Cardiovascular System - Lymphatic Development

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Introduction

Human embryo (23 mm) mesenteric sac and cisterna chyli
Thoracic and right lymphatic ducts

An important part of the cardiovascular system is the lymphatic vasculature, which functions to both return interstitial fluid (lymph) to the bloodstream and also as part of the immune system. In the embryo, lymphatic development begins at the cardinal vein, where venous endothelial cells differentiate (express Prox1) to form lymphatic endothelial cells that out-pocket and bud to form lymph sacs. During development these lymph sacs remodel to form both the lymphatic space within future nodes, formed by engulfed connective tissue, and the associated afferent and efferent vessel network.


This system was first identified by Aselli G. (1627) in a paper "De Lacteibus sive Lacteis Venis", Quarto Vasorum Mesarai corum Genere novo invento. Milan: Mediolani. Then postulated by Sabin (1902)[1] as venous in origin, it required a recent 2007 lineage tracing study to confirm this theory.[2] Only vertebrates possess a true lymphatic vascular system, with primitive fish possessing a lymphatic-like secondary vascular system that also contains blood. Clinically, important for roles in immune surveillance and oncogenic (cancer) processes.

Immune Links: Introduction | Blood | Spleen | Thymus | Lymphatic | Lymph Node | Antibody | Med Lecture - Lymphatic Structure | Med Practical | Immune Movies | Vaccination | Bacterial Infection | Abnormalities | Category:Immune
Historic Embryology  
1909 Lymph glands | 1912 Development of the Lymphatic System | 1918 Gray's Lymphatic Images | 1916 Pig Lymphatics | 1919 Chicken Lymphatic | 1921 Spleen | 1922 Pig Stomach Lymphatics | 1932 Cat Pharyngeal Tonsil | Historic Disclaimer


Cardiovascular Links: Introduction | Heart Tutorial | Lecture - Early Vascular | Lecture - Heart | Movies | Heart | Coronary Circulation | Heart Valve | Heart Rate | Circulation | Blood | Blood Vessel | Blood Vessel Histology | Cardiac Muscle Histology | Lymphatic | Ductus Venosus | Spleen | Stage 22 | Abnormalities | OMIM | 2012 ECHO Meeting | 2016 Cardiac Review | Category:Cardiovascular
Historic Embryology - Cardiovascular 
1902 Vena cava inferior | 1905 Brain Blood Vessels | 1909 Cervical Veins | 1912 Heart | 1912 Human Heart | 1914 Earliest Blood-Vessels | 1915 Congenital Cardiac Disease | 1915 Dura Venous Sinuses | 1916 Pars Membranacea Septi | 1919 Lower Limb Arteries | 1921 Human Brain Vascular | 1921 Spleen | 1922 Aortic-Arch System | 1922 Pig Forelimb Arteries | 1922 Chicken Pulmonary | 1923 Head Subcutaneous Plexus | 1925 Venous Development | 1928 Heart Blood Flow | 1935 Aorta | 1935 Venous valves | 1938 Pars Membranacea Septi | 1938 Foramen Ovale | 1939 Atrio-Ventricular Valves | 1940 Vena cava inferior | 1940 Early Hematopoiesis | 1942 Truncus and Conus Partitioning | Ziegler Heart Models | 1951 Heart Movie | 1954 Week 9 Heart | 1957 Cranial venous system | 1959 Brain Arterial Anastomoses | Historic Embryology Papers | 2012 ECHO Meeting | 2016 Cardiac Review | Historic Disclaimer

Some Recent Findings

  • Development of the mammalian lymphatic vasculature[3] "The two vascular systems of our body are the blood and lymphatic vasculature. Our understanding of the cellular and molecular processes controlling the development of the lymphatic vasculature has progressed significantly in the last decade. In mammals, this is a stepwise process that starts in the embryonic veins, where lymphatic EC (LEC) progenitors are initially specified. The differentiation and maturation of these progenitors continues as they bud from the veins to produce scattered primitive lymph sacs, from which most of the lymphatic vasculature is derived. Here, we summarize our current understanding of the key steps leading to the formation of a functional lymphatic vasculature."
  • prox1b Activity is essential in zebrafish lymphangiogenesis[4] "The lymphatic vascular system, draining interstitial fluids from most tissues and organs, exerts crucial functions in several physiological and pathological processes. Lymphatic system development depends on Prox1, the first marker to be expressed in the endothelial cells of the cardinal vein from where lymph vessels originate."
  • Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature[2] "These studies, together with the analysis of Runx1-mutant embryos lacking definitive hematopoiesis, conclusively determined that from venous-derived lymph sacs, lymphatic endothelial cells sprouted, proliferated, and migrated to give rise to the entire lymphatic vasculature, and that hematopoietic cells did not contribute to the developing lymph sacs. We conclude that the mammalian lymphatic system has a solely venous origin."
  • The lymphatic vasculature: recent progress and paradigms[5] "The field of lymphatic research has been recently invigorated by the identification of genes and mechanisms that control various aspects of lymphatic development. We are beginning to understand how, starting from a subgroup of embryonic venous endothelial cells, the whole lymphatic system forms in a stepwise manner. The generation of genetically engineered mice with defects in different steps of the lymphangiogenic program has provided models that are increasing our understanding of the lymphatic system in health and disease."

