Kerever Aurelien, Nagahara Fumina, Keino-Masu Kazuko, Masu Masayuki, van Kuppevelt Toin H, Vivès Romain R, Arikawa-Hirasawa Eri
Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, 113-8421 Tokyo, Japan.
Department of Molecular Neurobiology, Faculty of Medicine, University of Tsukuba, 305-8575 Ibaraki, Japan.
Glycobiology. 2021 Dec 18;31(11):1531-1542. doi: 10.1093/glycob/cwab081.
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.
分形素是在脑室下区（SVZ）神经源性微环境中发现的特殊细胞外基质结构，它可以通过肝素结合机制从细胞外环境中捕获生长因子，如碱性成纤维细胞生长因子，以供神经干细胞（NSC）摄取，从而促进神经发生。在衰老过程中，神经发生的减少与分形素内硫酸乙酰肝素（HS）组成的变化相关。在本研究中，我们使用了能够识别具有不同硫酸化修饰的特定短寡糖的抗体，来评估年轻和老年大脑中分形素的HS组成。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Sulf1和Sulf2双敲除（DKO）小鼠。Sulf1/2 DKO小鼠SVZ中的分形素对HS表位显示出免疫反应性，表明6-O硫酸化程度更高。虽然野生型和Sulf1/2 DKO小鼠老年SVZ中的神经发生均减少，但我们在Sulf1/2 DKO小鼠的年轻和老年SVZ中观察到了更多的神经母细胞。这些结果共同表明，硫酸酯酶去除分形素HS中的6-O硫酸化会抑制SVZ中的神经发生。我们的研究结果推进了目前对最适合神经干细胞生长的细胞外环境的理解，这对未来干细胞治疗的设计至关重要。
