Regulation of fractone heparan sulfate composition in young and aged subventricular zone neurogenic niches
Regulation of fractone heparan sulfate composition in young and aged subventricular zone neurogenic niches
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DOI：
10.1093/glycob/cwab081
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发表时间：
2021-07-29
期刊：
影响因子：
4.3
通讯作者：
Arikawa-Hirasawa, Eri
中科院分区：
文献类型：
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作者：
Kerever, Aurelien;Nagahara, Fumina;Arikawa-Hirasawa, Eri
Fractone是在脑室下区（SVZ）神经原性龛中发现的特化细胞外基质结构，可以通过肝素结合机制从细胞外环境捕获生长因子，如碱性成纤维细胞生长因子，用于神经干细胞（NSC）呈递，这促进了神经发生。在衰老过程中，神经发生的下降与碎片内硫酸乙酰肝素（HS）组成的变化相关。在这项研究中，我们使用的抗体，识别特定的短寡糖与不同的硫酸化，以评估HS组成的碎片在年轻和老年人的大脑。为了进一步了解调节6-O硫酸化水平的条件及其对神经发生的影响，我们使用了硫酸酯酶Sulf 1和Sulf 2双敲除（DKO）小鼠。Sulf 1/2 DKO小鼠SVZ中的碎片显示HS表位的免疫反应性，表明6-O硫酸化程度较高。虽然野生型和Sulf 1/2 DKO小鼠的老年SVZ中的神经发生下降，但我们在Sulf 1/2 DKO小鼠的年轻和老年SVZ中观察到大量的神经母细胞。总之，这些结果表明，通过内硫酸酯酶去除碎片HS中的6-O-硫酸化抑制SVZ中的神经发生。我们的研究结果推进了目前对最适合NSC茁壮成长的细胞外环境的理解，这对未来干细胞疗法的设计至关重要。
Fractones, specialized extracellular matrix structures found in the subventricular zone (SVZ) neurogenic niche, can capture growth factors, such as basic fibroblast growth factor, from the extracellular milieu through a heparin-binding mechanism for neural stem cell (NSC) presentation, which promotes neurogenesis. During aging, a decline in neurogenesis correlates with a change in the composition of heparan sulfate (HS) within fractones. In this study, we used antibodies that recognize specific short oligosaccharides with varying sulfation to evaluate the HS composition in fractones in young and aged brains. To further understand the conditions that regulate 6-O sulfation levels and its impact on neurogenesis, we used endosulfatase Sulf1 and Sulf2 double knockout (DKO) mice. Fractones in the SVZ of Sulf1/2 DKO mice showed immunoreactivity for the HS epitope, suggesting higher 6-O sulfation. While neurogenesis declined in the aged SVZ of both wild-type and Sulf1/2 DKO mice, we observed a larger number of neuroblasts in the young and aged SVZ of Sulf1/2 DKO mice. Together, these results show that the removal of 6-O-sulfation in fractones HS by endosulfatases inhibits neurogenesis in the SVZ. Our findings advance the current understanding regarding the extracellular environment that is best suited for NSCs to thrive, which is critical for the design of future stem cell therapies.