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Visualization of Lymphatic Vessel Development, Growth, and Function

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Developmental Aspects of the Lymphatic Vascular System

Part of the book series: Advances in Anatomy, Embryology and Cell Biology ((ADVSANAT,volume 214))

Abstract

Despite their important physiological and pathophysiological functions, lymphatic endothelial cells and lymphatic vessels remain less well studied compared to the blood vascular system. Lymphatic endothelium differentiates from venous blood vascular endothelium after initial arteriovenous differentiation. Only recently by the use of light sheet microscopy, the precise mechanism of separation of the first lymphatic endothelial progenitors from the cardinal vein has been described as delamination followed by mesenchymal cell migration of lymphatic endothelial cells. Dorsolaterally of the embryonic cardinal vein, lymphatic endothelial cells reaggregate to form the first lumenized lymphatic vessels, the dorsal peripheral longitudinal vessel and the more ventrally positioned primordial thoracic duct. Despite this progress in our understanding of the first lymph vessel formation, intravital observation of lymphatic vessel behavior in the intact organism, during development and in the adult, is prerequisite to a precise understanding of this tissue. Transgenic models and two-photon microscopy, in combination with optical windows, have made live intravital imaging possible: however, new imaging modalities and novel approaches promise gentler, more physiological, and longer intravital imaging of lymphatic vessels.

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References

  • Abtahian, F., Guerriero, A., Sebzda, E., Lu, M. M., Zhou, R., Mocsai, A., et al. (2003). Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science, 299, 247–251.

    Article  PubMed  CAS  Google Scholar 

  • Alitalo, K. (2011). The lymphatic vasculature in disease. Nature Medicine, 17, 1371–1380.

    Article  PubMed  CAS  Google Scholar 

  • Baumeister, R. G., & Frick, A. (2003). [The microsurgical lymph vessel transplantation]. Handchirurgie, Mikrochirurgie, Plastische Chirurgie, 35, 202–209.

    Article  PubMed  CAS  Google Scholar 

  • Becker, K., Jahrling, N., Kramer, E. R., Schnorrer, F., & Dodt, H. U. (2008). Ultramicroscopy: 3D reconstruction of large microscopical specimens. Journal of Biophotonics, 1, 36–42.

    Article  PubMed  CAS  Google Scholar 

  • Becker, K., Jahrling, N., Saghafi, S., Weiler, R., & Dodt, H. U. (2012). Chemical clearing and dehydration of GFP expressing mouse brains. PLoS One, 7, e33916.

    Article  PubMed  CAS  Google Scholar 

  • Bertozzi, C. C., Schmaier, A. A., Mericko, P., Hess, P. R., Zou, Z., Chen, M., et al. (2010). Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling. Blood, 116, 661–670.

    Article  PubMed  CAS  Google Scholar 

  • Bohmer, R., Neuhaus, B., Buhren, S., Zhang, D., Stehling, M., Bock, B., et al. (2010). Regulation of developmental lymphangiogenesis by Syk(+) leukocytes. Developmental Cell, 18, 437–449.

    Article  PubMed  Google Scholar 

  • Bos, F. L., Caunt, M., Peterson-Maduro, J., Planas-Paz, L., Kowalski, J., Karpanen, T., et al. (2011). CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo. Circulation Research, 109, 486–491.

    Article  PubMed  CAS  Google Scholar 

  • Carramolino, L., Fuentes, J., García-Andrés, C., Azcoitia, V., Riethmacher, D., & Torres, M. (2010). Platelets play an essential role in separating the blood and lymphatic vasculatures during embryonic angiogenesis. Circulation Research, 106, 1197–1201.

    Article  PubMed  CAS  Google Scholar 

  • Choi, I., Chung, H. K., Ramu, S., Lee, H. N., Kim, K. E., Lee, S., et al. (2011). Visualization of lymphatic vessels by Prox1-promoter directed GFP reporter in a bacterial artificial chromosome-based transgenic mouse. Blood, 117, 362–365.

    Article  PubMed  CAS  Google Scholar 

  • Chung, K., Wallace, J., Kim, S. Y., Kalyanasundaram, S., Andalman, A. S., Davidson, T. J., et al. (2013). Structural and molecular interrogation of intact biological systems. Nature, 497, 332–337.

    Article  PubMed  CAS  Google Scholar 

  • Cursiefen, C., Chen, L., Borges, L. P., Jackson, D., Cao, J., Radziejewski, C., et al. (2004). VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. Journal of Clinical Investigation, 113, 1040–1050.

