Toll-like receptor 4 modulation influences human neural stem cell proliferation and differentiation.
Toll-like receptor 4 modulation influences human neural stem cell proliferation and differentiation.
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DOI：
10.1038/s41419-017-0139-8
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发表时间：
2018-02-15
影响因子：
9
通讯作者：
De Filippis L
中科院分区：
文献类型：
--
作者：
Grasselli C;Ferrari D;Zalfa C;Soncini M;Mazzoccoli G;Facchini FA;Marongiu L;Granucci F;Copetti M;Vescovi AL;Peri F;De Filippis L
Toll样受体4（TLR 4）的激活是先天免疫的关键，并已被证明在体内调节人神经干细胞（hNSCs）的增殖和分化。在这里，我们研究了TLR 4在调节人神经干细胞中的作用，所述人神经干细胞来源于胎儿脑的人端脑-间脑区域，并在体外培养为符合良好制造程序（GMP）指南的神经球。类似批次已用于ALS患者的近期临床试验。我们发现TLR 2和4在hNSCs以及CD 14和MD-2共受体中表达，并且TLR 4表达在分化后下调。通过脂多糖（LPS）激活TLR 4信号传导对增殖和/或存活具有积极作用，而通过合成拮抗剂抑制TLR 4观察到相反的作用。TLR 4激活促进神经元和少突胶质细胞分化和/或存活，而TLR 4抑制导致细胞凋亡增加。一致地，TLR 4的内源性表达被移植到ALS大鼠或免疫受损小鼠中后存活的hNSC保留，因此与神经炎症环境无关。hNSC中TLR 4下游信号传导的表征表明炎性体途径的一些激活。这项研究表明，TLR 4信号转导是hNSC自我更新所必需的，也是神经发生机制研究的新靶点。
Toll-like receptor 4 (TLR4) activation is pivotal to innate immunity and has been shown to regulate proliferation and differentiation of human neural stem cells (hNSCs) in vivo. Here we study the role of TLR4 in regulating hNSC derived from the human telencephalic-diencephalic area of the fetal brain and cultured in vitro as neurospheres in compliance with Good Manifacture Procedures (GMP) guidelines. Similar batches have been used in recent clinical trials in ALS patients. We found that TLR2 and 4 are expressed in hNSCs as well as CD14 and MD-2 co-receptors, and TLR4 expression is downregulated upon differentiation. Activation of TLR4 signaling by lipopolysaccharide (LPS) has a positive effect on proliferation and/or survival while the inverse is observed with TLR4 inhibition by a synthetic antagonist. TLR4 activation promotes neuronal and oligodendrocyte differentiation and/or survival while TLR4 inhibition leads to increased apoptosis. Consistently, endogenous expression of TLR4 is retained by hNSC surviving after transplantation in ALS rats or immunocompromised mice, thus irrespectively of the neuroinflammatory environment. The characterization of downstream signaling of TLR4 in hNSCs has suggested some activation of the inflammasome pathway. This study suggests TLR4 signaling as essential for hNSC self-renewal and as a novel target for the study of neurogenetic mechanisms.
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影响因子：
5.7
作者：
Zanoni I;Granucci F
通讯作者：
Granucci F
影响因子：
15.9
作者：
Okun, Eitan;Griffioen, Kathleen J.;Mattson, Mark P.
通讯作者：
Mattson, Mark P.
影响因子：
3.8
作者：
Choi AJ;Ryter SW
通讯作者：
Ryter SW
影响因子：
3.3
作者：
Gonzalez-Perez, O.;Gutierrez-Fernandez, F.;Lopez-Virgen, V.;Collas-Aguilar, J.;Quinones-Hinojosa, A.;Garcia-Verdugo, J. M.
通讯作者：
Garcia-Verdugo, J. M.
影响因子：
3.4
作者：
Li J;Csakai A;Jin J;Zhang F;Yin H
通讯作者：
Yin H