Intussusceptive lymphangiogenesis in the sinuses of developing human foetal lymph nodes

A meshwork of intraluminal processes in lymph node (LN) sinuses originates during LN development. Lymph flows through the meshwork, which has an important role in immunology and pathology. However, the formation mechanism of intraluminal processes has not been sufficiently studied. Our objective is to assess whether this mechanism is by intussusception, as occurs in transcapillary pillar formation in blood vessel intussusceptive angiogenesis. For this purpose, LNs with developing intrasinusal processes were used (human foetuses, 13-18GW) for serial histologic sections and immunohistochemical procedures. The studies showed (a) sinuses originating from lymphatic sacs around expanded LN anlagen, (b) intra-sinus structures (lined by anti-podoplanin⁺, VEGFR3⁺, Prox-1⁺, CD31⁺ lymphatic endothelial cells) with characteristics (in serial sections and 3D images) similar to those considered the hallmarks of intussusceptive angiogenesis, including pillars (≤2.5μm, with a collagen core), interstitial tissue structures (ITSs) or larger pillars (>2.5μm, with a more cellular core) and folds (that form pillars when spanning), and (c) remodelled and fused pillars, ITSs and folds, which formed meshworks, compartmentalizing the sinuses into small intercommunicating spaces (segmentation). In conclusion, intussusception participates in the formation of the meshwork of processes in LN sinuses during LN development. This mechanism is also of interest because it contributes to the general knowledge of intussusceptive lymphangiogenesis (which has received less attention than intussusception in blood vessels), provides a basis for further studies and supports a new role for vessel intussusception (formation of an intraluminal meshwork with known action in fluid filtering, cell interactions and immunology).