Lymphatic Origin from Embryonic Stem Cells

  • Michael Dictor
  • Sofia Mebrahtu
  • Manuel Selg
  • Zerina Lokmic
  • Lydia Sorokin
Part of the Cancer Treatment and Research book series (CTAR, volume 135)

Lymph circulation is unidirectional and commences in the tissue within highly permeable but blind-ended capillaries composed of a single layer of endothelial cells. These capillaries (lymphatic initiators) are characterized by loosely arranged, overlapping endothelial cells, few intercellular tight junctions and occasional fragments of basement membrane, which account for lymphatic permeability to fluid, macromolecules, pathogens, immune cells, and metastatic tumor cells. The lymphatic vessels are anchored to the surrounding extracellular matrix via anchoring filaments arising from the endothelial cells. As the lymphatic capillaries coalesce into larger collecting ducts, they acquire smooth muscle cells outside of the endothelial layer and start to structurally resemble veins. The larger, collecting vessel has valves to prevent the retrograde flow of lymph, a continuous basement membrane, a muscle layer, and an adventitial layer anchoring it to the surrounding tissue (18).


Embryonic Stem Cell Hepatocyte Growth Factor Embryoid Body Lymphatic Endothelium Lymphatic Vasculature 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Achen MG, Jeltsch M, Kukk E, Makinen T, Vitali A, Wilks AF, Alitalo K, Stacker SA (1998) Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci U S A 95:548–553.PubMedCrossRefGoogle Scholar
  2. 2.
    Banerji S, Ni J, Wang SX, Clasper S, Su J, Tammi R, Jones M, Jackson DG (1999) LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 144:789–801.PubMedCrossRefGoogle Scholar
  3. 3.
    Bloch W, Forsberg E, Lentini S, Brakebusch C, Martin K, Krell HW, Weidle UH, Addicks K, Fassler R (1997) Beta 1 integrin is essential for teratoma growth and angiogenesis. J Cell Biol 139:265–278.PubMedCrossRefGoogle Scholar
  4. 4.
    Breiteneder-Geleff S, Soleiman A, Kowalski H, Horvat R, Amann G, Kriehuber E, Diem K, Weninger W, Tschachler E, Alitalo K, Kerjaschki D (1999) Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol 154:385–394.PubMedGoogle Scholar
  5. 5.
    Gale NW, Thurston G, Hackett SF, Renard R, Wang Q, McClain J, Martin C, Witte C, Witte MH, Jackson D, Suri C, Campochiaro PA, Wiegand SJ, Yancopoulos GD (2002) Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. Dev Cell 3:411–423.PubMedCrossRefGoogle Scholar
  6. 6.
    Hallmann R, Horn N, Selg M, Wendler O, Pausch F, Sorokin LM (2005) Expression and function of laminins in the embryonic and mature vasculature. Physiol Rev 85:979–1000.PubMedCrossRefGoogle Scholar
  7. 7.
    Hallmann R, Mayer DN, Berg EL, Broermann R, Butcher EC (1995) Novel mouse endothelial cell surface marker is suppressed during differentiation of the blood brain barrier. Dev Dyn 202:325–332.PubMedGoogle Scholar
  8. 8.
    Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K (1996) A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. Embo J 15:1751.PubMedGoogle Scholar
  9. 9.
    Kaipainen A, Korhonen J, Mustonen T, van Hinsbergh VW, Fang GH, Dumont D, Breitman M, Alitalo K (1995) Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci U S A 92:3566–3570.PubMedCrossRefGoogle Scholar
  10. 10.
    Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV, Jeltsch M, Jackson DG, Talikka M, Rauvala H, Betsholtz C, Alitalo K (2004) Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol 5:74–80.PubMedCrossRefGoogle Scholar
  11. 11.
    Kreuger J, Nilsson I, Kerjaschki D, Petrova T, Alitalo K, Claesson-Welsh L (2006) Early lymph vessel development from embryonic stem cells. Arterioscler Thromb Vasc Biol 26:1073–1078.PubMedCrossRefGoogle Scholar
  12. 12.
    Liersch R, Nay F, Lu L, Detmar M (2006) Induction of lymphatic endothelial cell differentiation in embryoid bodies. Blood 107:1214–1216.PubMedCrossRefGoogle Scholar
  13. 13.
    Maatta M, Liakka A, Salo S, Tasanen K, Bruckner-Tuderman L, Autio-Harmainen H (2004) Differential expression of basement membrane components in lymphatic tissues. J Histochem Cytochem 52:1073–1081.PubMedCrossRefGoogle Scholar
