Patritti-Cram Jennifer, Rahrmann Eric P, Rizvi Tilat A, Scheffer Katherine C, Phoenix Timothy N, Largaespada David A, Ratner Nancy
Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Neuroscience Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0713, USA.
iScience. 2024 Jun 17;27(7):110294. doi: 10.1016/j.isci.2024.110294. eCollection 2024 Jul 19.
The blood-nerve-barrier (BNB) that regulates peripheral nerve homeostasis is formed by endoneurial capillaries and perineurial cells surrounding the Schwann cell (SC)-rich endoneurium. Barrier dysfunction is common in human tumorigenesis, including in some nerve tumors. We identify barrier disruption in human deficient neurofibromas, which were characterized by reduced perineurial cell glucose transporter 1 (GLUT1) expression and increased endoneurial fibrin(ogen) deposition. Conditional loss in murine SCs recapitulated these alterations and revealed decreased tight junctions and decreased caveolin-1 () expression in mutant nerves and in tumors, implicating reduced mediated transcytosis in barrier disruption and tumorigenesis. Additionally, elevated receptor tyrosine kinase activity and genetic deletion of increased endoneurial fibrin(ogen), and promoted SC tumor formation. Finally, when SC lacked , genetic loss or pharmacological inhibition of P2RY14 rescued expression and barrier function. Thus, loss of in SC causes dysfunction of the BNB via P2RY14-mediated G-protein coupled receptor (GPCR) signaling.
调节周围神经内环境稳定的血神经屏障（BNB）由富含施万细胞（SC）的神经内膜周围的神经内膜毛细血管和神经束膜细胞形成。屏障功能障碍在人类肿瘤发生中很常见，包括一些神经肿瘤。我们在人类缺陷型神经纤维瘤中发现了屏障破坏，其特征是神经束膜细胞葡萄糖转运蛋白1（GLUT1）表达降低和神经内膜纤维蛋白（原）沉积增加。小鼠SCs中的条件性缺失重现了这些改变，并揭示了突变神经和肿瘤中紧密连接减少和小窝蛋白-1（）表达降低，这表明介导的转胞吞作用减少与屏障破坏和肿瘤发生有关。此外，受体酪氨酸激酶活性升高和的基因缺失增加了神经内膜纤维蛋白（原），并促进了SCs肿瘤形成。最后，当SCs缺乏时，P2RY14的基因缺失或药理学抑制可挽救表达和屏障功能。因此，SCs中 的缺失通过P2RY14介导的G蛋白偶联受体（GPCR）信号传导导致BNB功能障碍。
