Recent studies have shown important roles for autophagy genes in the regulation of different tissue stem cells, including neural stem/progenitor cells (NSCs). However, little is known about whether autophagy can regulate NSCs through cell-extrinsic mechanisms. Here, we show that deletion of an essential autophagy gene, FIP200, in NSCs increased expression of Ccl5 and Cxcl10 in a p53-independent manner, mediating increased infiltration of microglia into the subventricular zone of both FIP200hGFAP conditional knockout (cKO) and FIP200;p53hGFAP 2cKO mice. The microglia exhibited an activated M1 phenotype consistent with their potential to inhibit differentiation of FIP200-null NSCs. Blocking either microglia infiltration or activation rescued the deficient differentiation of FIP200-null NSCs from FIP200;p53hGFAP 2cKO mice. Lastly, we showed that increased chemokine expression in FIP200-null NSCs was induced by abnormal p62 aggregate formation and activation of NF-κB signaling. Our results suggest that autophagy plays a crucial role in regulating neurogenesis and restricting local immune response in postnatal NSCs through non-cell autonomous mechanisms.

译文

:最近的研究表明自噬基因在调节不同组织干细胞(包括神经干/祖细胞(NSC))中的重要作用。然而,关于自噬是否可以通过细胞外源性机制调节NSC的了解甚少。在这里,我们显示出在NSC中缺失必不可少的自噬基因FIP200以不依赖p53的方式增加了Ccl5和Cxcl10的表达,介导了小胶质细胞浸润入FIP200hGFAP条件性基因敲除(cKO)和FIP200; p53hGFAP的脑室下区域2cKO小鼠。小胶质细胞表现出活化的M1表型,与其抑制FIP200无效的NSCs分化的潜力一致。阻断小胶质细胞浸润或激活可以从FIP200; p53hGFAP 2cKO小鼠中拯救FIP200-null NSC的不足分化。最后,我们表明,FIP200-null NSCs中趋化因子表达的增加是由异常的p62聚集体形成和NF-κB信号传导引起的。我们的结果表明自噬在调节神经发生和通过非细胞自主机制限制产后NSC中的局部免疫反应中起着至关重要的作用。

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