The Experts below are selected from a list of 171 Experts worldwide ranked by ideXlab platform
Mario Novkovic - One of the best experts on this subject based on the ideXlab platform.
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b Cell zone Reticular Cell microenvironments shape cxcl13 gradient formation
Nature Communications, 2020Co-Authors: Mario Novkovic, Jovana Cupovic, Lucas Onder, Natalia Pikor, Jason Cosgrove, Stefan Albrecht, Zhaoukun Zhou, Urs Morbe, Helen MillerAbstract:Through the formation of concentration gradients, morphogens drive graded responses to extraCellular signals, thereby fine-tuning Cell behaviors in complex tissues. Here we show that the chemokine CXCL13 forms both soluble and immobilized gradients. Specifically, CXCL13+ follicular Reticular Cells form a small-world network of guidance structures, with computer simulations and optimization analysis predicting that immobilized gradients created by this network promote B Cell trafficking. Consistent with this prediction, imaging analysis show that CXCL13 binds to extraCellular matrix components in situ, constraining its diffusion. CXCL13 solubilization requires the protease cathepsin B that cleaves CXCL13 into a stable product. Mice lacking cathepsin B display aberrant follicular architecture, a phenotype associated with effective B Cell homing to but not within lymph nodes. Our data thus suggest that Reticular Cells of the B Cell zone generate microenvironments that shape both immobilized and soluble CXCL13 gradients. Morphogens such as chemokines form gradients to direct graded responses and modulate Cell behaviors. Here the authors show, using imaging and computer simulation, that the chemokine CXCL13 originated from follicular Reticular Cells in the lymph nodes forms both soluble and immobilized gradients to regulate B Cell recruitment and migration.
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Origin and differentiation trajectories of fibroblastic Reticular Cells in the splenic white pulp.
Nature Communications, 2019Co-Authors: Hung-wei Cheng, Mario Novkovic, Elke Scandella, Lucas Onder, Charlotte Soneson, Mechthild Lütge, Natalia Pikor, Mark D. Robinson, Jun-ichi Miyazaki, Anne TersteegenAbstract:The splenic white pulp is underpinned by poorly characterized stromal Cells that demarcate distinct immune Cell microenvironments. Here we establish fibroblastic Reticular Cell (FRC)-specific fate-mapping in mice to define their embryonic origin and differentiation trajectories. Our data show that all Reticular Cell subsets descend from multipotent progenitors emerging at embryonic day 19.5 from periarterial progenitors. Commitment of FRC progenitors is concluded during the first week of postnatal life through occupation of niches along developing central arterioles. Single Cell transcriptomic analysis facilitated deconvolution of FRC differentiation trajectories and indicated that perivascular Reticular Cells function both as adult lymphoid organizer Cells and mural Cell progenitors. The lymphotoxin-β receptor-independent sustenance of postnatal progenitor stemness unveils that systemic immune surveillance in the splenic white pulp is governed through subset specification of Reticular Cells from a multipotent periarterial progenitor Cell. In sum, the finding that discrete signaling events in perivascular niches determine the differentiation trajectories of Reticular Cell networks explains the development of distinct microenvironmental niches in secondary and tertiary lymphoid tissues that are crucial for the induction and regulation of innate and adaptive immune processes.
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graph theory based analysis of the lymph node fibroblastic Reticular Cell network
Methods of Molecular Biology, 2017Co-Authors: Mario Novkovic, Gennady Bocharov, Lucas Onder, Burkhard LudewigAbstract:Secondary lymphoid organs have developed segregated niches that are able to initiate and maintain effective immune responses. Such global organization requires tight control of diverse Cellular components, specifically those that regulate lymphocyte trafficking. Fibroblastic Reticular Cells (FRCs) form a densely interconnected network in lymph nodes and provide key factors necessary for T Cell migration and retention, and foster subsequent interactions between T Cells and dendritic Cells. Development of integrative systems biology approaches has made it possible to elucidate this multilevel complexity of the immune system. Here, we present a graph theory-based analysis of the FRC network in murine lymph nodes, where generation of the network topology is performed using high-resolution confocal microscopy and 3D reconstruction. This approach facilitates the analysis of physical Cell-to-Cell connectivity, and estimation of topological robustness and global behavior of the network when it is subjected to perturbation in silico.
