Department of Oncology, Ludwig Institute for Cancer Research Lausanne and University of Lausanne, Lausanne, Switzerland.
Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Nat Commun. 2022 Jul 9;13(1):3983. doi: 10.1038/s41467-022-31571-2.
The small intestinal villus tip is the first point of contact for lumen-derived substances including nutrients and microbial products. Electron microscopy studies from the early 1970s uncovered unusual spatial organization of small intestinal villus tip blood vessels: their exterior, epithelial-facing side is fenestrated, while the side facing the villus stroma is non-fenestrated, covered by pericytes and harbors endothelial nuclei. Such organization optimizes the absorption process, however the molecular mechanisms maintaining this highly specialized structure remain unclear. Here we report that perivascular LGR5 villus tip telocytes (VTTs) are necessary for maintenance of villus tip endothelial cell polarization and fenestration by sequestering VEGFA signaling. Mechanistically, unique VTT expression of the protease ADAMTS18 is necessary for VEGFA signaling sequestration through limiting fibronectin accumulation. Therefore, we propose a model in which LGR5 ADAMTS18 telocytes are necessary to maintain a "just-right" level and location of VEGFA signaling in intestinal villus blood vasculature to ensure on one hand the presence of sufficient endothelial fenestrae, while avoiding excessive leakiness of the vessels and destabilization of villus tip epithelial structures.
小肠绒毛尖端是腔衍生物质（包括营养物质和微生物产物）的第一个接触点。20 世纪 70 年代初的电子显微镜研究揭示了小肠绒毛尖端血管的异常空间组织：其外表面，朝向上皮的一侧是有窗孔的，而朝向绒毛基质的一侧无窗孔，由周细胞覆盖，并含有内皮核。这种组织优化了吸收过程，但维持这种高度特化结构的分子机制仍不清楚。在这里，我们报告说，血管周 LGR5 绒毛尖端间质细胞（VTT）通过隔离 VEGFA 信号对于维持绒毛尖端内皮细胞极化和窗孔形成是必需的。在机制上，蛋白酶 ADAMTS18 的独特 VTT 表达对于通过限制纤维连接蛋白积累来隔离 VEGFA 信号是必需的。因此，我们提出了一个模型，即 LGR5-ADAMTS18 间质细胞对于维持肠道绒毛血管中 VEGFA 信号的“恰到好处”水平和位置是必需的，以确保一方面存在足够的内皮窗孔，同时避免血管过度渗漏和绒毛尖端上皮结构的不稳定。
