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

被引：28

作者：

Bernier-Latmani, Jeremiah ^{[1
,2
]}

Mauri, Cristina ^{[1
,2
]}

Marcone, Rachel ^{[3
]}

Renevey, Francois ^{[4
]}

Durot, Stephan ^{[5
]}

He, Liqun ^{[6
]}

Vanlandewijck, Michael ^{[6
,7
]}

Maclachlan, Catherine ^{[8
]}

Davanture, Suzel ^{[1
,2
]}

Zamboni, Nicola ^{[5
]}

Knott, Graham W. ^{[8
]}

Luther, Sanjiv A. ^{[4
]}

Betsholtz, Christer ^{[6
,7
]}

Delorenzi, Mauro ^{[1
,2
,3
]}

Brisken, Cathrin ^{[9
]}

Petrova, Tatiana, V ^{[1
,2
,9
]}

机构：

[1] Ludwig Inst Canc Res Lausanne, Dept Oncol, Lausanne, Switzerland

[2] Univ Lausanne, Lausanne, Switzerland

[3] SIB Swiss Inst Bioinformat, Bioinformat Core Facil, Lausanne, Switzerland

[4] Univ Lausanne, Dept Immunobiol, Lausanne, Switzerland

[5] ETH, Inst Mol Syst Biol, Zurich, Switzerland

[6] Uppsala Univ, Dept Immunol Genet & Pathol, Rudbeck Lab, Uppsala, Sweden

[7] Karolinska Inst, Dept Med Huddinge, Huddinge, Sweden

[8] Ecole Polytech Fed Lausanne, Bio Electron Microscopy Lab, Sch Life Sci, Lausanne, Switzerland

[9] Ecole Polytech Fed Lausanne, Swiss Inst Expt Canc Res ISREC, Sch Life Sci, Lausanne, Switzerland

来源：

NATURE COMMUNICATIONS | 2022年 / 13卷 / 01期

基金：

瑞典研究理事会; 瑞士国家科学基金会;

关键词：

GROWTH-FACTOR BINDING; EXTRACELLULAR-MATRIX; VASCULAR-PERMEABILITY; STEM-CELLS; ENDOTHELIAL FENESTRATIONS; DEVELOPMENTAL EXPRESSION; HIGH-THROUGHPUT; LAMINA PROPRIA; STROMAL CELLS; ANGIOGENESIS;

D O I：

10.1038/s41467-022-31571-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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. The molecular mechanisms ensuring the specialized structure of small intestinal villus tip blood vessels are incompletely understood. Here the authors show that ADAMTS18(+) telocytes maintain a "just-right" level and location of VEGFA signaling on intestinal villus blood vessels, thereby ensuring the presence of endothelial fenestrae for nutrient absorption, while avoiding excessive leakiness and destabilization of villus tip epithelial structures.

引用

页数：17

共 101 条

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