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topological small world organization of the fibroblastic Reticular Cell network determines lymph node functionality
PLOS Biology, 2016Co-Authors: Mario Novkovic, Viviana Cremasco, Elke Scandella, Jens V. Stein, Gennady Bocharov, D Bomze, Jovana Cupovic, Lucas Onder, Shannon J. Turley, Burkhard LudewigAbstract:Fibroblastic Reticular Cells (FRCs) form the Cellular scaffold of lymph nodes (LNs) and establish distinct microenvironmental niches to provide key molecules that drive innate and adaptive immune responses and control immune regulatory processes. Here, we have used a graph theory-based systems biology approach to determine topological properties and robustness of the LN FRC network in mice. We found that the FRC network exhibits an imprinted small-world topology that is fully regenerated within 4 wk after complete FRC ablation. Moreover, in silico perturbation analysis and in vivo validation revealed that LNs can tolerate a loss of approximately 50% of their FRCs without substantial impairment of immune Cell recruitment, intranodal T Cell migration, and dendritic Cell-mediated activation of antiviral CD8+ T Cells. Overall, our study reveals the high topological robustness of the FRC network and the critical role of the network integrity for the activation of adaptive immune responses.
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Topological Small-World Organization of the Fibroblastic Reticular Cell Network Determines Lymph Node Functionality
PLoS Biology, 2016Co-Authors: Mario Novkovic, Viviana Cremasco, Elke Scandella, Jens V. Stein, Gennady Bocharov, Jun Abe, D Bomze, Jovana Cupovic, Lucas Onder, Shannon J. TurleyAbstract:Topological complex network analysis reveals an underlying robust
Lucas Onder - One of the best experts on this subject based on the ideXlab platform.
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b Cell zone Reticular Cell microenvironments shape cxcl13 gradient formation
Nature Communications, 2020Co-Authors: Mario Novkovic, Jovana Cupovic, Lucas Onder, Natalia Pikor, Jason Cosgrove, Stefan Albrecht, Zhaoukun Zhou, Urs Morbe, Helen MillerAbstract:Through the formation of concentration gradients, morphogens drive graded responses to extraCellular signals, thereby fine-tuning Cell behaviors in complex tissues. Here we show that the chemokine CXCL13 forms both soluble and immobilized gradients. Specifically, CXCL13+ follicular Reticular Cells form a small-world network of guidance structures, with computer simulations and optimization analysis predicting that immobilized gradients created by this network promote B Cell trafficking. Consistent with this prediction, imaging analysis show that CXCL13 binds to extraCellular matrix components in situ, constraining its diffusion. CXCL13 solubilization requires the protease cathepsin B that cleaves CXCL13 into a stable product. Mice lacking cathepsin B display aberrant follicular architecture, a phenotype associated with effective B Cell homing to but not within lymph nodes. Our data thus suggest that Reticular Cells of the B Cell zone generate microenvironments that shape both immobilized and soluble CXCL13 gradients. Morphogens such as chemokines form gradients to direct graded responses and modulate Cell behaviors. Here the authors show, using imaging and computer simulation, that the chemokine CXCL13 originated from follicular Reticular Cells in the lymph nodes forms both soluble and immobilized gradients to regulate B Cell recruitment and migration.
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Origin and differentiation trajectories of fibroblastic Reticular Cells in the splenic white pulp.
