Biological functions of lymphatic vessels Petrova, Tatiana V.; Koh, Gou Young
Science (American Association for the Advancement of Science),
07/2020, Letnik:
369, Številka:
6500
Journal Article
Recenzirano
Roles of organ-specific lymphatic vessels
Lymphatic vessels are spread throughout the human body and have critical functions in mammalian physiology. Petrova
et al.
review emerging roles of the ...lymphatic vasculature in organ function and pathology and provide perspectives beyond the traditional view of lymphatic vessels in the maintenance of fluid homeostasis. The authors highlight new insights into lymphatic vessel function and lymphatic endothelial cell biology as it relates to intestinal lacteals, lymph nodes, central nervous system meninges, and cancer. Recent steps toward therapeutic opportunities that could alter lymphatic function or growth are also discussed.
Science
, this issue p.
eaax4063
BACKGROUND
Blood and lymphatic vessel networks form two arms of the vertebrate cardiovascular system that play complementary roles in body homeostasis maintenance and multiple diseases. Lymphatic vessels are lined with lymphatic endothelial cells (LECs), which represent a distinct endothelial cell lineage characterized by a specific transcriptional and metabolic program. The general functions of lymphatic vessels in fluid transport and immunosurveillance are well recognized, as is their specialization into capillaries, serving as an entrance point of interstitial components and immune cells and collecting vessels that deliver lymph to lymph nodes (LNs) and blood circulation. It is becoming increasingly clear that adult lymphatic vessels, exposed to different organ-specific environments, acquire distinct characteristics and in turn execute multiple tissue-specific functions.
ADVANCES
This Review provides an overview of the recent advances in our understanding of new functions of adult mammalian lymphatic vessels, such as immunomodulation, contribution to neurodegenerative and neuroinflammatory diseases, and response to anticancer therapies. LN LECs have been shown to archive antigens and directly regulate immune cell properties, including immune cell survival and positioning within the LN. Rediscovery of meningeal lymphatic vessels has uprooted the dogma of brain immune privilege, and these vessels now emerge as key regulators of neuroinflammation and neurodegeneration. Intestinal lacteals display distinct cellular characteristics that make them especially suitable for dietary fat uptake and designate them as promising targets for the treatment of obesity. Tumor lymphatics have long been recognized as conduits for metastatic cell dissemination; however, recent data show that lymphatic vessels have multiple additional functions, such as forming metastatic cancer cell niches but also controlling productive response to antitumor immune therapies. Last, discovery of vascular beds with hybrid blood and lymphatic characteristics, such as the Schlemm’s canal in the eye and the kidney ascending vasa recta, underscores the degree and potential of endothelial cell plasticity.
OUTLOOK
Molecular characteristics of organ-specific vascular beds and understanding their organotypic functions are among the current fundamental questions of vascular biology. Emerging evidence points to the major contribution of lymphatic vessels, a vascular system generally associated only with tissue-drainage functions. High-resolution analyses of endothelial heterogeneity and organotypic lymphatic vessel architecture, in addition to deciphering the molecular codes that LECs use for communication with other cell types, are necessary to fully understand the role of lymphatics in organ physiology and pathology. Integration of such knowledge with research from other fields, such as immunology and bioengineering, will uncover new possibilities for promoting tissue regeneration and developing new therapies for cancer, obesity, neuroinflammation, and neurodegeneration.
Organ-specific lymphatic vessels in small intestine, meninges, and LN.
(Left) Small intestine. Shown are LYVE-1
+
(green) lacteal, CD31
+
(red) capillary plexus, and α-smooth actin
+
(blue) longitudinal smooth muscle cells. (Middle) Meninges. Shown are LYVE-1
+
(green) and VEGFR3
+
(blue) lymphatic vessels and CD31
+
(red) blood vessels. (Right) LN. Shown are LYVE-1
+
(green) lymphatic vessels and CD31
+
(red) blood vessels, including high endothelial venules.
