FGF family members differentially regulate maturation and proliferation of stem cell-derived astrocytes
FGF family members differentially regulate maturation and proliferation of stem cell-derived astrocytes
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DOI：
10.1038/s41598-019-46110-1
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发表时间：
2019-07-03
影响因子：
4.6
通讯作者：
Roybon, Laurent
中科院分区：
文献类型：
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作者：
Savchenko, Ekaterina;Teku, Gabriel N.;Roybon, Laurent
谷氨酸转运蛋白1（GLT 1）在体内星形胶质细胞发育和成熟过程中上调，对星形胶质细胞功能至关重要。然而，它在大多数培养的星形胶质细胞中以低水平表达。我们先前表明，人和小鼠干细胞衍生的星形胶质细胞的成熟-包括功能性谷氨酸摄取-可以通过成纤维细胞生长因子（FGF）1或FGF 2增强。在这里，我们研究了FGF 2和其他FGF家族成员，以及神经营养和分化因子对小鼠胚胎干细胞衍生的星形胶质细胞的特异性和作用机制。我们发现，一些FGF-包括FGF 2，强烈增加GLT 1表达和增强星形胶质细胞增殖，而其他（FGF 16和FGF 18）主要影响成熟。有趣的是，BMP 4增加星形胶质细胞GFAP表达，BMP 4处理的星形胶质细胞未能促进运动神经元的存活。全转录组分析表明，FGF 2处理调节与细胞分裂相关的多个基因，并且编码GLT 1的mRNA是所有星形胶质细胞典型标志物中上调最强烈的基因之一。由于GLT 1在许多神经退行性疾病中以降低的水平表达，因此该途径的激活具有潜在的治疗意义。此外，用FGF处理提供了用于临床前研究的功能成熟干细胞衍生的星形胶质细胞扩增的稳健手段。
The glutamate transporter 1 (GLT1) is upregulated during astrocyte development and maturation in vivo and is vital for astrocyte function. Yet it is expressed at low levels by most cultured astrocytes. We previously showed that maturation of human and mouse stem cell-derived astrocytes -including functional glutamate uptake - could be enhanced by fibroblast growth factor (FGF) 1 or FGF2. Here, we examined the specificity and mechanism of action of FGF2 and other FGF family members, as well as neurotrophic and differentiation factors, on mouse embryonic stem cell-derived astrocytes. We found that some FGFs - including FGF2, strongly increased GLT1 expression and enhanced astrocyte proliferation, while others ( FGF16 and FGF18) mainly affected maturation. Interestingly, BMP4 increased astrocytic GFAP expression, and BMP4-treated astrocytes failed to promote the survival of motor neurons in vitro. Whole transcriptome analysis showed that FGF2 treatment regulated multiple genes linked to cell division, and that the mRNA encoding GLT1 was one of the most strongly upregulated of all astrocyte canonical markers. Since GLT1 is expressed at reduced levels in many neurodegenerative diseases, activation of this pathway is of potential therapeutic interest. Furthermore, treatment with FGFs provides a robust means for expansion of functionally mature stem cell-derived astrocytes for preclinical investigation.