Nature Communications, 2019Co-Authors: Hung-wei Cheng, Mario Novkovic, Elke Scandella, Lucas Onder, Charlotte Soneson, Mechthild Lütge, Natalia Pikor, Mark D. Robinson, Jun-ichi Miyazaki, Anne TersteegenAbstract:The splenic white pulp is underpinned by poorly characterized stromal Cells that demarcate distinct immune Cell microenvironments. Here we establish fibroblastic Reticular Cell (FRC)-specific fate-mapping in mice to define their embryonic origin and differentiation trajectories. Our data show that all Reticular Cell subsets descend from multipotent progenitors emerging at embryonic day 19.5 from periarterial progenitors. Commitment of FRC progenitors is concluded during the first week of postnatal life through occupation of niches along developing central arterioles. Single Cell transcriptomic analysis facilitated deconvolution of FRC differentiation trajectories and indicated that perivascular Reticular Cells function both as adult lymphoid organizer Cells and mural Cell progenitors. The lymphotoxin-β receptor-independent sustenance of postnatal progenitor stemness unveils that systemic immune surveillance in the splenic white pulp is governed through subset specification of Reticular Cells from a multipotent periarterial progenitor Cell. In sum, the finding that discrete signaling events in perivascular niches determine the differentiation trajectories of Reticular Cell networks explains the development of distinct microenvironmental niches in secondary and tertiary lymphoid tissues that are crucial for the induction and regulation of innate and adaptive immune processes.
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graph theory based analysis of the lymph node fibroblastic Reticular Cell network
Methods of Molecular Biology, 2017Co-Authors: Mario Novkovic, Gennady Bocharov, Lucas Onder, Burkhard LudewigAbstract:Secondary lymphoid organs have developed segregated niches that are able to initiate and maintain effective immune responses. Such global organization requires tight control of diverse Cellular components, specifically those that regulate lymphocyte trafficking. Fibroblastic Reticular Cells (FRCs) form a densely interconnected network in lymph nodes and provide key factors necessary for T Cell migration and retention, and foster subsequent interactions between T Cells and dendritic Cells. Development of integrative systems biology approaches has made it possible to elucidate this multilevel complexity of the immune system. Here, we present a graph theory-based analysis of the FRC network in murine lymph nodes, where generation of the network topology is performed using high-resolution confocal microscopy and 3D reconstruction. This approach facilitates the analysis of physical Cell-to-Cell connectivity, and estimation of topological robustness and global behavior of the network when it is subjected to perturbation in silico.
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topological small world organization of the fibroblastic Reticular Cell network determines lymph node functionality
PLOS Biology, 2016Co-Authors: Mario Novkovic, Viviana Cremasco, Elke Scandella, Jens V. Stein, Gennady Bocharov, D Bomze, Jovana Cupovic, Lucas Onder, Shannon J. Turley, Burkhard LudewigAbstract:Fibroblastic Reticular Cells (FRCs) form the Cellular scaffold of lymph nodes (LNs) and establish distinct microenvironmental niches to provide key molecules that drive innate and adaptive immune responses and control immune regulatory processes. Here, we have used a graph theory-based systems biology approach to determine topological properties and robustness of the LN FRC network in mice. We found that the FRC network exhibits an imprinted small-world topology that is fully regenerated within 4 wk after complete FRC ablation. Moreover, in silico perturbation analysis and in vivo validation revealed that LNs can tolerate a loss of approximately 50% of their FRCs without substantial impairment of immune Cell recruitment, intranodal T Cell migration, and dendritic Cell-mediated activation of antiviral CD8+ T Cells. Overall, our study reveals the high topological robustness of the FRC network and the critical role of the network integrity for the activation of adaptive immune responses.
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Central Nervous System Stromal Cells Control Local CD8+ T Cell Responses during Virus-Induced Neuroinflammation
Immunity, 2016Co-Authors: Jovana Cupovic, Lucas Onder, Elke Weiler, Sonja Caviezel-firner, Christian Perez-shibayama, Cristina Cruz, Ingo Bechmann, Thomas Rulicke, Burkhard LudewigAbstract:Summary Stromal Cells generate a complex Cellular scaffold that provides specialized microenvironments for lymphocyte activation in secondary lymphoid organs. Here, we assessed whether local activation of stromal Cells in the central nervous system (CNS) is mandatory to transfer immune recognition from secondary lymphoid organs into the infected tissue. We report that neurotropic virus infection in mice triggered the establishment of such stromal Cell niches in the CNS. CNS stromal Cell activation was dominated by a rapid and vigorous production of CC-motif chemokine receptor (CCR) 7 ligands CCL19 and CCL21 by vascular endothelial Cells and adjacent fibroblastic Reticular Cell (FRC)-like Cells in the perivascular space. Moreover, CCR7 ligands produced by CNS stromal Cells were crucial to support recruitment and local re-activation of antiviral CD8 + T Cells and to protect the host from lethal neuroinflammatory disease, indicating that CNS stromal Cells generate confined microenvironments that control protective T Cell immunity.
