V., additional, Martynova, Galina P., additional, Salmina, Alla B., additional, Bueno, David, additional, Garcia-Fernàndez, Jordi, additional, Castro, Victor, additional, Skowronska, Marta, additional, Chupel, Matheus Uba, additional, Minuzzi, Luciele Guerra, additional, Filaire, Edith, additional, Teixeira, Ana Maria, additional, Corsi, Mariangela, additional, Versele, Romain, additional, Fuso, Andrea, additional, Sevin, Emmanuel, additional, Di Lorenzo, Cherubino, additional, Businaro, Rita, additional, Fenart, Laurence, additional, Gosselet, Fabien, additional, Candela, Pietra, additional, Deli, Mária A., additional, Delaney, Conor, additional, O’Keefe, Eoin, additional, Farrell, Michael, additional, Doyle, Sarah, additional, Campbell, Matthew, additional, Drewes, Lester R., additional, Appelt-Menzel, A., additional, Cubukova, A., additional, Metzger, M., additional, Fischer, R., additional, Francisco, David M. F., additional, Bruggmann, Rémy, additional, Fries, Alexa, additional, Blecharz, Kinga G., additional, Wagner, Josephin, additional, Winkler, Lars, additional, Schneider, Ulf, additional, Vajkoczy, Peter, additional, Furuse, Mikio, additional, Gabbert, Lydia, additional, Dilling, Christina, additional, Sisario, Dmitri, additional, Soukhoroukov, Vladimir, additional, Burek, Malgorzata, additional, Guérit, S., additional, Fidan, E., additional, Devraj, K., additional, Czupalla, C. J., additional, Macas, J., additional, Thom, S., additional, Plate, K. H., additional, Gerhardt, H., additional, Liebner, S., additional, Harazin, András, additional, Bocsik, Alexandra, additional, Váradi, Judit, additional, Fenyvesi, Ferenc, additional, Tubak, Vilmos, additional, Vecsernyés, Miklós, additional, Helms, Hans Christian, additional, Waagepetersen, Helle Sønderby, additional, Nielsen, Carsten Uhd, additional, Brodin, Birger, additional, Hoyk, Zsófia, additional, Tóth, Melinda E., additional, Lénárt, Nikolett, additional, Dukay, Brigitta, additional, Kittel, Ágnes, additional, Vígh, Judit, additional, Veszelka, Szilvia, additional, Walter, Fruzsina, additional, Zvara, Ágnes, additional, Puskás, László, additional, Sántha, Miklós, additional, Engelhardt, Sabrina, additional, Ogunshola, Omolara O., additional, Huber, Anna, additional, Reitner, Alexander, additional, Osmen, Samar, additional, Hahn, Kathrin, additional, Bounzina, Neli, additional, Gerhartl, Anna, additional, Schönegger, Anna, additional, Steinkellner, Hannes, additional, Laccone, Franco, additional, Neuhaus, Winfried, additional, Hudson, Natalie, additional, Celkova, Lucia, additional, Iltzsche, Anne, additional, Drndarski, Svetlana, additional, Begley, David J, additional, Janiurek, Mette Mathiesen, additional, Kucharz, Krzysztof, additional, Christoffersen, Christina, additional, Nielsen, Lars Bo, additional, Lauritzen, Martin, additional, Johnson, Rebecca H, additional, Kho, Dan T, additional, O’Carroll, Simon J, additional, Angel, Catherine E, additional, Graham, E. Scott, additional, Pereira, Jennifer, additional, Karali, Christina Simoglou, additional, Cheng, Vinton, additional, Zarghami, Niloufar, additional, Soto, Manuel Sarmiento, additional, Couch, Yvonne, additional, Anthony, Daniel C., additional, Sibson, Nicola R., additional, Kealy, John, additional, Keep, Richard F., additional, Routhe, Lisa J., additional, Xiang, Jianming, additional, Ye, Hong, additional, Hua, Ya, additional, Moos, Torben, additional, Xi, Guohua, additional, Kristensen, M., additional, Bach, A., additional, Strømgaard, K., additional, Kutuzov, Nikolay, additional, Lopes-Pinheiro, Melissa A., additional, Lim, Jamie, additional, Kamermans, Alwin, additional, van Horssen, Jack, additional, Unger, Wendy W.J., additional, Fontijn, Ruud, additional, de Vries, Helga E., additional, Majerova, Petra, additional, Garruto, Ralph