    PubMed  CAS  Google Scholar 

  • D’Amico, G., & Alitalo, K. (2010). Inside bloody lymphatics. Blood, 116, 512–513.

    Article  PubMed  Google Scholar 

  • Erturk, A., Mauch, C. P., Hellal, F., Forstner, F., Keck, T., Becker, K., et al. (2012). Three-dimensional imaging of the unsectioned adult spinal cord to assess axon regeneration and glial responses after injury. Nature Medicine, 18, 166–171.

    Article  Google Scholar 

  • Finney, B. A., Schweighoffer, E., Navarro-Núñez, L., Bénézech, C., Barone, F., Hughes, C. E., et al. (2012). CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development. Blood, 119, 1747–1756.

    Article  PubMed  CAS  Google Scholar 

  • Francois, M., Caprini, A., Hosking, B., Orsenigo, F., Wilhelm, D., Browne, C., et al. (2008). Sox18 induces development of the lymphatic vasculature in mice. Nature, 456, 643–647.

    Article  PubMed  CAS  Google Scholar 

  • Francois, M., Short, K., Secker, G. A., Combes, A., Schwarz, Q., Davidson, T. L., et al. (2012). Segmental territories along the cardinal veins generate lymph sacs via a ballooning mechanism during embryonic lymphangiogenesis in mice. Developmental Biology, 364, 89–98.

    Article  PubMed  CAS  Google Scholar 

  • Hägerling, R., Pollmann, C., Andreas, M., Schmidt, C., Nurmi, H., Adams, R. H., et al. (2013). A novel multistep mechanism for initial lymphangiogenesis in mouse embryos based on ultramicroscopy. EMBO Journal, 32(5), 629–644.

    Article  PubMed  Google Scholar 

  • Hägerling, R., Pollmann, C., Kremer, L., Andresen, V., & Kiefer, F. (2011). Intravital two-photon microscopy of lymphatic vessel development and function using a transgenic Prox1 promoter-directed mOrange2 reporter mouse. Biochemical Society Transactions, 39, 1674–1681.

    Article  PubMed  Google Scholar 

  • Hama, H., Kurokawa, H., Kawano, H., Ando, R., Shimogori, T., Noda, H., et al. (2011). Scale: A chemical approach for fluorescence imaging and reconstruction of transparent mouse brain. Nature Neuroscience, 14, 1481–1488.

    Article  PubMed  CAS  Google Scholar 

  • Herz, J., Siffrin, V., Hauser, A. E., Brandt, A. U., Leuenberger, T., Radbruch, H., et al. (2010). Expanding two-photon intravital microscopy to the infrared by means of optical parametric oscillator. Biophysical Journal, 98, 715–723.

    Article  PubMed  CAS  Google Scholar 

  • Hong, Y. K., Harvey, N., Noh, Y. H., Schacht, V., Hirakawa, S., Detmar, M., et al. (2002). Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Developmental Dynamics, 225, 351–357.

    Article  PubMed  CAS  Google Scholar 

  • Huggenberger, R., Siddiqui, S. S., Brander, D., Ullmann, S., Zimmermann, K., Antsiferova, M., et al. (2011). An important role of lymphatic vessel activation in limiting acute inflammation. Blood, 117, 4667–4678.

    Article  PubMed  CAS  Google Scholar 

  • Huggenberger, R., Ullmann, S., Proulx, S. T., Pytowski, B., Alitalo, K., & Detmar, M. (2010). Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation. Journal of Experimental Medicine, 207, 2255–2269.

    Article  PubMed  CAS  Google Scholar 

  • Huisken, J., Swoger, J., Del Bene, F., Wittbrodt, J., & Stelzer, E. H. K. (2004). Optical sectioning deep inside live embryos by selective plane illumination microscopy. Science, 305, 1007–1009.

    Article  PubMed  CAS  Google Scholar 

  • Ingersoll, M. A., Platt, A. M., Potteaux, S., & Randolph, G. J. (2011). Monocyte trafficking in acute and chronic inflammation. Trends in Immunology, 32, 470–477.

    Article  PubMed  CAS  Google Scholar 

  • Kalchenko, V., Kuznetsov, Y., Meglinski, I., & Harmelin, A. (2012). Label free in vivo laser speckle imaging of blood and lymph vessels. Journal of Biomedical Optics, 17, 050502.

    Article  PubMed  Google Scholar 

  • Karkkainen, M. J., Haiko, P., Sainio, K., Partanen, J., Taipale, J., Petrova, T. V., et al. (2004). Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nature Immunology, 5, 74–80.