Shannon J. Turley - One of the best experts on this subject based on the ideXlab platform.
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topological small world organization of the fibroblastic Reticular Cell network determines lymph node functionality
PLOS Biology, 2016Co-Authors: Mario Novkovic, Viviana Cremasco, Elke Scandella, Jens V. Stein, Gennady Bocharov, D Bomze, Jovana Cupovic, Lucas Onder, Shannon J. Turley, Burkhard LudewigAbstract:Fibroblastic Reticular Cells (FRCs) form the Cellular scaffold of lymph nodes (LNs) and establish distinct microenvironmental niches to provide key molecules that drive innate and adaptive immune responses and control immune regulatory processes. Here, we have used a graph theory-based systems biology approach to determine topological properties and robustness of the LN FRC network in mice. We found that the FRC network exhibits an imprinted small-world topology that is fully regenerated within 4 wk after complete FRC ablation. Moreover, in silico perturbation analysis and in vivo validation revealed that LNs can tolerate a loss of approximately 50% of their FRCs without substantial impairment of immune Cell recruitment, intranodal T Cell migration, and dendritic Cell-mediated activation of antiviral CD8+ T Cells. Overall, our study reveals the high topological robustness of the FRC network and the critical role of the network integrity for the activation of adaptive immune responses.
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Topological Small-World Organization of the Fibroblastic Reticular Cell Network Determines Lymph Node Functionality
PLoS Biology, 2016Co-Authors: Mario Novkovic, Viviana Cremasco, Elke Scandella, Jens V. Stein, Gennady Bocharov, Jun Abe, D Bomze, Jovana Cupovic, Lucas Onder, Shannon J. TurleyAbstract:Topological complex network analysis reveals an underlying robust
Jovana Cupovic - One of the best experts on this subject based on the ideXlab platform.
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b Cell zone Reticular Cell microenvironments shape cxcl13 gradient formation
Nature Communications, 2020Co-Authors: Mario Novkovic, Jovana Cupovic, Lucas Onder, Natalia Pikor, Jason Cosgrove, Stefan Albrecht, Zhaoukun Zhou, Urs Morbe, Helen MillerAbstract:Through the formation of concentration gradients, morphogens drive graded responses to extraCellular signals, thereby fine-tuning Cell behaviors in complex tissues. Here we show that the chemokine CXCL13 forms both soluble and immobilized gradients. Specifically, CXCL13+ follicular Reticular Cells form a small-world network of guidance structures, with computer simulations and optimization analysis predicting that immobilized gradients created by this network promote B Cell trafficking. Consistent with this prediction, imaging analysis show that CXCL13 binds to extraCellular matrix components in situ, constraining its diffusion. CXCL13 solubilization requires the protease cathepsin B that cleaves CXCL13 into a stable product. Mice lacking cathepsin B display aberrant follicular architecture, a phenotype associated with effective B Cell homing to but not within lymph nodes. Our data thus suggest that Reticular Cells of the B Cell zone generate microenvironments that shape both immobilized and soluble CXCL13 gradients. Morphogens such as chemokines form gradients to direct graded responses and modulate Cell behaviors. Here the authors show, using imaging and computer simulation, that the chemokine CXCL13 originated from follicular Reticular Cells in the lymph nodes forms both soluble and immobilized gradients to regulate B Cell recruitment and migration.
