Neural stem cells of the adult rodent ventricular-subventricular zone: self-renewal of B1 cells and interactions of their subcellular domains with the niche

成年啮齿动物心室-室下区的神经干细胞：B1细胞的自我更新及其亚细胞结构域与生态位的相互作用

• 批准号: 201064443
• 负责人: Dr. Kirsten Obernier, Ph.D.
• 金额: --
• 依托单位: Department of Neurological Surgery
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/201064443?language=en
• 关键词: Neural; stem; cells; adult; rodent

Neural stem cells (NSCs, B1 cells) in the adult rodent ventricular-subventricular zone (V-SVZ) generate thousands of young neurons destined for the olfactory bulb every day. B1 cells have a remarkable morphology consisting of at least three subcellular domains that make specific contacts with their niche: I. apical: B1 cells contact the CSF of the lateral ventricles with a small apical surface that contains a single primary cilium and is surrounded by ependymal cells in a pinwheel-like structure; II. intermediate: B1 cells cell body with lateral processes is in intimate contact with their progeny (C and A cells) and possible intercellular feedback mechanism might control the tight balance between NSC proliferation and differentiation; III. basal: with a long basal end foot B1 cells contact blood vessels. It remains unclear how these subcellular domains and their interaction with their environment affects NSC behavior, their mode of division and lineage progression. Moreover, one cardinal property of stem cells - self-renewal - has not been directly demonstrated for B1 cells. Here I propose to investigate whether B1 cells can self-renew and how their domains might control their behavior. The project is aimed to directly observe neurogenesis by live-imaging and to investigate possible intercellular regulations of V-SVZ cell lineage progression. Preliminary data using time-lapse microscopy of ex vivo whole mount preparations reveal for the first time the dynamic interactions of B1 cells and their niche. B1 cells have lateral processes that frequently touch C cells (possibly their own progeny). The basal process is very dynamic; shifting position on the surface of the blood vessels and between neighboring vessels and also makes transitory contacts with other B1 cells. These previously unknown B1-B1 contacts appear to be correlated with B1 cells divisions. During cell division B1 cells maintain their unique morphology and remain in contact with blood vessels. Finally, these movies indicate self-renewing symmetric and asymmetric divisions of B1 cells. NSC division might be regulated by feedback mechanism between B1 cells and neighboring cells, for example via Notch signaling. Interestingly, short-term infusion of epidermal growth factor into the lateral ventricle induces overproliferation of C cells that is paralleled by increased apical contacts of B1 cells without affecting their proliferation. Preliminary data suggest that the increased proliferation of C cells is only transient and Notch signaling seems to be upregulated, whereas the number of proliferating B1 cells increases after restoration of C cell proliferation. This suggests a feedback mechanism between C and B1 cells controlling stem cell proliferation. Importantly, the additional B1 cells contacting the ventricle contribute to olfactory bulb neurogenesis.

成年啮齿动物心室-室下区 (V-SVZ) 中的神经干细胞（NSC、B1 细胞）每天会产生数千个年轻神经元，这些神经元将被输送到嗅球。 B1 细胞具有显着的形态，由至少三个亚细胞结构域组成，这些亚细胞结构域与它们的生态位进行特定接触： I. 顶端：B1 细胞通过一个小的顶端表面接触侧脑室的 CSF，该表面包含单个初级纤毛，并被风车状结构的室管膜细胞包围；二.中间：具有侧突的B1细胞细胞体与其后代（C和A细胞）密切接触，可能的细胞间反馈机制可能控制NSC增殖和分化之间的紧密平衡；三．基底：基底端有长足B1细胞接触血管。目前尚不清楚这些亚细胞结构域及其与环境的相互作用如何影响 NSC 的行为、其分裂模式和谱系进展。此外，干细胞的一项重要特性——自我更新——尚未在 B1 细胞中得到直接证实。在这里，我建议研究 B1 细胞是否可以自我更新以及它们的域如何控制它们的行为。该项目旨在通过实时成像直接观察神经发生，并研究 V-SVZ 细胞谱系进展可能的细胞间调节。使用延时显微镜对离体整体制备物进行的初步数据首次揭示了 B1 细胞及其生态位的动态相互作用。 B1 细胞具有经常接触 C 细胞（可能是它们自己的后代）的侧突。基本过程是非常动态的；在血管表面和相邻血管之间移动位置，并与其他 B1 细胞进行短暂接触。 这些以前未知的 B1-B1 接触似乎与 B1 细胞分裂相关。在细胞分裂期间，B1 细胞保持其独特的形态并保持与血管接触。最后，这些电影表明 B1 细胞的自我更新对称和不对称分裂。 NSC 分裂可能受到 B1 细胞和邻近细胞之间的反馈机制的调节，例如通过 Notch 信号传导。有趣的是，短期将表皮生长因子输注到侧脑室会诱导 C 细胞过度增殖，同时 B1 细胞顶端接触也会增加，但不会影响其增殖。初步数据表明，C 细胞增殖的增加只是暂时的，Notch 信号似乎上调，而在 C 细胞增殖恢复后，增殖的 B1 细胞数量增加。 这表明 C 细胞和 B1 细胞之间存在控制干细胞增殖的反馈机制。重要的是，接触心室的额外 B1 细胞有助于嗅球神经发生。