    Article  PubMed  CAS  Google Scholar 

  • Kholová, I., Dragneva, G., Cermakova, P., Laidinen, S., Kaskenpää, N., Hazes, T., et al. (2011). Lymphatic vasculature is increased in heart valves, ischaemic and inflamed hearts and in cholesterol-rich and calcified atherosclerotic lesions. European Journal of Clinical Investigation, 41, 487–497.

    Article  PubMed  Google Scholar 

  • Kiefer, F., Brumell, J., Al-Alawi, N., Latour, S., Cheng, A., Veillette, A., et al. (1998). The Syk protein tyrosine kinase is essential for Fcγ receptor signaling in macrophages and neutrophils. Molecular and Cellular Biology, 18, 4209–4220.

    PubMed  CAS  Google Scholar 

  • Kim, H., & Koh, G. Y. (2010). Platelets take the lead in lymphatic separation. Circulation Research, 106, 1184–1186.

    Article  PubMed  CAS  Google Scholar 

  • Konigsberger, S., Prodohl, J., Stegner, D., Weis, V., Andreas, M., Stehling, M., et al. (2012). Altered BCR signalling quality predisposes to autoimmune disease and a pre-diabetic state. EMBO Journal, 31, 3363–3374.

    Article  PubMed  Google Scholar 

  • Kuwajima, T., Sitko, A. A., Bhansali, P., Jurgens, C., Guido, W., & Mason, C. (2013). ClearT: A detergent- and solvent-free clearing method for neuronal and non-neuronal tissue. Development, 140, 1364–1368.

    Article  PubMed  CAS  Google Scholar 

  • Kwon, S., & Sevick-Muraca, E. M. (2007). Noninvasive quantitative imaging of lymph function in mice. Lymphatic Research and Biology, 5, 219–231.

    Article  PubMed  Google Scholar 

  • Kwon, S., & Sevick-Muraca, E. M. (2010). Functional lymphatic imaging in tumor-bearing mice. Journal of Immunological Methods, 360, 167–172.

    Article  PubMed  CAS  Google Scholar 

  • Laufer, J., Norris, F., Cleary, J., Zhang, E., Treeby, B., Cox, B., et al. (2012). In vivo photoacoustic imaging of mouse embryos. Journal of Biomedical Optics, 17, 061220.

    Article  PubMed  Google Scholar 

  • Lehr, H. A., Leunig, M., Menger, M. D., Nolte, D., & Messmer, K. (1993). Dorsal skinfold chamber technique for intravital microscopy in nude mice. American Journal of Pathology, 143, 1055–1062.

    PubMed  CAS  Google Scholar 

  • Martinez-Corral, I., Olmeda, D., Diéguez-Hurtado, R., Tammela, T., Alitalo, K., & Ortega, S. (2012). In vivo imaging of lymphatic vessels in development, wound healing, inflammation, and tumor metastasis. Proceedings of the National Academy of Sciences of the United States of America, 109, 6223–6228.

    Article  PubMed  CAS  Google Scholar 

  • May, F., Hagedorn, I., Pleines, I., Bender, M., Vögtle, T., Eble, J., et al. (2009). CLEC-2 is an essential platelet-activating receptor in hemostasis and thrombosis. Blood, 114, 3464–3472.

    Article  PubMed  CAS  Google Scholar 

  • Mertz, J. (2011). Optical sectioning microscopy with planar or structured illumination. Nature Methods, 8, 811–819.

    Article  PubMed  CAS  Google Scholar 

  • Mounzer, R., Shkarin, P., Papademetris, X., Constable, T., Ruddle, N. H., & Fahmy, T. M. (2007). Dynamic imaging of lymphatic vessels and lymph nodes using a bimodal nanoparticulate contrast agent. Lymphatic Research and Biology, 5, 151–158.

    Article  PubMed  Google Scholar 

  • Mumprecht, V., Honer, M., Vigl, B., Proulx, S. T., Trachsel, E., Kaspar, M., et al. (2010). In vivo imaging of inflammation- and tumor-induced lymph node lymphangiogenesis by immuno—Positron emission tomography. Cancer Research, 70, 8842–8851.

    Article  PubMed  CAS  Google Scholar 

  • Niesner, R. A., Andresen, V., & Gunzer, M. (2008). Intravital two-photon microscopy: Focus on speed and time resolved imaging modalities. Immunological Reviews, 221, 7–25.