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topological small world organization of the fibroblastic Reticular Cell network determines lymph node functionality
PLOS Biology, 2016Co-Authors: Mario Novkovic, Viviana Cremasco, Elke Scandella, Jens V. Stein, Gennady Bocharov, D Bomze, Jovana Cupovic, Lucas Onder, Shannon J. Turley, Burkhard LudewigAbstract:Fibroblastic Reticular Cells (FRCs) form the Cellular scaffold of lymph nodes (LNs) and establish distinct microenvironmental niches to provide key molecules that drive innate and adaptive immune responses and control immune regulatory processes. Here, we have used a graph theory-based systems biology approach to determine topological properties and robustness of the LN FRC network in mice. We found that the FRC network exhibits an imprinted small-world topology that is fully regenerated within 4 wk after complete FRC ablation. Moreover, in silico perturbation analysis and in vivo validation revealed that LNs can tolerate a loss of approximately 50% of their FRCs without substantial impairment of immune Cell recruitment, intranodal T Cell migration, and dendritic Cell-mediated activation of antiviral CD8+ T Cells. Overall, our study reveals the high topological robustness of the FRC network and the critical role of the network integrity for the activation of adaptive immune responses.
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Central Nervous System Stromal Cells Control Local CD8+ T Cell Responses during Virus-Induced Neuroinflammation
Immunity, 2016Co-Authors: Jovana Cupovic, Lucas Onder, Elke Weiler, Sonja Caviezel-firner, Christian Perez-shibayama, Cristina Cruz, Ingo Bechmann, Thomas Rulicke, Burkhard LudewigAbstract:Summary Stromal Cells generate a complex Cellular scaffold that provides specialized microenvironments for lymphocyte activation in secondary lymphoid organs. Here, we assessed whether local activation of stromal Cells in the central nervous system (CNS) is mandatory to transfer immune recognition from secondary lymphoid organs into the infected tissue. We report that neurotropic virus infection in mice triggered the establishment of such stromal Cell niches in the CNS. CNS stromal Cell activation was dominated by a rapid and vigorous production of CC-motif chemokine receptor (CCR) 7 ligands CCL19 and CCL21 by vascular endothelial Cells and adjacent fibroblastic Reticular Cell (FRC)-like Cells in the perivascular space. Moreover, CCR7 ligands produced by CNS stromal Cells were crucial to support recruitment and local re-activation of antiviral CD8 + T Cells and to protect the host from lethal neuroinflammatory disease, indicating that CNS stromal Cells generate confined microenvironments that control protective T Cell immunity.
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Topological Small-World Organization of the Fibroblastic Reticular Cell Network Determines Lymph Node Functionality
PLoS Biology, 2016Co-Authors: Mario Novkovic, Viviana Cremasco, Elke Scandella, Jens V. Stein, Gennady Bocharov, Jun Abe, D Bomze, Jovana Cupovic, Lucas Onder, Shannon J. TurleyAbstract:Topological complex network analysis reveals an underlying robust
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Maturation of Lymph Node Fibroblastic Reticular Cells from Myofibroblastic Precursors Is Critical for Antiviral Immunity
Immunity, 2013Co-Authors: Qian Chai, Elke Scandella, Jovana Cupovic, Lucas Onder, Christian Perez-shibayama, Cristina Cruz, Renzo Danuser, Tim Sparwasser, Sanjiv A. Luther, Volker ThielAbstract:The stromal scaffold of the lymph node (LN) paracortex is built by fibroblastic Reticular Cells (FRCs). Conditional ablation of lymphotoxin-β receptor (LTβR) expression in LN FRCs and their mesenchymal progenitors in developing LNs revealed that LTβR-signaling in these Cells was not essential for the formation of LNs. Although T Cell zone Reticular Cells had lost podoplanin expression, they still formed a functional conduit system and showed enhanced expression of myofibroblastic markers. However, essential immune functions of FRCs, including homeostatic chemokine and interleukin-7 expression, were impaired. These changes in T Cell zone Reticular Cell function were associated with increased susceptibility to viral infection. Thus, myofibroblasic FRC precursors are able to generate the basic T Cell zone infrastructure, whereas LTβR-dependent maturation of FRCs guarantees full immunocompetence and hence optimal LN function during infection.
Elke Scandella - One of the best experts on this subject based on the ideXlab platform.
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Origin and differentiation trajectories of fibroblastic Reticular Cells in the splenic white pulp.