M., additional, Marchetti, Luca, additional, Francisco, David, additional, Gruber, Isabelle, additional, Lyck, Ruth, additional, Mészáros, Mária, additional, Porkoláb, Gergő, additional, Kiss, Lóránd, additional, Pilbat, Ana-Maria, additional, Török, Zsolt, additional, Bozsó, Zsolt, additional, Fülöp, Lívia, additional, Michalicova, Alena, additional, Galba, Jaroslav, additional, Mihaljevic, Sandra, additional, Novak, Michal, additional, Kovac, Andrej, additional, Morofuji, Yoichi, additional, Fujimoto, Takashi, additional, Watanabe, Daisuke, additional, Nakagawa, Shinsuke, additional, Ujifuku, Kenta, additional, Horie, Nobutaka, additional, Izumo, Tsuyoshi, additional, Anda, Takeo, additional, Matsuo, Takayuki, additional, Niu, Fang, additional, Buch, Shilpa, additional, Nyúl-Tóth, Ádám, additional, Kozma, Mihály, additional, Nagyőszi, Péter, additional, Nagy, Krisztina, additional, Fazakas, Csilla, additional, Haskó, János, additional, Molnár, Kinga, additional, Farkas, Attila E., additional, Galajda, Péter, additional, Wilhelm, Imola, additional, Krizbai, István A., additional, Kelly, Eoin, additional, Wallace, Eugene, additional, Greene, Chris, additional, Hughes, Stephanie, additional, Doyle, Niamh, additional, Humphries, Marian M., additional, Grant, Gerald A., additional, Friedman, Alon, additional, Veksler, Ronel, additional, Molloy, Michael G., additional, Meaney, James F., additional, Pender, Niall, additional, Doherty, Colin P., additional, Park, Minseon, additional, Liskiewicz, Arkadiusz, additional, Przybyla, Marta, additional, Kasprowska-Liśkiewicz, Daniela, additional, Nowacka-Chmielewska, Marta, additional, Malecki, Andrzej, additional, Pombero, Ana, additional, Garcia-Lopez, Raquel, additional, Martinez-Morga, Marta, additional, Martinez, Salvador, additional, Prager, Ofer, additional, Solomon-Kamintsky, Lyna, additional, Schoknecht, Karl, additional, Bar-Klein, Guy, additional, Milikovsky, Dan, additional, Vazana, Udi, additional, Rosenbach, Dror, additional, Kovács, Richard, additional, Radak, Zsolt, additional, Rodríguez-Lorenzo, Sabela, additional, Bruggmann, Remy, additional, Kooij, Gijs, additional, de Vries, Helga E, additional, Oxana, Semyachkina-Glushkovskaya, additional, Denis, Bragin, additional, Elena, Vodovozova, additional, Anna, Alekseeva, additional, Alla, Salmina, additional, Vladimir, Salmin, additional, Andrey, Morgun, additional, Nataliya, Malinovskaya, additional, Elena, Khilazheva, additional, Elizaveta, Boytsova, additional, Alexander, Shirokov, additional, Nikita, Navolokin, additional, Alla, Bucharskaya, additional, Yirong, Yang, additional, Arkady, Abdurashitov, additional, Artem, Gekalyuk, additional, Mariya, Ulanova, additional, Anastasia, Shushunova, additional, Madina, Bodrova, additional, Artem, Sagatova, additional, Alexander, Khorovodov, additional, Esmat, Shareef Ali, additional, Valery, Pavlov, additional, Artem, Tuchin, additional, Jürgen, Kurths, additional, de Abreu, Marcelle Silva, additional, Calpena, Ana C., additional, Espina, Marta, additional, García, Maria Luisa, additional, Romero, Ignacio A., additional, Male, David, additional, Storck, Steffen, additional, Hartz, Anika, additional, Pahnke, Jens, additional, Surma, Claus U., additional, Surma, M., additional, Giżejewski, Z., additional, Zieliński, H., additional, Szczepkowska, Aleksandra, additional, Kowalewska, Marta, additional, Krawczynska, Agata, additional, Herman, Andrzej P., additional, Skipor, Janina, additional, Kachappilly, Nicole, additional, Veenstra, Mike, additional, Rivera, Rosiris Leon, additional, Williams, Dionna W., additional, Morgello, Susan, additional, Berman, Joan W., additional, Wyneken, Ursula, additional, Batiz, Luis Federico, additional, Temizyürek, Arzu, additional, Khodadust, Rouhollah, additional, Küçük, Mutlu, additional, Gürses, Candan, additional, Emik, Serkan, additional, Zielińska, Magdalena, additional, Obara-Michlewska, Marta, additional, Milewski, Krzysztof, additional, Skonieczna, Edyta, additional, Fręśko, Inez, additional, Neuwelt, Edward A., additional, Maria, Ana Raquel Santa, additional, Bras, Ana Rita, additional, Lipka, Dóra, additional, Valkai, Sándor, additional, Kincses, András, additional, Dér, András, additional, and Deli, Maria A., additional

