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      Cardiac Lymphatic Vessels, Transport, and Healing of the Infarcted Heart

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          Summary

          The lymphatic vasculature plays a key role in regulating tissue fluid homeostasis, lipid transport, and immune surveillance throughout the body. Although it has been appreciated that the heart relies on lymphatic vessels to maintain fluid balance and that such balance must be tightly maintained to allow for normal cardiac output, it has only recently come to light that the lymphatic vasculature may serve as a therapeutic target with which to promote optimal healing following myocardial ischemia and infarction. This article reviews the subject of cardiac lymphatic vessels and highlights studies that imply targeting of lymphatic vessel development or transport using vascular endothelial growth factor-C therapy may serve as a promising avenue for future clinical application in the context of ischemic injury.

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          The haemangioblast generates haematopoietic cells through a haemogenic endothelium stage

          It has been proposed that during embryonic development haematopoietic cells arise from a mesodermal progenitor with both endothelial and haematopoietic potential called the haemangioblast1,2. A conflicting theory associates instead the first haematopoietic cells with a phenotypically differentiated endothelial cell with haematopoietic potential, i.e. a haemogenic endothelium3-5. Support for the haemangioblast concept was initially provided by the identification during embryonic stem (ES) cells differentiation of a clonal precursor, the blast colony-forming cell (BL-CFC), which gives rise to blast colonies with both endothelial and haematopoietic components6,7. Although recent studies have now provided evidence for the presence of this bipotential precursor in vivo 8,9, the precise mechanism of generation of haematopoietic cells from the haemangioblast still remains completely unknown. Here we demonstrate that the haemangioblast generates haematopoietic cells through the formation of a haemogenic endothelium intermediate, providing the first direct link between these two precursor populations. The cell population containing the haemogenic endothelium is transiently generated during BL-CFC development. This cell population is also present in gastrulating embryos and generates haematopoietic cells upon further culture. At the molecular level, we demonstrate that the transcription factor Scl/Tal110 is indispensable for the establishment of this haemogenic endothelium population whereas the core binding factor Runx1/AML111 is critical for generation of definitive haematopoietic cells from haemogenic endothelium. Together our results merge into a single linear developmental process the two a priori conflicting theories on the origin of haematopoietic development.
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            Selective Stimulation of Cardiac Lymphangiogenesis Reduces Myocardial Edema and Fibrosis Leading to Improved Cardiac Function Following Myocardial Infarction.

            The lymphatic system regulates interstitial tissue fluid balance, and lymphatic malfunction causes edema. The heart has an extensive lymphatic network displaying a dynamic range of lymph flow in physiology. Myocardial edema occurs in many cardiovascular diseases, eg, myocardial infarction (MI) and chronic heart failure, suggesting that cardiac lymphatic transport may be insufficient in pathology. Here, we investigate in rats the impact of MI and subsequent chronic heart failure on the cardiac lymphatic network. Further, we evaluate for the first time the functional effects of selective therapeutic stimulation of cardiac lymphangiogenesis post-MI.
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              The Lymphatic System: Integral Roles in Immunity.

              The lymphatic vasculature is not considered a formal part of the immune system, but it is critical to immunity. One of its major roles is in the coordination of the trafficking of antigen and immune cells. However, other roles in immunity are emerging. Lymphatic endothelial cells, for example, directly present antigen or express factors that greatly influence the local environment. We cover these topics herein and discuss how other properties of the lymphatic vasculature, such as mechanisms of lymphatic contraction (which immunologists traditionally do not take into account), are nonetheless integral in the immune system. Much is yet unknown, and this nascent subject is ripe for exploration. We argue that to consider the impact of lymphatic biology in any given immunological interaction is a key step toward integrating immunology with organ physiology and ultimately many complex pathologies.
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                Author and article information

                Contributors
                Journal
                JACC Basic Transl Sci
                JACC Basic Transl Sci
                JACC: Basic to Translational Science
                Elsevier
                2452-302X
                28 August 2017
                August 2017
                28 August 2017
                : 2
                : 4
                : 477-483
                Affiliations
                [a ]Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
                [b ]Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
                Author notes
                [] Address for correspondence: Dr. Li-Hao Huang, Department of Pathology and Immunology, Washington University School of Medicine, 425 South Euclid Avenue, BJCIH 8307, St. Louis, Missouri 63110. paul.huang@ 123456wustl.edu
                [∗∗ ]Dr. Gwendalyn J. Randolph, Department of Pathology and Immunology, Washington University School of Medicine, 425 South Euclid Avenue, BJCIH 8307, St. Louis, Missouri 63110. gjrandolph@ 123456wuslt.edu
                Article
                S2452-302X(17)30128-6
                10.1016/j.jacbts.2017.02.005
                5628514
                28989985
                4f2f173d-2aea-4c63-921e-9fafd994a77b
                © 2017 Washington University School of Medicine

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

                History
                : 10 January 2017
                : 15 February 2017
                : 20 February 2017
                Categories
                STATE-OF-THE-ART REVIEW

                cardiac lymphatic vessels,immune responses,interstitial edema,lymphangiogenesis,myocardial infarction,tissue fibrosis,vascular endothelial growth factor-c,lyve1, lymphatic vessel endothelial hyaluronan receptor 1,pdgfrβ, platelet-derived growth factor receptor β,prox1, prospero hemeobox1,vegf, vascular endothelial growth factor,vegfr3, vascular endothelial growth factor receptor

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