Glioma-derived exosomes drive the differentiation of neural stem cells to astrocytes
Glioma-derived exosomes drive the differentiation of neural stem cells to astrocytes
复制标题
DOI：
10.1371/journal.pone.0234614
复制
发表时间：
2020-07-10
期刊：
影响因子：
3.7
通讯作者：
Xie, Jennifer Yanhua
中科院分区：
文献类型：
--
作者：
Sharma, Krishna D.;Schaal, Danielle;Xie, Jennifer Yanhua
外泌体似乎是有效的细胞间通讯器，可传递多种类型的分子，例如蛋白质和 RNA，这表明它们可以影响神经干细胞 (NSC) 的分化。我们的RNA测序研究表明，当与从人胶质瘤细胞（U87）培养基中获得的外泌体共培养时，人间充质干细胞（hMSC）中与细胞增殖和星形胶质细胞分化相关的RNA上调。与细胞增殖相关的金属硫蛋白3和弹性蛋白基因分别增加了10倍和7.2倍。星形胶质细胞分化基因的表达，如肿瘤生长因子α、NOTCH1家族的诱导蛋白3、STAT3家族的集落刺激因子和白细胞介素6以及Hes家族bHLH转录因子1的表达也分别增加了2.3、10、4.7和2.9倍。我们使用U87神经胶质瘤细胞分泌的外泌体或用白细胞介素1β（IL-1β）刺激的U87细胞的外泌体进一步检查了这些外泌体对大鼠胎儿神经干细胞（rNSC）分化的影响。 rNSCs 在胚胎第 14 天 (E14) 从大鼠大脑中提取，经过培养方案，通常会导致主要（类似于 90%）分化为 ODC。然而，在来自未处理或IL-1β处理的U87细胞的外泌体存在下，明显更多的细胞分化为星形胶质细胞，特别是在从IL-1β攻击的神经胶质瘤细胞获得的外泌体存在下。此外，神经胶质瘤来源的外泌体似乎抑制 rNSC 分化为 ODC 或星形胶质细胞，未标记细胞群显着增加表明了这一点。所得星形胶质细胞的一部分共表达 CD133 和胶质纤维酸性蛋白 (GFAP)，表明来自 U87 细胞的外泌体可以促进具有转化细胞预期特征的 NSC 星形胶质细胞分化。我们的数据清楚地表明，人胶质瘤细胞分泌的外泌体为大鼠神经干细胞分化为星形胶质细胞提供了强大的驱动力，揭示了可能控制这种侵袭性肿瘤类型的潜在途径和治疗靶点。
Exosomes appear to be effective inter-cellular communicators delivering several types of molecules, such as proteins and RNAs, suggesting that they could influence neural stem cell (NSC) differentiation. Our RNA sequencing studies demonstrated that the RNAs related to cell proliferation and astrocyte differentiation were upregulated in human mesenchymal stem cells (hMSC) when co-cultured with exosomes obtained from the culture medium of human glioma cells (U87). Metallothionein 3 and elastin genes, which are related to cell proliferation, increased 10 and 7.2 fold, respectively. Expression of genes for astrocyte differentiation, such as tumor growth factor alpha, induced protein 3 of the NOTCH1 family, colony stimulating factor and interleukin 6 of the STAT3 family and Hes family bHLH transcription factor 1 also increased by 2.3, 10, 4.7 and 2.9 fold, respectively. We further examined the effects of these exosomes on rat fetal neural stem cell (rNSC) differentiation using the secreted exosomes from U87 glioma cells or exosomes from U87 cells that were stimulated with interleukin 1 beta (IL-1 beta). The rNSCs, extracted from rat brains at embryonic day 14 (E14), underwent a culture protocol that normally leads to predominant (similar to 90%) differentiation to ODCs. However, in the presence of the exosomes from untreated or IL-1 beta-treated U87 cells, significantly more cells differentiated into astrocytes, especially in the presence of exosomes obtained from the IL-1 beta-challenged glioma cells. Moreover, glioma-derived exosomes appeared to inhibit rNSC differentiation into ODCs or astrocytes as indicated by a significantly increased population of unlabeled cells. A portion of the resulting astrocytes co-expressed both CD133 and glial fibrillary acidic protein (GFAP) suggesting that exosomes from U87 cells could promote astrocytic differentiation of NSCs with features expected from a transformed cell. Our data clearly demonstrated that exosomes secreted by human glioma cells provide a strong driving force for rat neural stem cells to differentiate into astrocytes, uncovering potential pathways and therapeutic targets that might control this aggressive tumor type.