The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

Choi, Inho; Lee, Sun-Ju; Hong, Young Kwon

doi:10.1101/cshperspect.a006445

Cited by 122 publications

(115 citation statements)

References 231 publications

(237 reference statements)

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“…Identification of the same TSC2 mutation in LAM and AML in patients bearing both lesions (Carsillo et al 2000) also supports a neural crest origin of these neoplasms. The media (smooth muscular layer) portion of the anterior cardinal vein was found to be neural crest derived (Bergwerff et al 1998;Adams and Alitalo 2007), and it is from this vein that PROX1-positive endothelial cells bud off to form rudimentary lymphatic vessels during embryonic development (Choi et al 2012). However, no studies have been conducted showing derivation of the endothelium of blood or lymphatic vessels from neural crest cells.…”

Section: Discussionmentioning

confidence: 99%

Lymphatic Endothelial Differentiation in Pulmonary Lymphangioleiomyomatosis Cells

Davis

Hyjek

Husain

et al. 2013

J Histochem Cytochem.

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Pulmonary lymphangioleiomyomatosis (LAM) is a rare, low-grade neoplasm affecting almost exclusively women of childbearing age. LAM belongs to the family of perivascular epithelioid cell tumors, characterized by spindle and epithelioid cells with smooth muscle and melanocytic differentiation. LAM cells infiltrate the lungs, producing multiple, bilateral lesions rich in lymphatic channels and forming cysts, leading to respiratory insufficiency. Here we used antibodies against four lymphatic endothelial markers—podoplanin (detected by D2-40), prospero homeobox 1 (PROX1), vascular endothelial growth factor receptor 3 (VEGFR-3), and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1)—to determine whether LAM cells show lymphatic differentiation. Twelve of 12 diagnostic biopsy specimens (early-stage LAM) and 19 of 19 explants (late-stage LAM) showed immunopositivity for D2-40 in most neoplastic cells. PROX1, VEGFR-3, and LYVE1 immunoreactivity varied from scarce in the early stage to abundant in the late stage. Lymphatic endothelial, smooth muscle, and melanocytic markers were partially co-localized. These findings indicate that lymphatic endothelial differentiation is a feature of LAM and provide evidence of a previously unidentified third lineage of differentiation in this neoplasm. This study has implications for the histological diagnosis of LAM, the origin of the neoplastic cells, and potential future treatment with drugs targeting lymphangiogenesis.

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Section: Discussionmentioning

confidence: 99%

Lymphatic Endothelial Differentiation in Pulmonary Lymphangioleiomyomatosis Cells

Davis

Hyjek

Husain

et al. 2013

J Histochem Cytochem.

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“…Although the hemovascular system has been studied extensively, lymphatics have been neglected. 1 "Lymph" is Latin for "connected to water," reflecting lymph's translucency, yet our understanding of lymphatics is unclear. Several recent studies have helped to clarify lymphatics' roles in health and disease.…”

Section: Introductionmentioning

confidence: 99%

Anatomy and roles of lymphatics in inflammatory diseases

Al‐Kofahi

Yun

Minagar

et al. 2017

Clinical & Exp Neuroim

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The lymphatic system maintains tissue homeostasis by transporting interstitial fluid, lipids and debris from tissues to the main circulation, and delivers antigen and antigen presenting cells to local lymph nodes where they elicit immune responses. During inflammation, lymph flow increases to limit edema and prevents tissue antigen-presenting cell transport. Lymphatics also adjust their contractile activity to increase fluid transfer during acute inflammation. Conversely, chronic inflammation can provoke lymphostasis, which might limit pathogen spread within the circulation; however, decreased lymph flow leads to the persistence of immune cells and mediators in tissues to intensifying injury. Here, we review lymphatic structure function within the gut, heart and central nervous system, discussing potential roles of these lymphatics in the etiology of inflammatory bowel disease, myocarditis and neurovascular disease, and as novel targets for therapeutic management of several disease states.

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“…Both blood and lymphatic vessels are lined with endothelial cells (ECs), which are critical for the function and maintenance of both vascular networks (1). Normal lymphatic vascular function is required for maintaining fluid balance, immune surveillance, and lipid homeostasis (2,3).…”

mentioning

confidence: 99%

Endothelial Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Is Critical for Lymphatic Vascular Development and Function

Flach

Guo

Danai

et al. 2016

Molecular and Cellular Biology

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The molecular mechanisms underlying lymphatic vascular development and function are not well understood. Recent studies have suggested a role for endothelial cell (EC) mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) in developmental angiogenesis and atherosclerosis. Here, we show that constitutive loss of EC Map4k4 in mice causes postnatal lethality due to chylothorax, suggesting that Map4k4 is required for normal lymphatic vascular function. Mice constitutively lacking EC Map4k4 displayed dilated lymphatic capillaries, insufficient lymphatic valves, and impaired lymphatic flow; furthermore, primary ECs derived from these animals displayed enhanced proliferation compared with controls. Yeast 2-hybrid analyses identified the Ras GTPase-activating protein Rasa1, a known regulator of lymphatic development and lymphatic endothelial cell fate, as a direct interacting partner for Map4k4. Map4k4 silencing in ECs enhanced basal Ras and extracellular signal-regulated kinase (Erk) activities, and primary ECs lacking Map4k4 displayed enhanced lymphatic EC marker expression. Taken together, these results reveal that EC Map4k4 is critical for lymphatic vascular development by regulating EC quiescence and lymphatic EC fate. The vascular system is comprised of arteries and veins, which deliver nutrients to organs via capillaries and lymphatic vessels, which in turn reabsorb fluid from tissues for delivery back into the circulation. Both blood and lymphatic vessels are lined with endothelial cells (ECs), which are critical for the function and maintenance of both vascular networks (1). Normal lymphatic vascular function is required for maintaining fluid balance, immune surveillance, and lipid homeostasis (2, 3). In contrast, lymphatic vascular dysfunction is associated with numerous diseases, including developmental abnormalities, cancer metastasis, and lymphedema (4, 5). Though common pathways are involved in early vascular development, specialized molecules are required to drive and maintain lymphatic endothelial cell fate specification both during and after development (6, 7), and the signaling pathways that specifically promote lymphatic vascular development are still not well understood.Our laboratory recently demonstrated that mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) has a profound role within the endothelium to promote atherosclerosis development and lymphocyte recruitment in inducible, endotheliumspecific Map4k4 knockout animals on an Apoe Ϫ/Ϫ background (8). The present studies were designed to investigate the role of Map4k4 in endothelial cell function in more detail. We observed that mouse pups lacking endothelial Map4k4 displayed postnatal lethality due to chyle leakage into the thoracic cavity after birth (chylothorax) when constitutively expressed Cdh5 Cre (Ve-cadherin Cre) (9) was used to delete Map4k4 in the endothelium. Furthermore, animals constitutively lacking EC Map4k4 displayed dilated lymphatic capillaries, abnormal valves, and impaired lymphatic flow. Yeast 2-hybr...

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The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

Cited by 122 publications

References 231 publications

Lymphatic Endothelial Differentiation in Pulmonary Lymphangioleiomyomatosis Cells

Lymphatic Endothelial Differentiation in Pulmonary Lymphangioleiomyomatosis Cells

Anatomy and roles of lymphatics in inflammatory diseases

Endothelial Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Is Critical for Lymphatic Vascular Development and Function

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