Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Departments of Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511, USA.
Department of Cell Biology, Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Cell Rep. 2023 Apr 25;42(4):112371. doi: 10.1016/j.celrep.2023.112371. Epub 2023 Apr 11.
The subventricular zone (SVZ) is the largest neural stem cell (NSC) niche in the adult brain; herein, the blood-brain barrier is leaky, allowing direct interactions between NSCs and endothelial cells (ECs). Mechanisms by which direct NSC-EC interactions in the adult SVZ control NSC behavior are unclear. We found that Cx43 is highly expressed by SVZ NSCs and ECs, and its deletion in either leads to increased NSC proliferation and neuroblast generation, suggesting that Cx43-mediated NSC-EC interactions maintain NSC quiescence. This is further supported by single-cell RNA sequencing and in vitro studies showing that ECs control NSC proliferation by regulating expression of genes associated with NSC quiescence and/or activation in a Cx43-dependent manner. Cx43 mediates these effects in a channel-independent manner involving its cytoplasmic tail and ERK activation. Such insights inform adult NSC regulation and maintenance aimed at stem cell therapies for neurodegenerative disorders.
室下区（SVZ）是成人脑中最大的神经干细胞（NSC）龛；在此，血脑屏障是渗漏的，允许 NSCs 和内皮细胞（ECs）之间直接相互作用。直接的 NSC-EC 相互作用在成人 SVZ 中控制 NSC 行为的机制尚不清楚。我们发现 Cx43 在 SVZ NSCs 和 ECs 中高度表达，其缺失会导致 NSC 增殖和神经母细胞生成增加，表明 Cx43 介导的 NSC-EC 相互作用维持 NSC 静止。单细胞 RNA 测序和体外研究进一步支持了这一观点，表明 ECs 通过调节与 NSC 静止和/或激活相关的基因的表达，以 Cx43 依赖性方式控制 NSC 增殖。Cx43 通过其细胞质尾巴和 ERK 激活以非通道依赖性方式介导这些效应。这些见解为旨在针对神经退行性疾病的干细胞疗法的成人 NSC 调节和维持提供了信息。
