Heterogeneity of the origin of the lymphatic system

lop? This question is as simple as it is fundamental to the understanding of the lymphatic system (LS) under physiological and pathological conditions. Moreover, it is also critical for the development of therapeutic interventions. In 1902, the anatomist Florence Sabin published her studies on the development of the earliest lymphatic vessels in pigs [1 ] and thereby laid the foundation for a controversy that would last for more than a century into the present. Sabin visualized lymphatic vessels by dye injections into living embryos, and her results implied that already the earliest lymphatic vessels are connected to the venous system and that the development of the lymphatic system starts by radial sprouting from lymph sacs, which arise from four outgrowths of the venous system. Sabin thus provided experimental support for the centrifugal development hypothesis that had been proposed earlier by Ranvier, who, however, had not been able to support his claims experimentally [2] . In 1905, Frederic T. Lewis, a proponent of the centrifugal hypothesis, modified Sabin's original idea based on serial sections of rabbit embryos. He observed that the original lymphatic outgrowths from the veins would disappear giving rise to closed lymph sacs in the mesenchyme, and that only later, the permanent openings of the lymphatic system into the cardiovascular system would form [3] . He also described the existence ofmore than only four venous locations from which the LS would originate. About 70 years later, his view of the lymphatic development received solid support by a detailed histological analysis of mouse and human embryos by van der Putte [4, 5] . Nevertheless, the centrifugal hypothesis of Sabin and Lewis was already early on challenged by others, notably by Huntington and McClure in 1908 [6] . They proposed the so-called centripetal model, in which lymphatic spaces could form de-novo by differentiation within the mesoderm. Those spaces would merge in the course of development to ultimately form a continuous vascular system, that would finally connect to the venous system. Huntington and McClure based their model on serial paraffin sections of early cat embryos, in which they could demonstrate that some lymphatic structures (e.g. the Ductus thoracicus) are never connected to the venous system during the early development of the lymphatic system.