  14. 14.
    Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55–60.PubMedCrossRefGoogle Scholar
  15. 15.
    Makinen T, Adams RH, Bailey J, Lu Q, Ziemiecki A, Alitalo K, Klein R, Wilkinson GA (2005) PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev 19:397–410.PubMedCrossRefGoogle Scholar
  16. 16.
    Makinen T, Jussila L, Veikkola T, Karpanen T, Kettunen MI, Pulkkanen KJ, Kauppinen R, Jackson DG, Kubo H, Nishikawa S, Yla-Herttuala S, Alitalo K (2001) Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med 7:199–205.PubMedCrossRefGoogle Scholar
  17. 17.
    Oliver G (2004) Lymphatic vasculature development. Nat Rev Immunol 4:35–45.PubMedCrossRefGoogle Scholar
  18. 18.
    Oliver G, Alitalo K (2005) The lymphatic vasculature: recent progress and paradigms. Annu Rev Cell Dev Biol 21:457–483.PubMedCrossRefGoogle Scholar
  19. 19.
    Petajaniemi N, Korhonen M, Kortesmaa J, Tryggvason K, Sekiguchi K, Fujiwara H, Sorokin L, Thornell LE, Wondimu Z, Assefa D, Patarroyo M, Virtanen I (2002) Localization of laminin alpha4-chain in developing and adult human tissues. J Histochem Cytochem 50:1113–1130.PubMedGoogle Scholar
  20. 20.
    Petrova TV, Karpanen T, Norrmen C, Mellor R, Tamakoshi T, Finegold D, Ferrell R, Kerjaschki D, Mortimer P, Yla-Herttuala S, Miura N, Alitalo K (2004) Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nat Med 10:974–981.PubMedCrossRefGoogle Scholar
  21. 21.
    Ringelmann B, Roder C, Hallmann R, Maley M, Davies M, Grounds M, Sorokin L (1999) Expression of laminin alpha1, alpha2, alpha4, and alpha5 chains, fibronectin, and tenascin-C in skeletal muscle of dystrophic 129ReJ dy/dy mice. Exp Cell Res 246:165–182.PubMedCrossRefGoogle Scholar
  22. 22.
    Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674.PubMedCrossRefGoogle Scholar
  23. 23.
    Schacht V, Ramirez MI, Hong YK, Hirakawa S, Feng D, Harvey N, Williams M, Dvorak AM, Dvorak HF, Oliver G, Detmar M (2003) T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. Embo J 22:3546–3556.PubMedCrossRefGoogle Scholar
  24. 24.
    Sixt M, Engelhardt B, Pausch F, Hallmann R, Wendler O, Sorokin LM (2001) Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood-brain barrier in experimental autoimmune encephalomyelitis. J Cell Biol 153:933–946.PubMedCrossRefGoogle Scholar
  25. 25.
    Sorokin LM, Conzelmann S, Ekblom P, Battaglia C, Aumailley M, Timpl R (1992) Monoclonal antibodies against laminin A chain fragment E3 and their effects on binding to cells and proteoglycan and on kidney development. Exp Cell Res 201:137–144.PubMedCrossRefGoogle Scholar
  26. 26.
    Sorokin LM, Pausch F, Frieser M, Kroger S, Ohage E, Deutzmann R (1997) Developmental regulation of the laminin alpha5 chain suggests a role in epithelial and endothelial cell maturation. Dev Biol 189:285–300.PubMedCrossRefGoogle Scholar
  27. 27.
    Thyboll J, Kortesmaa J, Cao R, Soininen R, Wang L, Iivanainen A, Sorokin L, Risling M, Cao Y, Tryggvason K (2002) Deletion of the laminin alpha4 chain leads to impaired microvessel maturation. Mol Cell Biol 22:1194–1202.PubMedCrossRefGoogle Scholar
  28. 28.
    Vittet D, Prandini MH, Berthier R, Schweitzer A, Martin-Sisteron H, Uzan G, Dejana E (1996) Embryonic stem cells differentiate in vitro to endothelial cells through successive maturation steps. Blood 88:3424–3431.PubMedGoogle Scholar
  29. 29.
    Wigle JT, Oliver G (1999) Prox1 function is required for the development of the murine lymphatic system. Cell 98:769–778.PubMedCrossRefGoogle Scholar
  30. 30.
    Yuan L, Moyon D, Pardanaud L, Breant C, Karkkainen MJ, Alitalo K, Eichmann A (2002) Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development 129:4797–4806.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Michael Dictor
    • 1
  • Sofia Mebrahtu
    • 1
  • Manuel Selg
    • 2
  • Zerina Lokmic
    • 2
  • Lydia Sorokin
    • 2
  1. 1.Department of PathologyLund University HospitalSweden
  2. 2.Department of Experimental PathologyLund University HospitalSweden

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