Lymphatic Vasculature Development
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R E V I E W S LYMPHATIC VASCULATURE DEVELOPMENT Guillermo Oliver Although the process of blood vasculature formation has been well documented, little is known about lymphatic vasculature development, despite its importance in normal and pathological conditions. The lack of specific lymphatic markers has hampered progress in this field. However, the recent identification of genes that participate in the formation of the lymphatic vasculature denotes the beginning of a new era in which better diagnoses and therapeutic treatment(s) of lymphatic disorders could become a reachable goal. LYMPHANGIOGENESIS Lymphatic vessels were first described in the seventeenth agent, afferent lymphatic vessels are the route through The growth of lymphatic vessels. century by G.Aselli1. However, until a few years ago, the which, after antigen uptake, dendritic cells migrate to lymphatic system was not considered an interesting topic the lymph nodes and lymphoid organs. Recent studies LYMPHOEDEMA among most scientists. Despite the importance of the indicate that spindle cells and cells lining the irregular Occlusion of lymphatic drainage followed by the lymphatic system and the belief that metastatic tumour spaces in Kaposi’s sarcoma have a lymphatic endothelial abnormal accumulation of cells are disseminated through the lymphatic vasculature, origin9,10. An increased understanding of normal interstitial fluid and swelling modern anatomy textbooks generally include only a lymphatic development should allow us to address in the affected body part. minimal description of the development of this system. pathological lymphatic conditions that lead to inflam- LYMPHATIC METASTASIS Interest in basic lymphatic research has radically mation, autoimmunity and cancer, and to improve the Invasion of detaching primary increased in the past few years,in part, thanks to the iden- clinical treatment of primary and secondary forms of tumour cells through the tification of lymphatic-specific markers and growth lymphoedema. Here, I discuss a working model for lymphatic system to lymph factors, the debate about tumour LYMPHANGIOGENESIS, and normal lymphatic vasculature development that nodes. After re-entering of the the efforts of patients suffering from LYMPHOEDEMA and focuses mainly on the early aspects,and that summarizes lymphatic vessels into the blood vasculature, tumour cells will their families, who have attracted public and govern- findings from different laboratories through the charac- also spread to distant organs. mental attention by creating the Lymphatic Research terization of newly identified lymphatic markers and Foundation (see further information for website). available mouse mutant lines. In this model, blood Although few life-threatening diseases (BOX 1) result venous endothelial cells are the ground condition from from malfunction of the lymphatic system, failure of which a lymphatic endothelial cell phenotype will be lymph transport promotes lymphoedema — a disfig- progressively acquired by the stepwise expression of uring, disabling and occasionally life-threatening different gene products. disorder for which present treatment is limited and ineffective2. Malignant tumours can directly activate Historical considerations lymphangiogenesis and LYMPHATIC METASTASIS3–8; so, During embryonic development, blood vessels originate Department of Genetics, understanding the basic biology that is involved in from mesodermally derived endothelial cell precursors St Jude Children’s Research lymphatic development is vital. Metastasis of most (vasculogenesis) (FIG. 1). These vessels grow and remodel Hospital, 332 N. Lauderdale, cancers mainly occurs through the lymphatic system, into the mature network by endothelial sprouting and Memphis, Tennessee 38105, and the extent of lymph-node involvement is a useful splitting (angiogenesis). The lymphatic vasculature USA. prognostic indicator. The lymphatic system is also appears after the blood vasculature forms, which was e-mail: guillermo.oliver@ stjude.org essential for the immune response to infectious agents, the first indication that lymphatics might have a blood doi:10.1038/nri1258 for example, during exposure to an inflammatory vasculature origin. NATURE REVIEWS | IMMUNOLOGY VOLUME 4 | JANUARY 2004 | 3 5 © 2004 Nature Publishing Group R E V I E W S Box 1 | Roles of the lymphatic system in health and disease thymus, all of which have key roles in the immune response to infectious agents. In health The lymphatic system develops in parallel, but sec- • Drains lymph fluid from the extracellular spaces ondary to the development of the blood vascular system, • Absorbs lipids from the intestinal tract and lymphatic vessels are not normally present in avascu- • Maintains the fluid homeostasis lar structures such as the epidermis, hair, nails, cartilage • Transports white blood cells and antigen-presenting cells to lymphoid organs and cornea, nor are they present in some vascularized organs such as the retina and probably the brain.From an Disease evolutionary point of view, specialized lymph hearts first • Congenital and acquired defects of the lymphatic system appeared in amphibians and reptiles11; later, lymph nodes • Lymphoedema: imbalance between lymph formation and adsorption into lymphatic appeared in birds, and the final refinement of the vessels lymphatic vasculature occurred in mammals2. 