In addition to the blood vascular system, vertebrates possess a completely separate network of endothelial vessels called the lymphatic vascular system that protects and maintains the fluid homeostasis of the body by filtering and draining away lymphatic fluid.Â Under normal conditions, the lymphatic system is necessary for the return of interstitial fluid and macromolecules to the blood circulation, for immune defense, and for the uptake of dietary fats. In addition to its important role during embryonic development, growth and proliferation of lymphatic vessels is an essential feature of tissue repair and inflammation in most organs.
Impaired functioning of lymphatic vessels can result in the formation of lymphoedema, while tumor-associated lymphangiogenesis may contribute to the spread of cancer cells from solid tumors.
In contrast to the extensive molecular and functional characterization of blood vascular endothelium, comparatively little is known about the mechanisms that control the formation, differentiation and function of lymphatic vessels. Furthermore, the ultimate origin of lymphatic endothelial cells still remains controversial.
The most widely accepted view of early lymphatic development was described by Sabin back in 1902. Based on ink injection experiments she postulated that primitive lymph sacs originated from endothelial cells that bud from large veins early during development.
An alternative model for the emergence of lymphatic vessels was proposed by Huntington and McClure in 1910. These authors proposed that mesenchymal lymphangioblast-like cells are the source of lymphatic vessels, and thaIt lymphatics arise in the mesenchyme independent of the veins and then subsequently establish venous connections.
The debate over LEC origins remains unresolved in large part because of lack of an effective model organism allowing one to easily observe lymphatic cells in vivo and perform defined genetic and experimental manipulation of the lymphatic system.
We have taken advantage of the genetic and experimental advantages of the zebrafish to study the early stages of lymphatic development. Although there is no previous published description of lymphatic vessels in the zebrafish, we have uncovered a lymphatic vascular system within the developing animal that shares characteristics of lymphatic vessels of other vertebrates.
Using time-lapse imaging of transgenic zebrafish we have been able to visualize and trace the formation of embryonic lymphatic vessels by following the migration of individual cells from their origin through their incorporation into the thoracic duct. These studies have allowed us to provide the first conclusive in vivo evidence supporting a venous origin for primitive lymphatic endothelial cells.
Our results highlight the zebrafish as a new and powerful experimental and genetic model for the study of early lymphangiogenesis in the living embryo, and provide the first detailed morphological and molecular characterization of the lymphatic vasculature in this organism, as well as the most conclusive evidence to date for the mechanism underlying the formation of the vertebrate lymphatic system.
- Yaniv K., Isogai S., Castranova D., Dye L., Hitomi J., and Weinstein B.M. Live imaging of lymphatic development in the zebrafish. Nature Medicine 12, 711 - 716 (2006)
- Yaniv K., and Weinstein B.M. Blood vessel formation. In Principles of Developmental Genetics. Sally Mood, Ed. Elsevier Press, San Diego. In press
- Yaniv K., Isogai S., Castranova D., Dye L., Hitomi J., and Weinstein B.M. Imaging the developing lymphatic system using the zebrafish. In Symposium on Vascular Development-Proceedings. Novartis Foundation, London. In pres