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      Macrophage-Induced Blood Vessels Guide Schwann Cell-Mediated Regeneration of Peripheral Nerves

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          Summary

          The peripheral nervous system has remarkable regenerative capacities in that it can repair a fully cut nerve. This requires Schwann cells to migrate collectively to guide regrowing axons across a ‘bridge’ of new tissue, which forms to reconnect a severed nerve. Here we show that blood vessels direct the migrating cords of Schwann cells. This multicellular process is initiated by hypoxia, selectively sensed by macrophages within the bridge, which via VEGF-A secretion induce a polarized vasculature that relieves the hypoxia. Schwann cells then use the blood vessels as “tracks” to cross the bridge taking regrowing axons with them. Importantly, disrupting the organization of the newly formed blood vessels in vivo, either by inhibiting the angiogenic signal or by re-orienting them, compromises Schwann cell directionality resulting in defective nerve repair. This study provides important insights into how the choreography of multiple cell-types is required for the regeneration of an adult tissue.

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          Highlights

          • Hypoxia within the nerve bridge is selectively sensed by macrophages

          • Macrophage-derived VEGF-A induces a polarized vasculature within the bridge

          • Blood vessels are used as tracks to direct Schwann cell migration across the wound

          • Macrophage-induced blood vessels are essential for nerve regeneration

          Abstract

          Repairing a cut nerve requires collective migration of Schwann cells guided by a polarized vasculature that is induced by macrophages within the hypoxic bridge.

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          Most cited references26

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          Conditional gene targeting in macrophages and granulocytes using LysMcre mice.

          Conditional mutagenesis in mice has recently been made possible through the combination of gene targeting techniques and site-directed mutagenesis, using the bacteriophage P1-derived Cre/loxP recombination system. The versatility of this approach depends on the availability of mouse mutants in which the recombinase Cre is expressed in the appropriate cell lineages or tissues. Here we report the generation of mice that express Cre in myeloid cells due to targeted insertion of the cre cDNA into their endogenous M lysozyme locus. In double mutant mice harboring both the LysMcre allele and one of two different loxP-flanked target genes tested, a deletion efficiency of 83-98% was determined in mature macrophages and near 100% in granulocytes. Partial deletion (16%) could be detected in CD11c+ splenic dendritic cells which are closely related to the monocyte/macrophage lineage. In contrast, no significant deletion was observed in tail DNA or purified T and B cells. Taken together, LysMcre mice allow for both specific and highly efficient Cre-mediated deletion of loxP-flanked target genes in myeloid cells.
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            Autocrine VEGF signaling is required for vascular homeostasis.

            Vascular endothelial growth factor (VEGF) is essential for developmental and pathological angiogenesis. Here we show that in the absence of any pathological insult, autocrine VEGF is required for the homeostasis of blood vessels in the adult. Genetic deletion of vegf specifically in the endothelial lineage leads to progressive endothelial degeneration and sudden death in 55% of mutant mice by 25 weeks of age. The phenotype is manifested without detectable changes in the total levels of VEGF mRNA or protein, indicating that paracrine VEGF could not compensate for the absence of endothelial VEGF. Furthermore, wild-type, but not VEGF null, endothelial cells showed phosphorylation of VEGFR2 in the absence of exogenous VEGF. Activation of the receptor in wild-type cells was suppressed by small molecule antagonists but not by extracellular blockade of VEGF. These results reveal a cell-autonomous VEGF signaling pathway that holds significance for vascular homeostasis but is dispensable for the angiogenic cascade.
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              From cells to organs: building polarized tissue.

              How do animal cells assemble into tissues and organs? A diverse array of tissue structures and shapes can be formed by organizing groups of cells into different polarized arrangements and by coordinating their polarity in space and time. Conserved design principles underlying this diversity are emerging from studies of model organisms and tissues. We discuss how conserved polarity complexes, signalling networks, transcription factors, membrane-trafficking pathways, mechanisms for forming lumens in tubes and other hollow structures, and transitions between different types of polarity, such as between epithelial and mesenchymal cells, are used in similar and iterative manners to build all tissues.
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                Author and article information

                Contributors
                Journal
                Cell
                Cell
                Cell
                Cell Press
                0092-8674
                1097-4172
                27 August 2015
                27 August 2015
                : 162
                : 5
                : 1127-1139
                Affiliations
                [1 ]MRC Laboratory for Molecular Cell Biology, UCL, Gower Street, London WC1E 6BT, UK
                [2 ]UCL Cancer Institute, UCL, 72 Huntley Street, London WC1E 6DD, UK
                [3 ]Department of Cell Biology, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
                Author notes
                []Corresponding author alison.lloyd@ 123456ucl.ac.uk
                Article
                S0092-8674(15)00898-3
                10.1016/j.cell.2015.07.021
                4553238
                26279190
                ed8af598-c4f0-41a0-b459-9bd9cee73538
                © 2015 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 19 April 2015
                : 11 June 2015
                : 30 June 2015
                Categories
                Article

                Cell biology
                Cell biology

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