Abstract
Millions of patients suffer from lymphedema worldwide. Supporting the contractility of lymphatic collectors is an attractive target for pharmacological therapy of lymphedema. However, lymphatics have mostly been studied in animals, while the cellular and molecular characteristics of human lymphatic collectors are largely unknown. We studied epifascial lymphatic collectors of the thigh, which were isolated for autologous transplantations. Our immunohistological studies identify additional markers for LECs (vimentin, CCBE1). We show and confirm differences between initial and collecting lymphatics concerning the markers ESAM1, D2-40 and LYVE-1. Our transmission electron microscopic studies reveal two types of smooth muscle cells (SMCs) in the media of the collectors with dark and light cytoplasm. We observed vasa vasorum in the media of the largest collectors, as well as interstitial Cajal-like cells, which are highly ramified cells with long processes, caveolae, and lacking a basal lamina. They are in close contact with SMCs, which possess multiple caveolae at the contact sites. Immunohistologically we identified such cells with antibodies against vimentin and PDGFRα, but not CD34 and cKIT. With Next Generation Sequencing we searched for highly expressed genes in the media of lymphatic collectors, and found therapeutic targets, suitable for acceleration of lymphatic contractility, such as neuropeptide Y receptors 1, and 5; tachykinin receptors 1, and 2; purinergic receptors P2RX1, and 6, P2RY12, 13, and 14; 5-hydroxytryptamine receptors HTR2B, and 3C; and adrenoceptors α2A,B,C. Our studies represent the first comprehensive characterization of human epifascial lymphatic collectors, as a prerequisite for diagnosis and therapy.
Highlights
The lymphatic vascular system is composed of initial lymphatics precollectors, collectors, lymph nodes, and trunks [1]
Initial lymphatics take up interstitial fluid, chylomicrons, migrating cells and pathogens, and conduct them via afferent lymphatic collectors to lymph nodes [2, 3]
The lymphatic vascular system consists of initial lymphatics, pre-collectors, collectors, lymph nodes, and trunks
Summary
The lymphatic vascular system is composed of initial lymphatics (sinusoids, capillaries) precollectors, collectors, lymph nodes, and trunks [1]. The centripetal flow of lymph is achieved by autonomous contractility of the lymphatic system, even in the complete absence of external mechanical stimuli such as skeletal muscle contraction or breathing. This has been shown experimentally in chick embryos, where specialized lymph hearts fulfill these functions [6]. Lymphatic collectors, which are spontaneously contractile and equipped with intraluminal, semilunar valves, induce lymph flow and direct it towards the venous angles. Spontaneous contractility of lymph collectors has been known for quite some time [8], but has never been demonstrated in the human as unequivocally as with the ICG technique [9]
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