Published
2017
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32. Claudin 3-Deficient C57BL/6 Mice Display Intact Brain Barriers

Author

Dias, Mariana, Coisne, Caroline, Baden, Pascale, Lazarevic, Ivana, Francisco, David, Lyck, Ruth, Enzmann, Gaby, Deutsch, Urban, Bruggmann, Remy, Betsholtz, Christer, Furuse, Mikio, Engelhardt, Britta, Dias, Mariana, Coisne, Caroline, Baden, Pascale, Lazarevic, Ivana, Francisco, David, Lyck, Ruth, Enzmann, Gaby, Deutsch, Urban, Bruggmann, Remy, Betsholtz, Christer, Furuse, Mikio, and Engelhardt, Britta

Published
2017

35. DARC shuttles inflammatory chemokines across the blood-brain barrier during autoimmune central nervous system inflammation

Author

Minten, Carsten, Alt, Carsten, Gentner, Melanie, Frei, Elisabeth, Deutsch, Urban, Lyck, Ruth, Schaeren-Wiemers, Nicole, Rot, Antal, Engelhardt, Britta, Minten, Carsten, Alt, Carsten, Gentner, Melanie, Frei, Elisabeth, Deutsch, Urban, Lyck, Ruth, Schaeren-Wiemers, Nicole, Rot, Antal, and Engelhardt, Britta

Abstract

Trafficking of T cells into the CNS is a pathophysiological hallmark of multiple sclerosis. Using an invitro model of the blood-brain barrier, Minten etal. reveal that the atypical chemokine receptor DARC shuttles inflammatory chemokines across the barrier, where they contribute to immune cell trafficking into the brain

Published
2017

36. Cellular shuttles: monocytes/macrophages exhibit transendothelial transport of nanoparticles under physiological flow

Author

Moore, Thomas L., Hauser, Daniel, Gruber, Thomas, Rothen-Rutishauser, Barbara, Lattuada, Marco, Petri-Fink, Alke, Lyck, Ruth, Moore, Thomas L., Hauser, Daniel, Gruber, Thomas, Rothen-Rutishauser, Barbara, Lattuada, Marco, Petri-Fink, Alke, and Lyck, Ruth

Abstract

A major hurdle in the development of biomedical nanoparticles (NP) is understanding how they interact with complex biological systems and navigate biological barriers to arrive at pathological targets. It is becoming increasingly evident that merely controlling particle physicochemical properties may not be sufficient to mediate particle biodistribution in dynamic environments. Thus, researchers are increasingly turning toward more complex but likewise more physiological in vitro systems to study particle–-cell/particle–system interactions. An emerging paradigm is to utilize naturally migratory cells to act as so-called “Trojan horses” or cellular shuttles. We report here the use of monocytes/macrophages to transport NP across a confluent endothelial cell layer using a microfluidic in vitro model. With a custom-built flow chamber, we showed that physiological shear stress, when compared to low flow or static conditions, increased NP uptake by macrophages. We further provided a mathematical explanation for the effect of flow on NP uptake, namely that the physical exposure times of NP to cells is dictated by shear stress (i.e., flow rate) and results in increased particle uptake under flow. This study was extended to a multicellular, hydrodynamic in vitro model. Because monocytes are cells that naturally translocate across biological barriers, we utilized a monocyte/macrophage cell line as cellular NP transporters across an endothelial layer. In this exploratory study, we showed that monocyte/macrophage cells adhere to an endothelial layer and dynamically interact with the endothelial cells. The monocytes/macrophages took up NP and diapedesed across the endothelial layer with NP accumulating within the cellular uropod. These data illustrate that monocytes/macrophages may therefore act as active shuttles to deliver particles across endothelial barriers.

