Chemokine Signaling Directs Trunk Lymphatic Network Formation along the Preexisting Blood Vasculature

Abstract

SUMMARY The lymphatic system is crucial for fluid homeostasis, immune responses, and numerous pathological processes. However, the molecular mechanisms responsible for establishing the anatomical form of the lymphatic vascular network remain largely unknown. Here, we show that chemokine signaling provides critical guidance cues directing early trunk lymphatic network assembly and patterning. The chemokine receptors Cxcr4a and Cxcr4b are expressed in lymphatic endothelium, while chemokine ligands Cxcl12a and Cxcl12b are expressed in adjacent tissues along which the developing lymphatics align. Loss- and gain- of function studies in the zebrafish demonstrate that chemokine signaling orchestrates the stepwise assembly of the trunk lymphatic network. In addition to providing evidence for a lymphatic vascular guidance mechanism, these results also suggest a molecular basis for the anatomical co-alignment of lymphatic and blood vessels.

Getting out and about: the emergence and morphogenesis of the vertebrate lymphatic vasculature

“…This study suggests that reiterative chemokine cues from multiple, adjacent tissues regulate the progressive migration of PLs through the In te rnalisatio n P h os phorylatio n Fig. 3 zebrafish embryonic environment and provides a mechanistic explanation for the location of lymphatic vessels alongside arteries (Cha et al, 2012). Supporting the likely conservation of chemokine signalling in lymphangiogenesis, CXCR4 is expressed in mammalian LECs and Cxcl12a promotes LEC migration in culture (Zhuo et al, 2012).…”

“…However, despite the anatomical and functional divergence, it is clear that the early, larger lymphatic vessels in mouse and zebrafish develop through very similar cellular processes of dorsal sprouting from embryonic veins, migration and remodelling (Küchler et al, 2006;Yaniv et al, 2006). Furthermore, zebrafish genetics can be applied to understand the formation of lymphatic vessels with relevance to mammalian development (Alders et al, 2009;Hogan et al, 2009a;Bussmann et al, 2010;Lim et al, 2011;Cha et al, 2012). Future studies exploring the developmental mechanisms underpinning the evolution of lymphatic systems are likely to greatly inform our understanding of embryonic lymphangiogenesis.…”

“…Live imaging and comprehensive quantification in this study identified a strong, almost exclusive, association between migrating PLs and aISVs, once PLs leave the HM from 60 hpf onwards. Although the mechanism responsible for this process was initially unclear, a role for chemokine signalling has recently emerged (Cha et al, 2012) (Fig. 4A,B).…”

“…All mammals have a complex lymphatic vasculature with highly developed lymphatic valves, nodes and hierarchical vessel subtypes (Sabin, 1902;Delamere and Cuneo, 1903). REVIEW Development 140 (9) development in zebrafish, because its expression correlates with a role in venous endothelium during the initiation of dorsal sprouting and knockdown of Prox1a can lead to absence of a TD (Yaniv et al, 2006;Del Giacco et al, 2010;Tao et al, 2011;Cha et al, 2012).…”

Lymph node spread of gallbladder cancer from the perspective of embryologically-based anatomy and significance of the lymphatic basin along the embryonic right hepatic artery

“…In the pN1 group, lymph node metastases characteristically arise in the pericholedochal area or the posterosuperior pancreaticoduodenal region, rather than around the hepatic artery (2,3). However, no feeding arteries are present around the pericholedochal lymph nodes and posterosuperior pancreaticoduodenal lymph nodes (PPLNs), although lymph nodes and lymphatic vessels generally exist along a feeding artery (4)(5)(6)(7).…”