IMAGES: J. BERNIER-LATMANI AND H. CHO
The general functions of lymphatic vessels in fluid transport and immunosurveillance are well recognized. However, accumulating evidence indicates that lymphatic vessels play active and versatile roles in a tissue- and organ-specific manner during homeostasis and in multiple disease processes. This Review discusses recent advances to understand previously unidentified functions of adult mammalian lymphatic vessels, including immunosurveillance and immunomodulation upon pathogen invasion, transport of dietary fat, drainage of cerebrospinal fluid and aqueous humor, possible contributions toward neurodegenerative and neuroinflammatory diseases, and response to anticancer therapies.
Recent discoveries of novel functions and diverse origins of lymphatic vessels have drastically changed our view of lymphatic vasculature. Traditionally regarded as passive conduits for fluid and ...immune cells, lymphatic vessels now emerge as active, tissue-specific players in major physiological and pathophysiological processes. Lymphatic vessels show remarkable plasticity and heterogeneity, reflecting their functional specialization to control the tissue microenvironment. Moreover, alternative developmental origins of lymphatic endothelial cells in some organs may contribute to the diversity of their functions in adult tissues. This review aims to summarize the most recent findings of organotypic differentiation of lymphatic endothelial cells in terms of their distinct (patho)physiological functions in skin, lymph nodes, small intestine, brain, and eye. We discuss recent advances in our understanding of the heterogeneity of lymphatic vessels with respect to the organ-specific functional and molecular specialization of lymphatic endothelium, such as the hybrid blood-lymphatic identity of Schlemm's canal, functions of intestinal lymphatics in dietary fat uptake, and discovery of meningeal lymphatic vasculature and perivascular brain lymphatic endothelial cells.
Tumours display considerable variation in the patterning and properties of angiogenic blood vessels, as well as in their responses to anti-angiogenic therapy. Angiogenic programming of neoplastic ...tissue is a multidimensional process regulated by cancer cells in concert with a variety of tumour-associated stromal cells and their bioactive products, which encompass cytokines and growth factors, the extracellular matrix and secreted microvesicles. In this Review, we discuss the extrinsic regulation of angiogenesis by the tumour microenvironment, highlighting potential vulnerabilities that could be targeted to improve the applicability and reach of anti-angiogenic cancer therapies.
The mammalian intestine is richly supplied with lymphatic vasculature, which has functions ranging from maintenance of interstitial fluid balance to transport of antigens, antigen-presenting cells, ...dietary lipids and fat-soluble vitamins. In this Review, we provide in-depth information concerning the organization and structure of intestinal lymphatics, the current view of their developmental origins, as well as molecular mechanisms of intestinal lymphatic patterning and maintenance. We will also discuss physiological aspects of intestinal lymph flow regulation and the known and emerging roles of intestinal lymphatic vessels in human diseases, such as IBD, infection and cancer.
The mammalian lymphatic system consists of strategically located lymph nodes (LNs) embedded into a lymphatic vascular network. Mechanisms underlying development of this highly organized system are ...not fully understood. Using high-resolution imaging, we show that lymphoid tissue inducer (LTi) cells initially transmigrate from veins at LN development sites using gaps in venous mural coverage. This process is independent of lymphatic vasculature, but lymphatic vessels are indispensable for the transport of LTi cells that egress from blood capillaries elsewhere and serve as an essential LN expansion reservoir. At later stages, lymphatic collecting vessels ensure efficient LTi cell transport and formation of the LN capsule and subcapsular sinus. Perinodal lymphatics also promote local interstitial flow, which cooperates with lymphotoxin-β signaling to amplify stromal CXCL13 production and thereby promote LTi cell retention. Our data unify previous models of LN development by showing that lymphatics intervene at multiple points to assist LN expansion and identify a new role for mechanical forces in LN development.
The lymphatic vasculature constitutes a highly specialized part of the vascular system that is essential for the maintenance of interstitial fluid balance, uptake of dietary fat, and immune response. ...Recently, there has been an increased awareness of the importance of lymphatic vessels in many common pathological conditions, such as tumor cell dissemination and chronic inflammation. Studies of embryonic development and genetically engineered animal models coupled with the discovery of mutations underlying human lymphedema syndromes have contributed to our understanding of mechanisms regulating normal and pathological lymphatic morphogenesis. It is now crucial to use this knowledge for the development of novel therapies for human diseases.
