Gautheron Flavie, Georgievski Aleksandra, Garrido Carmen, Quéré Ronan
UMR1231, Inserm/Université Bourgogne, Dijon, France.
LipSTIC Labex, Dijon, France.
Cell Death Discov. 2023 Apr 5;9(1):117. doi: 10.1038/s41420-023-01414-0.
Extracellular vesicles (EVs) released by cells in the bone marrow (BM) are important for regulating proliferation, differentiation, and other processes in hematopoietic stem cells (HSC). TGF-β signaling is now well known to be involved in HSC's quiescence and maintenance, but the TGF-β pathway related to EVs is still largely unknown in the hematopoietic system. We found that the EV inhibitor Calpeptin, when injected intravenously into mice, particularly affected the in vivo production of EVs carrying phosphorylated Smad2 (p-Smad2) in mouse BM. This was accompanied with an alteration in the quiescence and maintenance of murine HSC in vivo. EVs produced by murine mesenchymal stromal MS-5 cells also showed presence of p-Smad2 as a cargo. We treated MS-5 cells with the TGF-β inhibitor SB431542 in order to produce EVs lacking p-Smad2, and discovered that its presence was required for ex vivo maintenance of HSC. In conclusion, we revealed a new mechanism involving EVs produced in the mouse BM that transport bioactive phosphorylated Smad2 as a cargo to enhance the TGF-β signaling-mediated quiescence and maintenance of HSC.
骨髓（BM）细胞释放的细胞外囊泡（EVs）对于调节造血干细胞（HSC）的增殖、分化及其他过程至关重要。目前已知TGF-β信号传导参与HSC的静止和维持，但在造血系统中，与EVs相关的TGF-β途径仍 largely unknown。我们发现，当将EV抑制剂Calpeptin静脉注射到小鼠体内时，它特别影响小鼠BM中携带磷酸化Smad2（p-Smad2）的EVs的体内产生。这伴随着小鼠HSC在体内静止和维持的改变。小鼠间充质基质MS-5细胞产生的EVs也显示存在p-Smad2作为一种货物。我们用TGF-β抑制剂SB431542处理MS-5细胞以产生缺乏p-Smad2的EVs，并发现其存在是HSC体外维持所必需的。总之，我们揭示了一种新机制，涉及小鼠BM中产生的EVs，其将生物活性磷酸化Smad2作为货物运输，以增强TGF-β信号传导介导的HSC的静止和维持。