Published
2017

37. ALCAM (CD166) is involved in extravasation of monocytes rather than T cells across the blood–brain barrier

Author

Lyck, Ruth, primary, Lécuyer, Marc-André, additional, Abadier, Michael, additional, Wyss, Christof B, additional, Matti, Christoph, additional, Rosito, Maria, additional, Enzmann, Gaby, additional, Zeis, Thomas, additional, Michel, Laure, additional, García Martín, Ana B, additional, Sallusto, Federica, additional, Gosselet, Fabien, additional, Deutsch, Urban, additional, Weiner, Joshua A, additional, Schaeren-Wiemers, Nicole, additional, Prat, Alexandre, additional, and Engelhardt, Britta, additional

Published
2016
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38. The machinery underlying malaria parasite virulence is conserved between rodent and human malaria parasites

Author

De Niz, Mariana, primary, Ullrich, Ann-Katrin, additional, Heiber, Arlett, additional, Blancke Soares, Alexandra, additional, Pick, Christian, additional, Lyck, Ruth, additional, Keller, Derya, additional, Kaiser, Gesine, additional, Prado, Monica, additional, Flemming, Sven, additional, del Portillo, Hernando, additional, Janse, Chris J., additional, Heussler, Volker, additional, and Spielmann, Tobias, additional

Published
2016
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39. Intracellular domain of brain endothelial ICAM-1 is essential for T-lymphocyte-mediated signalling and migration1

Author

Greenwood, John, Amos, Claire L., Walters, Claire E., Couraud, Pierre-Olivier, Lyck, Ruth, Engelhardt, Britta, and Adamson, Peter

Subjects
Intracellular Fluid, Cytoplasm, Cell Membrane Permeability, Article, Cell Line, Cell Movement, T-Lymphocyte Subsets, Cell Adhesion, Animals, Humans, Phosphorylation, Cells, Cultured, Cell Line, Transformed, Sequence Deletion, Brain, Intercellular Adhesion Molecule-1, Coculture Techniques, Peptide Fragments, Protein Structure, Tertiary, Rats, Cross-Linking Reagents, Rats, Inbred Lew, Cell Migration Inhibition, Endothelium, Vascular, Dimerization, Signal Transduction
Abstract

In order to examine the role of the ICAM-1 C-terminal domain in mediating transendothelial T-lymphocyte migration and ICAM-1 mediated signal transduction. Mutant human ICAM-1 molecules were expressed in rat brain microvascular endothelial cells. Expression of human wild type ICAM-1 in rat brain endothelial cells (EC) resulted in a significant increase over basal levels in both adhesion and transendothelial migration of rat T-lymphocytes. EC expressing ICAM-1, in which the conserved tyrosine residue at codon 512 was substituted with phenylalanine (hICAM-1Y512F), also exhibited increased lymphocyte migration albeit less than with wild type ICAM-1. Conversely, expression of truncated human ICAM-1 proteins, in which either the intracellular domain was deleted (hICAM-1ΔC) or both the intracellular and transmembrane domains were deleted through construction of a glycophospholipid anchor (GPI-hICAM-1), did not result in an increase in lymphocyte adhesion and their ability to increase transendothelial migration was attenuated. Truncated ICAM-1 proteins were also unable to induce ICAM-1 mediated Rho GTPase activation. Rat EC treated with cell permeant penetratin-ICAM-1 peptides comprising human or rat ICAM-1 intracellular domain sequences inhibited transendothelial lymphocyte migration but not adhesion. Peptides containing a phosphotyrosine residue were equally potent at inhibiting lymphocyte migration. These data demonstrate that the intracellular domain of ICAM-1 is essential for transendothelial migration of lymphocytes, and that peptidomimetics of the ICAM-1 intracellular domain can also inhibit this process. Such competitive inhibition of transendothelial lymphocyte migration, in the absence of an affect on adhesion, further implicates ICAM-1-mediated signalling events in the facilitation of T-lymphocyte migration across brain EC. Thus agents which mimic the ICAM-1 intracellular domain may be attractive targets for novel anti-inflammatory therapeutics.

Published
2003

42. VE-PTP maintains the endothelial barrier via plakoglobin and becomes dissociated from VE-cadherin by leukocytes and by VEGF

Author

Nottebaum, Astrid F., primary, Cagna, Giuseppe, additional, Winderlich, Mark, additional, Gamp, Alexander C., additional, Linnepe, Ruth, additional, Polaschegg, Christian, additional, Filippova, Kristina, additional, Lyck, Ruth, additional, Engelhardt, Britta, additional, Kamenyeva, Olena, additional, Bixel, Maria Gabriele, additional, Butz, Stefan, additional, and Vestweber, Dietmar, additional

Published
2008
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45. HIV-1 Nef interferes with T-lymphocyte circulation through confined environments in vivo.

