The new era of the lymphatic system: no longer secondary to the blood vascular system

Abstract

The blood and lymphatic systems are the two major circulatory systems in our body. Although the blood system has been studied extensively, the lymphatic system has received much less scientific and medical attention because of its elusive morphology and mysterious pathophysiology. However, a series of landmark discoveries made in the past decade has begun to change the previous misconception of the lymphatic system to be secondary to the more essential blood vascular system. In this article, we review the current understanding of the development and pathology of the lymphatic system. We hope to convince readers that the lymphatic system is no less essential than the blood circulatory system for human health and well-being.

Figure 1.

Macroscopic view of the blood versus lymphatic system and illustration of the structures of lymphatic capillaries. (A) The blood vascular system is a circular and closed system in which the fluid (blood) leaves from and returns to the same organ (heart). In comparison, the lymphatic system is a linear system in which the lymphatic capillaries at the peripheral tissues drain the fluid (lymph) containing cells, proteins, and macromolecules and transport it back to the blood vascular system through the lymphatic–blood junction at the end of the thoracic duct. (Diagram modified from Karkkainen et al. 2002.) (B) Microstructure of lymphatic capillaries in the skin. Lymphatic capillaries are irregular shaped and stay collapsed. When the interstitial fluid pressure increases because of fluid accumulation, the anchoring filament bundles pull lymphatic endothelial cells and open up the cell–cell junctions so that the lymph fluids can enter the lumen of lymphatic vessels for transport. (Illustration modified from Skobe and Detmar 2000.)

Figure 2.

Current model of a stepwise embryonic development of the mammalian lymphatic system. At mouse E8.5, endothelial cells in the vein express LYVE-1, VEGFR-3, COUP-TFII, and SOX18 and are potentially capable of lymphatic differentiation (“lymphatic competence”). At E9.5–E10.5, Prox1, the master regulator for lymphatic development, is up-regulated in a subset of venous endothelial cells by an inductive signal (“lymphatic bias”). These Prox1-positive cells begin to migrate out and form the rudimentary lymphatic vessels, known as jugular lymph sacs, at E11.5, expressing additional lymphatic molecules such as podoplanin and SLC (“lymphatic specification”). (Diagram modified from Oliver and Detmar 2002.)