Abstract
The small intestinal villus tip is the first point of contact for lumen-derived substances including nutrients and microbial products. Electron microscopy studies from the early 1970s ...uncovered unusual spatial organization of small intestinal villus tip blood vessels: their exterior, epithelial-facing side is fenestrated, while the side facing the villus stroma is non-fenestrated, covered by pericytes and harbors endothelial nuclei. Such organization optimizes the absorption process, however the molecular mechanisms maintaining this highly specialized structure remain unclear. Here we report that perivascular LGR5
+
villus tip telocytes (VTTs) are necessary for maintenance of villus tip endothelial cell polarization and fenestration by sequestering VEGFA signaling. Mechanistically, unique VTT expression of the protease ADAMTS18 is necessary for VEGFA signaling sequestration through limiting fibronectin accumulation. Therefore, we propose a model in which LGR5
+
ADAMTS18
+
telocytes are necessary to maintain a “just-right” level and location of VEGFA signaling in intestinal villus blood vasculature to ensure on one hand the presence of sufficient endothelial fenestrae, while avoiding excessive leakiness of the vessels and destabilization of villus tip epithelial structures.
Here we detail a protocol for whole-mount immunostaining of mouse small-intestinal villi that can be used to generate high-resolution 3D images of all gut cell types, including blood and lymphatic ...vessel cells, neurons, smooth muscle cells, fibroblasts and immune cells. The procedure describes perfusion, fixation, dissection, immunostaining, mounting, clearing, confocal imaging and quantification, using intestinal vasculature as an example. As intestinal epithelial cells prevent visualization with some antibodies, we also provide an optional protocol to remove these cells before fixation. In contrast to alternative current techniques, our protocol enables the entire villus to be visualized with increased spatial resolution of cell location, morphology and cell-cell interactions, thus allowing for easy quantification of phenotypes. The technique, which takes 7 d from mouse dissection to microscopic examination, will be useful for researchers who are interested in most aspects of intestinal biology, including mucosal immunology, infection, nutrition, cancer biology and intestinal microbiota.
The signalling pathways operational in quiescent, post-development vasculature remain enigmatic. Here we show that unlike neovascularization, endothelial Akt signalling in established vasculature is ...crucial not for endothelial cell (EC) survival, but for sustained interactions with pericytes and vascular smooth muscle cells (VSMCs) regulating vascular stability and function. Inducible endothelial-specific Akt1 deletion in adult global Akt2KO mice triggers progressive VSMC apoptosis. In hearts, this causes a loss of arteries and arterioles and, despite a high capillary density, diminished vascular patency and severe cardiac dysfunction. Similarly, endothelial Akt deletion induces retinal VSMC loss and basement membrane deterioration resulting in vascular regression and retinal atrophy. Mechanistically, the Akt/mTOR axis controls endothelial Jagged1 expression and, thereby, Notch signalling regulating VSMC maintenance. Jagged1 peptide treatment of Akt1ΔEC;Akt2KO mice and Jagged1 re-expression in Akt-deficient endothelium restores VSMC coverage. Thus, sustained endothelial Akt1/2 signalling is critical in maintaining vascular stability and homeostasis, thereby preserving tissue and organ function.
Spontaneous CD8 T-cell responses occur in growing tumors but are usually poorly effective. Understanding the molecular and cellular mechanisms that drive these responses is of major interest as they ...could be exploited to generate a more efficacious antitumor immunity. As such, stimulator of IFN genes (STING), an adaptor molecule involved in cytosolic DNA sensing, is required for the induction of antitumor CD8 T responses in mouse models of cancer. Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer. The ability of cGAMP to trigger antitumor immunity was further enhanced by the blockade of both PD1 and CTLA4. The STING-dependent antitumor immunity, either induced spontaneously in growing tumors or induced by intratumoral cGAMP injection was dependent on type I IFNs produced in the tumor microenvironment. In response to cGAMP injection, both in the mouse melanoma model and an ex vivo model of cultured human melanoma explants, the principal source of type I IFN was not dendritic cells, but instead endothelial cells. Similarly, endothelial cells but not dendritic cells were found to be the principal source of spontaneously induced type I IFNs in growing tumors. These data identify an unexpected role of the tumor vasculature in the initiation of CD8 T-cell antitumor immunity and demonstrate that tumor endothelial cells can be targeted for immunotherapy of melanoma.
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