Author

StoIp, Bettina, ImIe, Andrea, Coelho, Fernanda Matos, Hons, Miroslav, Gorina, Roser, Lyck, Ruth, Stein, Jens V., and Fackler, Oliver T.

Subjects
HIV, T cells, LYMPH nodes, ACTIN, LYMPHOCYTES
Abstract

HIV-1 negative factor (Nef) elevates virus replication and contributes to immune evasion in vivo. As one of its established in vitro activities, Nef interferes with T-lymphocyte chemotaxis by reducing host cell actin dynamics. To explore Nef's influence on in vivo recirculation of T lymphocytes, we assessed lymph-node homing of Nef-expressing primary murine lymphocytes and found a drastic impairment in homing to peripheral lymph nodes. Intravital imaging and 3D immunofluorescence reconstruction of lymph nodes revealed that Nef potently impaired T-lymphocyte extravasation through high endothelial venules and reduced subsequent parenchymal motility. Ex vivo analyses of transendothelial migration revealed that Nef disrupted T-lymphocyte polarization and interfered with diapedesis and migration in the narrow subendothelial space. Consistently, Nef specifically affected T-lymphocyte motility modes used in dense environments that pose high physical barriers to migration. Mechanistically, inhibition of lymph node homing, subendothelial migration and cell polarization, but not diapedesis, depended on Nef's ability to inhibit host cell actin remodeling. Nef-mediated interference with in vivo recirculation of T lymphocytes may compromise T-cell help and thus represents an important mechanism for its function as a HIV pathogenicity factor. [ABSTRACT FROM AUTHOR]

Published
2012
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46. Lectin Staining of Microvascular Glycocalyx in Microfluidic Cancer Cell Extravasation Assays.

Author

Beyer, Sebastian, Blocki, Anna, Cheung, Matthew Chung Yin, Wan, Zoe Ho Ying, Mehrjou, Babak, Kamm, Roger Dale, Jung, Friedrich, and Lyck, Ruth

Subjects
GLYCOCALYX, CANCER cells, EXTRAVASATION, MICROFLUIDIC devices, UMBILICAL veins, DISEASE progression
Abstract

The endothelial glycocalyx forms the inner-most lining of human microvasculature. It ensures the physiological function of blood vessels and plays a crucial role in the occurrence and progression of microvascular diseases. The present communication aims to highlight the usefulness of high-resolution imaging of lectin (Bandeiraea Simplicifolia) stained endothelial glycocalyx in 3-dimensional microfluidic cell cultures. The microfluidic system allowed visualizing cancer cell extravasation, which is a key event in metastasis formation in cancer pathologies. In brief, microvascular networks were created through spontaneous vasculogenesis. This occurred from 3 dimensional (3D) suspensions of human umbilical vein endothelial cells (HUVECs) in hydrogels confined within microfluidic devices. Extravasation of MDA-MB-231 breast cancer cells from perfusable endothelial lumens was observed with confocal imaging of lectin-stained microvascular networks. The present work provides guidance towards optimizing the methodology used to elucidate the role of the endothelial glycocalyx during cancer cell extravasation. In particular, a high-resolution view of the endothelial glycocalyx at the site of extravasation is presented. The occurrence of glycocalyx defects is well aligned with the contemporary notion in the field that glycocalyx shedding precedes cancer cell extravasation. [ABSTRACT FROM AUTHOR]

Published
2021
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48. PECAM-1 stabilizes blood-brain barrier integrity and favors paracellular T-Cell diapedesis across the blood-brain barrier during neuroinflammation

Author

Wimmer, Isabella, Tietz, Silvia, Nishihara, Hideaki, Deutsch, Urban, Sallusto, Federica, Gosselet, Fabien, Lyck, Ruth, Muller, William A., Lassmann, Hans, Engelhardt, Britta, Wimmer, Isabella, Tietz, Silvia, Nishihara, Hideaki, Deutsch, Urban, Sallusto, Federica, Gosselet, Fabien, Lyck, Ruth, Muller, William A., Lassmann, Hans, and Engelhardt, Britta