Lymphatic Vessels

Lymph capillary
  1. Lymph capillaries - begin as blind-ending tubes in connective tissue, larger than blood capillaries, very irregularly shaped.
  2. Lymph collecting vessels - larger and form valves, morphology similar to lymph capillaries.
  3. Lymph ducts - 1 or 2 layers of smooth muscle cells in wall.
(Remember the anatomy acronym NAVL = Nerve, Artery, Vein and Lymph)

Lymphatic Capillaries

  • single-cell layer of overlapping endothelial cells
    • lack a basement membrane
    • lack smooth muscle cells or pericytes (pre-collecting and collecting trunks contain both)
  • linked by discontinuous endothelial cell-cell junctions (button-like).
  • junctions open in response to increased interstitial fluid pressure.


Lymphatic microvasculature model.jpg

Lymphatic microvasculature model[6]

Lymphatic Vessel Development

Lymphatic vessel formation model.jpg

Tunneling model of lymphatic vessel formation.

The model shown here is from a recent paper[7] and is based on ultrastructural observations performed in in vitro and in vivo models of lymphangiogenesis. Lymphatic endothelial cells (LEC) display tight junctions and interdigitations, and are connected to the surrounding collagen fibers by anchoring filaments.

Note that this postnatal model may differ from developmental lymphatic vessel development.


  • A - LEC alignment. Elongated LEC migrate and extend long cytoplasmic protrusions.


  • B - Vacuolization and matrix degradation. The continuity of LEC lining is mediated by interdigitations (i). Vesicle invaginations lead to the formation of intracellular vacuoles (v) in the cytoplasm and in protrusions. Matrix degradation (d) occurs intracellularly and extracellularly generating space between cells.


  • C - Luminogenesis. The lumen (lu) is formed de novo in the intercellular space. The intracellular vacuoles coalesce (cv) and likely fuse with the cytoplasmic membrane to increase the lumen.

Lymphatic Vessel Contraction

Lymphatic vessels undergo spontaneous rhythmic contractions which aid lymph flow. This is most easily demonstrated in models based upon mesentry lymphatics of the gastrointestinal tract. Contractile activity is regulated by physical factors (transmural pressure) and neurological (alpha-adrenergic, histamine, bradykinin) acting on lymphatic smooth muscle. Contractility and receptor expression may also be different in different parts of the lymphatic system.

Alpha-adrenergic - alpha 1- and not alpha 2-adrenoceptors.

Histamine - lymphatic smooth muscle via stimulation of H(1) (and in some vessels H(2)) receptors.

Bradykinin - chronotropic but not inotropic effects on lymphatic pump activity via stimulation of B1 receptors.

Lymphatic vasculature 01.jpg

Lymphatic Vasculature Organization[8]

Molecular Development

Angiopoietins (Ang1–Ang4)

Notch probably mediates choice of fate between arterial and venous.

Prox1 Prospero-related Homeobox 1 - expressed in a subpopulation of blood endothelial cells that then generate, by both budding and sprouting, cells of the lymphatic vascular system. Triggers the molecular program leading to the formation of the lymphatic system. (OMIM - PROSPERO-RELATED HOMEOBOX 1; PROX1)

Tie (Tie1 and Tie2) tyrosine kinase receptors.

Vascular endothelial growth factor (VEGF) family of proteins and angiopoietin/Tie, Notch, and ephrin/Eph pathways play major roles in eary vessel development. (VEGFR-3)

LYVE-1

Podoplanin

Abnormalities

Lymphangioma

Dysplasia of childhood form lymphatic capillaries or collectors, which form fluid-filled cysts.

  • lymphatic spaces lined by endothelium
  • smooth muscle fascicles in the septa between the lymphatic spaces
  • lymphoid aggregates in the delicate collagenous stroma

