Bobe Stefanie, Beckmann Daniel, Klump Dorothee Maria, Dierkes Cathrin, Kirschnick Nils, Redder Esther, Bauer Nadine, Schäfers Michael, Erapaneedi Raghu, Risse Benjamin, van de Pavert Serge A, Kiefer Friedemann
European Institute for Molecular Imaging, University of Münster, Münster, Germany.
Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster, Germany.
Front Cell Dev Biol. 2022 Aug 16;10:949896. doi: 10.3389/fcell.2022.949896. eCollection 2022.
The liver is a major biosynthetic and detoxifying organ in vertebrates, but also generates 25%-50% of the lymph passing through the thoracic duct and is thereby the organ with the highest contribution to lymph flow. In contrast to its metabolic function, the role of the liver for lymph generation and composition is presently severely understudied. We took a rigorous, volume imaging-based approach to describe the microarchitecture and spatial composition of the hepatic lymphatic vasculature with cellular resolution in whole mount immune stained specimen ranging from thick sections up to entire mouse liver lobes. Here, we describe that in healthy adult livers, lymphatic vessels were exclusively located within the portal tracts, where they formed a unique, highly ramified tree. Ragged, spiky initials enmeshed the portal veins along their entire length and communicated with long lymphatic vessels that followed the path of the portal vein in close association with bile ducts. Together these lymphatic vessels formed a uniquely shaped vascular bed with a delicate architecture highly adapted to the histological structure of the liver. Unexpectedly, with the exception of short collector stretches at the porta hepatis, which we identified as exit point of the liver lymph vessels, the entire hepatic lymph vessel system was comprised of capillary lymphatic endothelial cells only. Functional experiments confirmed the space of Disse as the origin of the hepatic lymph and flow the space of Mall to the portal lymph capillaries. After entry into the lymphatic initials, the lymph drained retrograde to the portal blood flow towards the exit at the liver hilum. Perinatally, the liver undergoes complex changes transforming from the main hematopoietic to the largest metabolic organ. We investigated the time course of lymphatic vessel development and identified the hepatic lymphatics to emerge postnatally in a process that relies on input from the VEGF-C/VERGFR-3 growth factor-receptor pair for formation of the fully articulate hepatic lymph vessel bed.
肝脏是脊椎动物主要的生物合成和解毒器官，但其产生的淋巴液占通过胸导管淋巴液的25%-50%，因此是对淋巴液生成贡献最大的器官。与它的代谢功能相比，肝脏在淋巴液生成和成分方面的作用目前研究严重不足。我们采用了一种严谨的、基于体积成像的方法，以细胞分辨率描述了全层免疫染色标本中肝淋巴管系统的微观结构和空间组成，这些标本范围从厚切片到整个小鼠肝叶。在此，我们描述在健康成年肝脏中，淋巴管仅位于门管区，在那里它们形成了独特的、高度分支的网络。参差不齐、尖锐的起始段沿着门静脉全长与之交织，并与沿着门静脉路径并紧密伴随胆管的长淋巴管相通。这些淋巴管共同形成了一个形状独特的血管床，其精细的结构高度适应肝脏的组织结构。出乎意料的是，除了在肝门处我们确定为肝淋巴管出口点的短收集段外，整个肝淋巴管系统仅由毛细血管淋巴管内皮细胞组成。功能实验证实狄氏间隙是肝淋巴液的起源，并将马洛间隙的淋巴液引流到门静脉淋巴毛细血管。淋巴液进入淋巴管起始段后，逆着门静脉血流向肝门处的出口引流。在围产期，肝脏经历复杂的变化，从主要的造血器官转变为最大的代谢器官。我们研究了淋巴管发育的时间进程，并确定肝淋巴管在出生后出现，这个过程依赖于血管内皮生长因子C/血管内皮生长因子受体-3生长因子-受体对的输入来形成完整的肝淋巴管床。
