Glycoengineering human neural stem cells (hNSCs) for adhesion improvement using a novel thiol-modified N-acetylmannosamine (ManNAc) analog.
Glycoengineering human neural stem cells (hNSCs) for adhesion improvement using a novel thiol-modified N-acetylmannosamine (ManNAc) analog.
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DOI：
10.1016/j.msec.2022.112675
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发表时间：
2022-03
影响因子：
--
通讯作者：
Jia, Xiaofeng
中科院分区：
文献类型：
--
作者：
Du, Jian;Liu, Xiao;Yarema, Kevin J.;Jia, Xiaofeng
该研究为Ac5ManNTProp的治疗应用奠定了基础，Ac5ManNTProp是一种n -乙酰甘露糖胺（ManNAc）类似物，可将巯基修饰的唾液聚糖安装到人类神经干细胞（hNSCs）表面。首先，我们比较了hNSC与细胞外基质（ECM）蛋白层粘连蛋白、纤维连接蛋白和胶原蛋白的粘附，发现ac5manntprop处理的细胞对层粘连蛋白的优先粘附和伴随的细胞形态和细胞扩散的变化，与纤维连接蛋白相比，层粘连蛋白有适度的反应，胶原蛋白没有明显的增加。PCR阵列转录分析发现了几种类型的细胞粘附分子，它们对Ac5ManNTProp和hNSC对层粘连蛋白的粘附有反应。其中，我们重点研究了整合素α6β1的表达，在层粘连蛋白培养的类似物处理细胞中，整合素α6β1的表达上调幅度最大。我们还描述了下游反应，包括血管蛋白显示以及局灶黏附激酶（FAK）和细胞外信号相关激酶（ERK）的磷酸化。在这些实验中，与Ac5ManNTGc相比，Ac5ManNTProp更强烈地诱导了所有被测试的生物终点，这表明在结构上分离两种类似物的单个亚甲基单元精细地调节了生物反应。总之，通过Ac5ManNTProp治疗对多种促再生活性的协同调节，以及与ECM成分的串扰，为使用我们的代谢糖工程方法通过有利地调节有助于移植的NSCs生存能力的终点来治疗神经系统疾病奠定了基础。
This study sets the stage for the therapeutic use of Ac5ManNTProp, an N-acetylmannosamine (ManNAc) analog that installs thiol-modified sialoglycans onto the surfaces of human neural stem cells (hNSCs). First, we compared hNSC adhesion to the extracellular matrix (ECM) proteins laminin, fibronectin, and collagen and found preferential adhesion and concomitant changes to cell morphology and cell spreading for Ac5ManNTProp-treated cells to laminin, compared to fibronectin where there was a modest response, and collagen where there was no observable increase. PCR array transcript analysis identified several classes of cell adhesion molecules that responded to combined Ac5ManNTProp treatment and hNSC adhesion to laminin. Of these, we focused on integrin α6β1 expression, which was most strongly upregulated in analog-treated cells incubated on laminin. We also characterized downstream responses including vinculin display as well as the phosphorylation of focal adhesion kinase (FAK) and extracellular signal-related kinase (ERK). In these experiments, Ac5ManNTProp more strongly induced all tested biological endpoints compared to Ac5ManNTGc, showing that the single methylene unit that structurally separates the two analogs finely tunes biological responses. Together, the concerted modulation of multiple pro-regenerative activities through Ac5ManNTProp treatment, in concert with crosstalk with ECM components, lays a foundation for using our metabolic glycoengineering approach to treat neurological disorders by favorably modulating endpoints that contribute to the viability of transplanted NSCs.
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影响因子：
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作者：
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通讯作者：
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作者：
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作者：
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通讯作者：
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作者：
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通讯作者：
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