ADAMTS18+ villus tip telocytes maintain a polarized VEGFA signaling domain and fenestrations in nutrient-absorbing intestinal blood vessels

Abstract

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.

Volumetric Printing across Melt Electrowritten Scaffolds Fabricates Multi-Material Living Constructs with Tunable Architecture and Mechanics

“…Another physiologically relevant application of the positional control of hydrogel printing within the MEW mesh is the creation of micron-scale fenestrations (Figure 4B), such as those commonly found in permeable vessels throughout the human body. These fenestrated vessel walls, already present in neovascular structures during development, [54] are abundant in different regions of the body where permeability is critical for nutrient and waste exchange, including the renal glomerulus, [55] intestinal blood vessels, [56] the nasal mucosa, [57] and are present in different areas of the central nervous system, [58] including the blood-brain barrier in certain neurological diseases including strokes. [59][60][61] Apart from these naturally occurring fenestrated structures, the clinical application of fenestrated stents for the repair of damaged vessels and aneurysms has also been a topic of interest, given the need to maintain transmembrane transport in the repaired vascular structures.…”

Mechanism of Tao Hong Decoction in the treatment of atherosclerosis based on network pharmacology and experimental validation

“…VEGFA was formerly considered a proinflammatory biomarker in endothelial cells involved in AS ( 50 ). Furthermore, It plays a crucial role in pathological and developmental angiogenesis ( 51 ). HIF-1α was closely associated with fibrosis of tissues and intracellular oxygen metabolism ( 52 ).…”

Immune niches orchestrated by intestinal mesenchymal stromal cells lining the crypt-villus

“…Another study has identified a villus tip telocyte expressing Adamts18 , which promotes the integrity of villus tip vessel and epithelium ( 29 ). Depleting villus tip telocytes via Lgr5 -DTA system would also affect the formation of villus tip endothelial cell network without affecting the maintenance of intestinal epithelial stem cell ( 29 ). Such function has been executed via VEGF-α ( 29 ).…”

“…Depleting villus tip telocytes via Lgr5 -DTA system would also affect the formation of villus tip endothelial cell network without affecting the maintenance of intestinal epithelial stem cell ( 29 ). Such function has been executed via VEGF-α ( 29 ). Crypt bottom telocytes, on the other hand, highly express F-spondin, Gremlin 1 and soluble Frizzled receptors ( 8 ).…”

“…The top of villus tip is also the place where intestinal epithelial cells undergo anoikic type of cell death ( 36 ). To cope with such complicated environment filled with immunogens and quickly respond to the invading microbes, the capillary bed where leukocytes extravasated is also seated in the villus tip ( 29 ). Thus, the villus tip may form an immune hub enriched with multiple villus tip-resident cells including villus tip telocytes, dendritic cells and type III innate lymphocytes.…”