Nature Communications, 2019Co-Authors: Hung-wei Cheng, Mario Novkovic, Elke Scandella, Lucas Onder, Charlotte Soneson, Mechthild Lütge, Natalia Pikor, Mark D. Robinson, Jun-ichi Miyazaki, Anne TersteegenAbstract:The splenic white pulp is underpinned by poorly characterized stromal Cells that demarcate distinct immune Cell microenvironments. Here we establish fibroblastic Reticular Cell (FRC)-specific fate-mapping in mice to define their embryonic origin and differentiation trajectories. Our data show that all Reticular Cell subsets descend from multipotent progenitors emerging at embryonic day 19.5 from periarterial progenitors. Commitment of FRC progenitors is concluded during the first week of postnatal life through occupation of niches along developing central arterioles. Single Cell transcriptomic analysis facilitated deconvolution of FRC differentiation trajectories and indicated that perivascular Reticular Cells function both as adult lymphoid organizer Cells and mural Cell progenitors. The lymphotoxin-β receptor-independent sustenance of postnatal progenitor stemness unveils that systemic immune surveillance in the splenic white pulp is governed through subset specification of Reticular Cells from a multipotent periarterial progenitor Cell. In sum, the finding that discrete signaling events in perivascular niches determine the differentiation trajectories of Reticular Cell networks explains the development of distinct microenvironmental niches in secondary and tertiary lymphoid tissues that are crucial for the induction and regulation of innate and adaptive immune processes.
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topological small world organization of the fibroblastic Reticular Cell network determines lymph node functionality
PLOS Biology, 2016Co-Authors: Mario Novkovic, Viviana Cremasco, Elke Scandella, Jens V. Stein, Gennady Bocharov, D Bomze, Jovana Cupovic, Lucas Onder, Shannon J. Turley, Burkhard LudewigAbstract:Fibroblastic Reticular Cells (FRCs) form the Cellular scaffold of lymph nodes (LNs) and establish distinct microenvironmental niches to provide key molecules that drive innate and adaptive immune responses and control immune regulatory processes. Here, we have used a graph theory-based systems biology approach to determine topological properties and robustness of the LN FRC network in mice. We found that the FRC network exhibits an imprinted small-world topology that is fully regenerated within 4 wk after complete FRC ablation. Moreover, in silico perturbation analysis and in vivo validation revealed that LNs can tolerate a loss of approximately 50% of their FRCs without substantial impairment of immune Cell recruitment, intranodal T Cell migration, and dendritic Cell-mediated activation of antiviral CD8+ T Cells. Overall, our study reveals the high topological robustness of the FRC network and the critical role of the network integrity for the activation of adaptive immune responses.
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Topological Small-World Organization of the Fibroblastic Reticular Cell Network Determines Lymph Node Functionality
PLoS Biology, 2016Co-Authors: Mario Novkovic, Viviana Cremasco, Elke Scandella, Jens V. Stein, Gennady Bocharov, Jun Abe, D Bomze, Jovana Cupovic, Lucas Onder, Shannon J. TurleyAbstract:Topological complex network analysis reveals an underlying robust
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Maturation of Lymph Node Fibroblastic Reticular Cells from Myofibroblastic Precursors Is Critical for Antiviral Immunity
Immunity, 2013Co-Authors: Qian Chai, Elke Scandella, Jovana Cupovic, Lucas Onder, Christian Perez-shibayama, Cristina Cruz, Renzo Danuser, Tim Sparwasser, Sanjiv A. Luther, Volker ThielAbstract:The stromal scaffold of the lymph node (LN) paracortex is built by fibroblastic Reticular Cells (FRCs). Conditional ablation of lymphotoxin-β receptor (LTβR) expression in LN FRCs and their mesenchymal progenitors in developing LNs revealed that LTβR-signaling in these Cells was not essential for the formation of LNs. Although T Cell zone Reticular Cells had lost podoplanin expression, they still formed a functional conduit system and showed enhanced expression of myofibroblastic markers. However, essential immune functions of FRCs, including homeostatic chemokine and interleukin-7 expression, were impaired. These changes in T Cell zone Reticular Cell function were associated with increased susceptibility to viral infection. Thus, myofibroblasic FRC precursors are able to generate the basic T Cell zone infrastructure, whereas LTβR-dependent maturation of FRCs guarantees full immunocompetence and hence optimal LN function during infection.