Establishment and maintenance of blood-lymph separation

Abstract

Hippocratic Corpus, a collection of Greek medical literature, described the functional anatomy of the lymphatic system in the fifth century B.C. Subsequent studies in cadavers and surgical patients firmly established that lymphatic vessels drain extravasated interstitial fluid, also known as lymph, into the venous system at the bilateral lymphovenous junctions. Recent advances revealed that lymphovenous valves and platelet-mediated hemostasis at the lymphovenous junctions maintain life-long separation of the blood and lymphatic vascular systems. Here, we review murine models that exhibit failure of blood-lymph separation to highlight the novel mechanisms and molecular targets for the modulation of lymphatic disorders. Specifically, we focus on the transcription factors, cofactors, and signaling pathways that regulate lymphovenous valve development and platelet-mediated lymphovenous hemostasis, which cooperate to maintain blood-lymph separation.

Keywords: Blood; Hemostasis; Lymph; Lymphatic development; Lymphovenous valve; Platelet.

Fig. 1

Cartoon model of developing murine lymphovenous valve (a) in a stage-specific (b–d) manner. LVV-EC differentiate at E12.0 (b) and undergo delamination (b), aggregation (c), and maturation (d) to form functional LVVs at LVJ. Lymph sac (LS, green), external jugular vein (EJV, blue), internal jugular vein (IJV, blue), superior vena cava (SVC, blue), lymphovenous valve endothelial cells (LVV-EC, yellow), and lymphatic endothelial cells (LECs, red)

Fig. 2

a, b Cartoon model of blood–lymph separation defect due to anomalous LVVs and/or lymphovenous hemostasis