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      Liver lymphatic drainage patterns follow segmental anatomy in a murine model

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          Abstract

          The liver’s cellular functions are sustained by a hierarchical, segmentally-organized vascular system. Additionally, liver lymphatic vessels are thought to drain to perihepatic lymph nodes. Surprisingly, while recent findings highlight the importance of organ-specific lymphatics, the functional anatomy of liver lymphatics has not been mapped out. In literature, no segmental or preferential lymphatic drainage patterns are known to exist. We employ a novel murine model of liver lymphangiography and in vivo microscopy to delineate the lymphatic drainage patterns of individual liver lobes. Our data from blue dye liver lymphangiography show preferential lymphatic drainage patterns: Right lobe mainly to hepatoduodenal ligament lymph node 1 (LN1); left lobe to hepatoduodenal ligament LN1 + LN2 concurrently; median lobe showed a more variable LN1/LN2 drainage pattern with increased (sometimes exclusive) mediastinal thoracic lymph node involvement, indicating that part of the liver can drain directly to the mediastinum. Upon ferritin lymphangiography, we observed no functional communication between the lobar lymphatics. Altogether, these results show the existence of preferential lymphatic drainage patterns in the murine liver. Moreover, this drainage can occur directly to mediastinal lymph nodes and there is no interlobar lymphatic flow. Collectively, these data provide the first direct evidence that liver lymphatic drainage patterns follow segmental anatomy.

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          Structural and functional features of central nervous system lymphatics

          One of the characteristics of the CNS is the lack of a classical lymphatic drainage system. Although it is now accepted that the CNS undergoes constant immune surveillance that takes place within the meningeal compartment 1–3 , the mechanisms governing the entrance and exit of immune cells from the CNS remain poorly understood 4–6 . In searching for T cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the CSF, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the CNS. The discovery of the CNS lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and shed new light on the etiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.
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            A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules

            Aspelund et al. discover the presence of a lymphatic vessel network in the dura mater of the mouse brain and show that these dural lymphatic vessels are important for the clearance of macromolecules from the brain.
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              Cardiac lymphatics are heterogeneous in origin and respond to injury

              The lymphatic vasculature is a blind-ended network crucial for tissue fluid homeostasis, immune surveillance and lipid absorption from the gut. Recent evidence has proposed an entirely venous-derived mammalian lymphatic system. In contrast, we reveal here that cardiac lymphatic vessels have a heterogeneous cellular origin, whereby formation of at least part of the cardiac lymphatic network is independent of sprouting from veins. Multiple cre-lox based lineage tracing revealed a potential contribution from the hemogenic endothelium during development and discrete lymphatic endothelial progenitor populations were confirmed by conditional knockout of Prox1 in Tie2+ and Vav1+ compartments. In the adult heart, myocardial infarction (MI) promoted a significant lymphangiogenic response, which was augmented by treatment with VEGF-C resulting in improved cardiac function. These data prompt the re-evaluation of a century-long debate on the origin of lymphatic vessels and suggest that lymphangiogenesis may represent a therapeutic target to promote cardiac repair following injury.
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                Author and article information

                Contributors
                j.hagendoorn-3@umcutrecht.nl
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                11 December 2020
                11 December 2020
                2020
                : 10
                : 21808
                Affiliations
                [1 ]GRID grid.7692.a, ISNI 0000000090126352, Laboratory for Translational Oncology, Cancer Center, , University Medical Center Utrecht and Utrecht University, ; Heidelberglaan 100, 3584CX Utrecht, The Netherlands
                [2 ]GRID grid.32224.35, ISNI 0000 0004 0386 9924, E.L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, , Massachusetts General Hospital and Harvard Medical School, ; Boston, MA USA
                Article
                78727
                10.1038/s41598-020-78727-y
                7732834
                33311587
                d1142334-2e2a-45d4-8088-0a8b50ecc2da
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 18 June 2020
                : 12 November 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004622, KWF Kankerbestrijding;
                Award ID: UU2014-6904
                Funded by: Alexandre Suerman Young Talent Stipend
                Categories
                Article
                Custom metadata
                © The Author(s) 2020

                Uncategorized
                gastrointestinal system,physiology,gastrointestinal models,hepatology,lymphangiogenesis

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