References

  1. Sabin, F. R. On the origin of the lymphatic system from the veins and the development of the lymph hearts and thoracic duct in the pig. (1902) Am. J. Anat. 1, 367-389.
  2. 2.0 2.1 R Sathish Srinivasan, Miriam E Dillard, Oleg V Lagutin, Fu-Jung Lin, Sophia Tsai, Ming-Jer Tsai, Igor M Samokhvalov, Guillermo Oliver Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev.: 2007, 21(19);2422-32 PubMed 17908929
  3. Ying Yang, Guillermo Oliver Development of the mammalian lymphatic vasculature. J. Clin. Invest.: 2014, 124(3);888-97 PubMed 24590273
  4. Luca Del Giacco, Anna Pistocchi, Anna Ghilardi prox1b Activity is essential in zebrafish lymphangiogenesis. PLoS ONE: 2010, 5(10);e13170 PubMed 20976189
  5. Guillermo Oliver, Kari Alitalo The lymphatic vasculature: recent progress and paradigms. Annu. Rev. Cell Dev. Biol.: 2005, 21;457-83 PubMed 16212503
  6. Michael S Pepper, Mihaela Skobe Lymphatic endothelium: morphological, molecular and functional properties. J. Cell Biol.: 2003, 163(2);209-13 PubMed 14581448 | JCB
  7. Benoit Detry, Françoise Bruyère, Charlotte Erpicum, Jenny Paupert, Françoise Lamaye, Catherine Maillard, Bénédicte Lenoir, Jean-Michel Foidart, Marc Thiry, Agnès Noël Digging deeper into lymphatic vessel formation in vitro and in vivo. BMC Cell Biol.: 2011, 12;29 PubMed 21702933 | PMC3141733 | BMC Cell Biol.
  8. Stefan Schulte-Merker, Amélie Sabine, Tatiana V Petrova Lymphatic vascular morphogenesis in development, physiology, and disease. J. Cell Biol.: 2011, 193(4);607-18 PubMed 21576390 | PMC3166860 | J Cell Biol.

Journals

Reviews

Guillermo Oliver, R Sathish Srinivasan Lymphatic vasculature development: current concepts. Ann. N. Y. Acad. Sci.: 2008, 1131;75-81 PubMed 18519960

C Bellini, F Boccardo, E Bonioli, C Campisi Lymphodynamics in the fetus and newborn. Lymphology: 2006, 39(3);110-7 PubMed 17036631

Guillermo Oliver, Kari Alitalo The lymphatic vasculature: recent progress and paradigms. Annu. Rev. Cell Dev. Biol.: 2005, 21;457-83 PubMed 16212503

Meiko Takahashi, Takanobu Yoshimoto, Hajime Kubo Molecular mechanisms of lymphangiogenesis. Int. J. Hematol.: 2004, 80(1);29-34 PubMed 15293565

Guillermo Oliver Lymphatic vasculature development. Nat. Rev. Immunol.: 2004, 4(1);35-45 PubMed 14704766

Guillermom Oliver, Natasha Harvey A stepwise model of the development of lymphatic vasculature. Ann. N. Y. Acad. Sci.: 2002, 979;159-65; discussion 188-96 PubMed 12543725


Articles

Nicole C Johnson, Miriam E Dillard, Peter Baluk, Donald M McDonald, Natasha L Harvey, Sharon L Frase, Guillermo Oliver Lymphatic endothelial cell identity is reversible and its maintenance requires Prox1 activity. Genes Dev.: 2008, 22(23);3282-91 PubMed 19056883

R Sathish Srinivasan, Miriam E Dillard, Oleg V Lagutin, Fu-Jung Lin, Sophia Tsai, Ming-Jer Tsai, Igor M Samokhvalov, Guillermo Oliver Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev.: 2007, 21(19);2422-32 PubMed 17908929

Fredrik Bäckhed, Peter A Crawford, David O'Donnell, Jeffrey I Gordon Postnatal lymphatic partitioning from the blood vasculature in the small intestine requires fasting-induced adipose factor. Proc. Natl. Acad. Sci. U.S.A.: 2007, 104(2);606-11 PubMed 17202268

Jay W Shin, Michael Min, Fréderic Larrieu-Lahargue, Xavier Canron, Rainer Kunstfeld, Lynh Nguyen, Janet E Henderson, Andreas Bikfalvi, Michael Detmar, Young-Kwon Hong Prox1 promotes lineage-specific expression of fibroblast growth factor (FGF) receptor-3 in lymphatic endothelium: a role for FGF signaling in lymphangiogenesis. Mol. Biol. Cell: 2006, 17(2);576-84 PubMed 16291864

Terhi Karpanen, Maria Wirzenius, Taija Mäkinen, Tanja Veikkola, Hidde J Haisma, Marc G Achen, Steven A Stacker, Bronislaw Pytowski, Seppo Ylä-Herttuala, Kari Alitalo Lymphangiogenic growth factor responsiveness is modulated by postnatal lymphatic vessel maturation. Am. J. Pathol.: 2006, 169(2);708-18 PubMed 16877368

Guillermo Oliver, Michael Detmar The rediscovery of the lymphatic system: old and new insights into the development and biological function of the lymphatic vasculature. Genes Dev.: 2002, 16(7);773-83 PubMed 11937485



Lymphatic endothelial cell identity is reversible and its maintenance requires Prox1 activity Nicole C. Johnson, Miriam E. Dillard, Peter Baluk, Donald M. McDonald, Natasha L. Harvey, Sharon L. Frase, and Guillermo Oliver Genes Dev. 2008;22 3282-3291

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Cite this page: Hill, M.A. 2017 Embryology Cardiovascular System - Lymphatic Development. Retrieved October 22, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/Cardiovascular_System_-_Lymphatic_Development

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