12,13 • Lymphangitis: inflammation of lymphatic vessels In 1902, Florence Sabin proposed the most widely accepted model of lymphatic vasculature • Lymphangioma: benign neoplasm of lymphatic vessels development. Sabin injected dye into pig embryos • Lymphangiosarcoma: malignant neoplasm of lymphatic vessels (FIG. 3), and her results culminated in the proposal • Role in metastasis: migration of tumour cells that endothelial cells bud from veins to form primary lymphatic sacs. From these sacs, budding cells then centrifugally sprout towards the periphery, forming PERICYTES The lymphatic system (FIG. 2) is composed of a vascu- capillaries that surround tissues and organs. In this Smooth-muscle-like cells that lar network of blind-ended, thin-walled capillaries and model, the two jugular lymph sacs develop near the cover the outer surface of the larger vessels that drain protein-rich interstitial fluid junction of the subclavian and anterior cardinal veins endothelial cells of blood vessels. (lymph) from the extracellular spaces within organs into (FIG. 3d). From these sacs, lymphatic capillaries spread WOLFFIAN BODIES larger collecting ducts. In contrast to blood capillaries, to the head, neck, arms and thorax. Later, the remaining A series of tubules that lymphatic capillaries lack fenestrations, a continuous lymph sacs originate from the mesonephric vein and constitute the mesonephros. basal membrane and PERICYTES; instead, these vessels are veins in the dorsomedial edge of the WOLFFIAN BODIES. lined with a continuous, single layer of overlapping The retroperitoneal lymph sac forms near the primi- endothelial cells that form loose intercellular junctions. tive inferior vena cava and mesonephric veins, and These characteristics make the lymphatic capillaries lymphatics spread to the abdominal viscera and highly permeable to large macromolecules, pathogens diaphragm. The thoracic duct, which carries most and migrating cells. lymph back to the blood vascular system, originates in Lymph returns to the venous circulation through the cisterna chyli — a dilated sac that lies anterior to the thoracic duct and the larger lymphatic collecting the uppermost lumbar vertebrae — which forms near vessels, which contain a muscular layer and an adventitial the wolffian bodies. The posterior lymph sacs occur layer. The lymphatic system is crucial for maintaining near the junctions of the primitive iliac veins and the the colloid osmotic volume (or pressure) and for posterior cardinal veins; from these sacs, lymphatics absorbing lipids from the intestinal tract. The lym- spread to the abdominal wall, pelvic region and legs phatic system also includes lymphoid organs such as (FIG. 3d) (for a detailed anatomical description of the the lymph nodes, tonsils, Peyer’s patches, spleen and lymphatic system in mice see REF. 14). Vasculogenesis Angiogenesis Endothelial Artery cell Basement Vein membrane Mesoderm Haemangioblasts Tube formation Pruning and remodelling cells Figure 1 | Blood vascular development. Mesodermally derived haemangioblasts give rise to angioblasts, the precursors of blood and vascular endothelial cells that will form the lining of the blood vessels (vasculogenesis). The remodelling of the primary capillary network and the formation of new blood vessels from pre-existing vessels by endothelial sprouting and splitting (angiogenesis) leads to the formation of mature arteries and veins. Figure reproduced, with permission, from REF. 68 © Sinauer Associates, Inc. (2003). 36 | JANUARY 2004 | VOLUME 4 www.nature.com/reviews/immunol © 2004 Nature Publishing Group R E V I E W S a b A model for lymphatic vasculature development In vertebrates, cell types are determined before mor- phological differentiation. Activation of certain genes Lymphatic areola before determination could be an early indication that the biological properties of the cell types are changing. On the basis of our results, as well as those of others, we recently proposed a working model for the develop- ment of the lymphatic vasculature that considers the Lymphatic classic embryological concepts of lens-cell-type deter- collector mination (for review see REF. 18).