Development of the mammalian lymphatic vasculature

Abstract

The two vascular systems of our body are the blood and lymphatic vasculature.Our understanding of the cellular and molecular processes controlling the development of the lymphatic vasculature has progressed significantly in the last decade.In mammals, this is a stepwise process that starts in the embryonic veins, where lymphatic EC (LEC) progenitors are initially specified.The differentiation and maturation of these progenitors continues as they bud from the veins to produce scattered primitive lymph sacs, from which most of the lymphatic vasculature is derived.Here, we summarize our current understanding of the key steps leading to the formation of a functional lymphatic vasculature.Origin and specification of lymphatic ECs Origin of lymphatic ECs in the mammalian embryo.The lymphatic vasculature is essential for maintaining interstitial fluid homeostasis.Deficiency in development and/or function of the lymphatic vasculature causes various lymphedema syndromes in humans, and active lymphangiogenesis plays a significant role in chronic inflammation and tumor metastasis.Research of the lymphatic vasculature dates back to the 17th century, but the anatomic features of the developing lymphatic vasculature were most extensively characterized during the 20th century by using pig and mouse embryos (1, 2).Florence Sabin first suggested that the lymphatic vessels arise from preexisting blood vessels, specifically the cardinal veins (CVs) (1).More than 100 years later, experiments using detailed lineage tracing in mammals and live imaging in zebrafish demonstrated that lymphatic EC (LEC) progenitors originate in the veins from venous ECs (VECs) (3, 4).Recent work in mouse embryos shows that the intersomitic veins (ISVs) and the superficial venous plexus are additional sources of LEC progenitors (5, 6).These findings support previous observations that LEC progenitors are of venous origin and that they leave the veins via specific migratory paths that extend radially from the dorsal half of the CV (7, 8).Additionally, they help to explain the rapid appearance of large numbers of migrating LECs within the mesenchymal tissue (Figure 1). LEC fate specification.Development of the mammalian lymphatic vasculature is a stepwise process in which LEC progenitors are first specified in the embryonic veins and then bud from the veins to form the primitive lymph sacs from which most of the lymphatic vasculature will eventually be derived (9).During the past few years, several key regulatory molecules and specific markers of the lymphatic endothelium have been identified (Table 1).The expression of the transcription factor Prox1 in a subpopulation of VECs (referred to as LEC progenitors) in the embryonic CVs at approximately E9.5 (3, 5, 7) is the initial step in the formation of the lymphatic vasculature.The transcription factors Sox18 and COUP-TFII are required for activation of Prox1 expression in VECs (Figure 1 and refs.10, 11), and loss of either Sox18 or COUP-TFII results in the absence of LEC progenitors (Tables 2,3,(4)(5)(6)(7)(8)(9)(10)(11)(12). Conflict of interest:The authors have declared that no conflict of interest exists.