Abstract

Breakdown of the blood-brain barrier (BBB) and increased immune cell trafficking into the central nervous system (CNS) are hallmarks of the pathogenesis of multiple sclerosis (MS). Platelet endothelial cell adhesion molecule-1 (PECAM-1; CD31) is expressed on cells of the vascular compartment and regulates vascular integrity and immune cell trafficking. Involvement of PECAM-1 in MS pathogenesis has been suggested by the detection of increased levels of soluble PECAM-1 (sPECAM-1) in the serum and CSF of MS patients. Here, we report profound upregulation of cell-bound PECAM-1 in initial (pre-phagocytic) white matter as well as active cortical grey matter MS lesions. Using a human in vitro BBB model we observed that PECAM-1 is not essential for the transmigration of human CD4+ T-cell subsets (Th1, Th1*, Th2, and Th17) across the BBB. Employing an additional in vitro BBB model based on primary mouse brain microvascular endothelial cells (pMBMECs) we show that the lack of endothelial PECAM-1 impairs BBB properties as shown by reduced transendothelial electrical resistance (TEER) and increases permeability for small molecular tracers. Investigating T-cell migration across the BBB under physiological flow by in vitro live cell imaging revealed that absence of PECAM-1 in pMBMECs did not influence arrest, polarization and crawling of effector/memory CD4+ T cells on the pMBMECs. Absence of endothelial PECAM-1 also did not affect the number of T cells able to cross the pMBMEC monolayer under flow, but surprisingly favored transcellular over paracellular T-cell diapedesis. Taken together, our data demonstrate that PECAM-1 is critically involved in regulating BBB permeability and although not required for T-cell diapedesis itself, its presence or absence influences the cellular route of T-cell diapedesis across the BBB. Upregulated expression of cell-bound PECAM-1 in human MS lesions may thus reflect vascular repair mechanisms aiming to restore BBB integrity and paracellular T-ce

49. DARC shuttles inflammatory chemokines across the blood-brain barrier during autoimmune central nervous system inflammation

Author

Minten, Carsten, Alt, Carsten, Gentner, Melanie, Frei, Elisabeth, Deutsch, Urban, Lyck, Ruth, Schaeren-Wiemers, Nicole, Rot, Antal, Engelhardt, Britta, Minten, Carsten, Alt, Carsten, Gentner, Melanie, Frei, Elisabeth, Deutsch, Urban, Lyck, Ruth, Schaeren-Wiemers, Nicole, Rot, Antal, and Engelhardt, Britta

Abstract

Trafficking of T cells into the CNS is a pathophysiological hallmark of multiple sclerosis. Using an invitro model of the blood-brain barrier, Minten etal. reveal that the atypical chemokine receptor DARC shuttles inflammatory chemokines across the barrier, where they contribute to immune cell trafficking into the brain

50. Cellular shuttles: monocytes/macrophages exhibit transendothelial transport of nanoparticles under physiological flow

Author

Moore, Thomas L., Hauser, Daniel, Gruber, Thomas, Rothen-Rutishauser, Barbara, Lattuada, Marco, Petri-Fink, Alke, Lyck, Ruth, Moore, Thomas L., Hauser, Daniel, Gruber, Thomas, Rothen-Rutishauser, Barbara, Lattuada, Marco, Petri-Fink, Alke, and Lyck, Ruth

Abstract

A major hurdle in the development of biomedical nanoparticles (NP) is understanding how they interact with complex biological systems and navigate biological barriers to arrive at pathological targets. It is becoming increasingly evident that merely controlling particle physicochemical properties may not be sufficient to mediate particle biodistribution in dynamic environments. Thus, researchers are increasingly turning toward more complex but likewise more physiological in vitro systems to study particle–-cell/particle–system interactions. An emerging paradigm is to utilize naturally migratory cells to act as so-called “Trojan horses” or cellular shuttles. We report here the use of monocytes/macrophages to transport NP across a confluent endothelial cell layer using a microfluidic in vitro model. With a custom-built flow chamber, we showed that physiological shear stress, when compared to low flow or static conditions, increased NP uptake by macrophages. We further provided a mathematical explanation for the effect of flow on NP uptake, namely that the physical exposure times of NP to cells is dictated by shear stress (i.e., flow rate) and results in increased particle uptake under flow. This study was extended to a multicellular, hydrodynamic in vitro model. Because monocytes are cells that naturally translocate across biological barriers, we utilized a monocyte/macrophage cell line as cellular NP transporters across an endothelial layer. In this exploratory study, we showed that monocyte/macrophage cells adhere to an endothelial layer and dynamically interact with the endothelial cells. The monocytes/macrophages took up NP and diapedesed across the endothelial layer with NP accumulating within the cellular uropod. These data illustrate that monocytes/macrophages may therefore act as active shuttles to deliver particles across endothelial barriers.

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