    Article  PubMed  CAS  Google Scholar 

  • Ntziachristos, V. (2010). Going deeper than microscopy: The optical imaging frontier in biology. Nature Methods, 7, 603–614.

    Article  PubMed  CAS  Google Scholar 

  • Oliver, G. (2004). Lymphatic vasculature development. Nature Reviews Immunology, 4, 35–45.

    Article  PubMed  CAS  Google Scholar 

  • Oliver, G., & Detmar, M. (2002). The rediscovery of the lymphatic system: Old and new insights into the development and biological function of the lymphatic vasculature. Genes & Development, 16, 773–783.

    Article  CAS  Google Scholar 

  • Petrova, T. V., Makinen, T., Makela, T. P., Saarela, J., Virtanen, I., Ferrell, R. E., et al. (2002). Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. EMBO Journal, 21, 4593–4599.

    Article  PubMed  CAS  Google Scholar 

  • Proulx, S., Luciani, P., Alitalo, A., Mumprecht, V., Christiansen, A., Huggenberger, R., et al. (2013). Non-invasive dynamic near-infrared imaging and quantification of vascular leakage in vivo. Angiogenesis, 16, 525–540.

    Article  PubMed  CAS  Google Scholar 

  • Quintana, L., & Sharpe, J. (2011). Preparation of mouse embryos for optical projection tomography imaging. Cold Spring Harbor Protocols, 2011(6), 664–669.

    PubMed  Google Scholar 

  • Rasmussen, J. C., Tan, I. C., Marshall, M. V., Fife, C. E., & Sevick-Muraca, E. M. (2009). Lymphatic imaging in humans with near-infrared fluorescence. Current Opinion in Biotechnology, 20, 74–82.

    Article  PubMed  CAS  Google Scholar 

  • Sabin, F. R. (1902). On the origin of the lymphatic system from the veins and the development of the lymph hearts and thoracic duct in the pig. American Journal of Anatomy, 1, 367–389.

    Article  Google Scholar 

  • Sabine, A., Agalarov, Y., Maby-El, H. H., Jaquet, M., Hagerling, R., Pollmann, C., et al. (2012). Mechanotransduction, PROX1, and FOXC2 cooperate to control connexin37 and calcineurin during lymphatic-valve formation. Developmental Cell, 22, 430–445.

    Article  PubMed  CAS  Google Scholar 

  • Schacht, V., Ramirez, M. I., Hong, Y. K., Hirakawa, S., Feng, D., Harvey, N., et al. (2003). T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO Journal, 22, 3546–3556.

    Article  PubMed  CAS  Google Scholar 

  • Schulte-Merker, S., Sabine, A., & Petrova, T. V. (2011). Lymphatic vascular morphogenesis in development, physiology, and disease. Journal of Cell Biology, 193, 607–618.

    Article  PubMed  CAS  Google Scholar 

  • Sebzda, E., Hibbard, C., Sweeney, S., Abtahian, F., Bezman, N., Clemens, G., et al. (2006). Syk and Slp-76 mutant mice reveal a cell-autonomous hematopoietic cell contribution to vascular development. Developmental Cell, 11, 349–361.

    Article  PubMed  CAS  Google Scholar 

  • Sevick-Muraca, E. M., Sharma, R., Rasmussen, J. C., Marshall, M. V., Wendt, J. A., Pham, H. Q., et al. (2008). Imaging of lymph flow in breast cancer patients after microdose administration of a near-infrared fluorophore: Feasibility study. Radiology, 246, 734–741.

    Article  PubMed  Google Scholar 

  • Simons, M., & Eichmann, A. (2013). Lymphatics are in my veins. Science, 341, 622–624.

    Article  PubMed  CAS  Google Scholar 

  • Srinivasan, R. S., Geng, X., Yang, Y., Wang, Y., Mukatira, S., Studer, M., et al. (2010). The nuclear hormone receptor Coup-TFII is required for the initiation and early maintenance of Prox1 expression in lymphatic endothelial cells. Genes and Development, 24, 696–707.

    Article  PubMed  CAS  Google Scholar 

  • Srinivasan, R. S., & Oliver, G. (2011). Prox1 dosage controls the number of lymphatic endothelial cell progenitors and the formation of the lymphovenous valves. Genes and Development, 25, 2187–2197.

    Article  PubMed  CAS  Google Scholar 

  • Steven, P., Bock, F., Huttmann, G., & Cursiefen, C. (2011). Intravital two-photon microscopy of immune cell dynamics in corneal lymphatic vessels. PLoS One, 6, e26253.

