Neurogenic niche modulation by activated microglia:: transforming growth factor β increases neurogenesis in the adult dentate gyrus
Neurogenic niche modulation by activated microglia:: transforming growth factor β increases neurogenesis in the adult dentate gyrus
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DOI：
10.1111/j.1460-9568.2005.04539.x
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发表时间：
2006-01-01
影响因子：
3.4
通讯作者：
Pitossi, FJ
中科院分区：
文献类型：
--
作者：
Battista, D;Ferrari, CC;Pitossi, FJ
成体神经干细胞（NSC）的增殖和分化取决于它们所处的细胞和分子生态位的组成。直到最近，小胶质细胞作为神经原性生态位的一部分一直被忽视。我们研究了肾上腺切除动物（ADX）海马齿状回（DG）神经干细胞增殖和分化的动态变化，并描述了神经原性生态位的变化。在细胞水平上，我们发现ADX动物的NSC增殖和神经发生增加。此外，检测到具有增加的增殖特征的形态学上不同的NSC亚群（Nestin+/GFAP-）。有趣的是，第2和第3阶段的小胶质细胞数量与神经发生增加（r（2）= 0.999）和Nestin阳性细胞数量（r（2）= 0.96）相关。在分子水平上，ADX动物的转化生长因子β（TGF-β）mRNA水平增加了10倍。有趣的是，TGF-β水平与检测到的神经发生的量（r（2）= 0.99）以及2期和3期小胶质细胞的数量（r（2）= 0.94）相关。此外，通过施用抗TGF-β II型受体抗体阻断TGF-β生物活性降低了体内5-溴-2 '-脱氧尿苷（BrdU）/ PSA-NCAM阳性细胞的百分比。此外，TGF-β能够促进NSC原代培养物中的神经发生。这项工作支持了这样一种观点，即激活的小胶质细胞本身不是促神经原性或抗神经原性的，而是促炎和抗炎分泌分子之间的平衡影响了这种激活的最终效果。重要的是，我们确定了一种抗炎细胞因子TGF-β，在成人大脑中具有神经原性潜力。
Adult neural stem cells (NSC) proliferate and differentiate depending on the composition of the cellular and molecular niche in which they are immersed. Until recently, microglial cells have been ignored as part of the neurogenic niche. We studied the dynamics of NSC proliferation and differentiation in the dentate gyrus of the hippocampus (DG) and characterized the changes of the neurogenic niche in adrenalectomized animals (ADX). At the cellular level, we found increased NSC proliferation and neurogenesis in the ADX animals. In addition, a morphologically distinct subpopulation of NSC (Nestin+/GFAP-) with increased proliferating profile was detected. Interestingly, the number of microglial cells at stages 2 and 3 of activation correlated with increased neurogenesis (r(2) = 0.999) and the number of Nestin-positive cells (r(2) = 0.96). At the molecular level, transforming growth factor beta (TGF-beta) mRNA levels were increased 10-fold in ADX animals. Interestingly, TGF-beta levels correlated with the amount of neurogenesis detected (r(2) = 0.99) and the number of stage 2 and 3 microglial cells (r(2) = 0.94). Furthermore, blockade of TGF-beta biological activity by administration of an anti-TGF-beta type II receptor antibody diminished the percentage of 5-bromo-2'-deoxyuridine (BrdU)/ PSA-NCAM-positive cells in vivo. Moreover, TGF-beta was able to promote neurogenesis in NSC primary cultures. This work supports the idea that activated microglial cells are not pro- or anti-neurogenic per se, but the balance between pro- and anti-inflammatory secreted molecules influences the final effect of this activation. Importantly, we identified an anti-inflammatory cytokine, TGF-beta, with neurogenic potential in the adult brain.