Lineage-Tracing Studies Reconcile a 100-Year-Old Debate on the Centrifugal Versus Centripetal Theories on the Origin of Lymphatic Endothelial Cells

Lineage-Tracing Studies Reconcile a 100-Year-Old Debate on the Centrifugal Versus Centripetal Theories on the Origin of Lymphatic Endothelial Cells A network of thin-walled lymphatic vessels is present in virtually every tissue of the body, where it carries out several important functions, such as transport of antigen-presenting cells to lymph nodes, uptake of dietary fat, and maintenance of interstitial fluid balance. The importance of the lymphatic vasculature to human pathology is only now beginning to be appreciated, as it becomes increasingly clear that lymphatic vessels play important roles in a host of common diseases, ranging from cancer metastasis to atherosclerosis and hypertension. Research in the past 2 decades has tremendously improved our understanding of molecular mechanisms involved in the regulation of lymphatic vasculature and its function. In particular, the atypical homeobox transcription factor Prox1 plays a key role in establishing and maintaining mammalian lymphatic endothelial cell (LEC) identity, whereas the Ccbe1/Adamts3/Vegf-c/Vegfr-3 signaling cascade is essential for LEC proliferation, migration, and survival. Novel therapies, which are a direct result of this knowledge, are now being developed for treatments that both promote lymphatic vessel regeneration and block excessive lymphangiogenesis. However, full comprehension into the intricacies of LEC biology is still being developed. The work of Martinez-Corral et al, based on lineage-tracing analyses of genetic mouse models, now provides first insights into an unexpected complexity of LEC origins in mammals.