    Article  PubMed  CAS  Google Scholar 

  • Suzuki-Inoue, K., Fuller, G. L. J., García, Á., Eble, J. A., Pöhlmann, S., Inoue, O., et al. (2006). A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. Blood, 107, 542–549.

    Article  PubMed  CAS  Google Scholar 

  • Suzuki-Inoue, K., Inoue, O., Ding, G., Nishimura, S., Hokamura, K., Eto, K., et al. (2010). Essential in vivo roles of the C-type lectin receptor CLEC-2: Embryonic/neonatal lethality of CLEC-2-deficient mice by blood/lymphatic misconnections and impaired thrombus formation of CLEC-2-deficient platelets. Journal of Biological Chemistry, 285, 24494–24507.

    Article  PubMed  CAS  Google Scholar 

  • Tammela, T., & Alitalo, K. (2010). Lymphangiogenesis: Molecular mechanisms and future promise. Cell, 140, 460–476.

    Article  PubMed  CAS  Google Scholar 

  • Truman, L. A., Bentley, K. L., Smith, E. C., Massaro, S. A., Gonzalez, D. G., Haberman, A. M., et al. (2012). ProxTom lymphatic vessel reporter mice reveal Prox1 expression in the adrenal medulla, megakaryocytes, and platelets. American Journal of Pathology, 180, 1715–1725.

    Article  PubMed  CAS  Google Scholar 

  • Uhrin, P., Zaujec, J., Breuss, J. M., Olcaydu, D., Chrenek, P., Stockinger, H., et al. (2010). Novel function for blood platelets and podoplanin in developmental separation of blood and lymphatic circulation. Blood, 115, 3997–4005.

    Article  PubMed  CAS  Google Scholar 

  • Vakoc, B. J., Fukumura, D., Jain, R. K., & Bouma, B. E. (2012). Cancer imaging by optical coherence tomography: Preclinical progress and clinical potential. Nature Reviews Cancer, 12, 363–368.

    Article  PubMed  CAS  Google Scholar 

  • Van Balkom, I. D. C., Alders, M., Allanson, J., Bellini, C., Frank, U., De Jong, G., et al. (2002). Lymphedema—lymphangiectasia—mental retardation (Hennekam) syndrome: A review. American Journal of Medical Genetics, 112, 412–421.

    Article  PubMed  Google Scholar 

  • Wigle, J. T., & Oliver, G. (1999). Prox1 function is required for the development of the murine lymphatic system. Cell, 98, 769–778.

    Article  PubMed  CAS  Google Scholar 

  • Yang, Y., Garcia-Verdugo, J. M., Soriano-Navarro, M., Srinivasan, R. S., Scallan, J. P., Singh, M. K., et al. (2012). Lymphatic endothelial progenitors bud from the cardinal vein and intersomitic vessels in mammalian embryos. Blood, 120, 2340–2348.

    Article  PubMed  CAS  Google Scholar 

  • Yuen, D., Wu, X., Kwan, A. C., LeDue, J., Zhang, H., Ecoiffier, T., et al. (2011). Live imaging of newly formed lymphatic vessels in the cornea. Cell Research, 21, 1745–1749.

    Article  PubMed  Google Scholar 

  • Zeeb, M., Axnick, J., Planas-Paz, L., Hartmann, T., Strilic, B., & Lammert, E. (2012). Pharmacological manipulation of blood and lymphatic vascularization in ex vivo-cultured mouse embryos. Nature Protocols, 7, 1970–1982.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

Work in the author’s laboratory has been supported by the Max Planck Society and the Deutsche Forschungsgemeinschaft SFB 629 and SFB 656. We apologize to many colleagues whose important work could not be cited due to space restrictions. The authors declare no conflicts of interest.

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  1. Mammalian Cell Signaling Laboratory, MPI for Molecular Biomedicine, Röntgenstrasse 20, 48149, Münster, Germany

    Cathrin Pollmann, René Hägerling & Friedemann Kiefer

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  1. MPI for Molecular Biomedicine, Münster, Germany

    Friedemann Kiefer

  2. Hubrecht Institute, Utrecht, The Netherlands

    Stefan Schulte-Merker

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Pollmann, C., Hägerling, R., Kiefer, F. (2014). Visualization of Lymphatic Vessel Development, Growth, and Function. In: Kiefer, F., Schulte-Merker, S. (eds) Developmental Aspects of the Lymphatic Vascular System. Advances in Anatomy, Embryology and Cell Biology, vol 214. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1646-3_13

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