Single cell approaches define forebrain neural stem cell niches and identify microglial ligands that enhance precursor-mediated remyelination (scRNA-Seq)

Here we used single cell RNA-sequencing and single cell spatial transcriptomics to characterize the forebrain neural stem cell (NSC) niche under homeostatic and injury conditions. We define the dorsal and lateral ventricular-subventricular zones (V-SVZ) as two distinct neighborhoods, and show that following white matter injury, dorsal NSCs are locally activated to make oligodendrocytes for remyelination. This activation is coincident with a robust increase in transcriptionally-distinct microglia in the dorsal V-SVZ niche. We modeled ligand-receptor interactions within this changing niche and identified two remyelination-associated microglial ligands, IGF1 and OSM, that promote precursor proliferation and oligodendrogenesis in culture. Infusion of either ligand into the lateral ventricles also enhanced oligodendrogenesis, even in the lateral V-SVZ, where NSCs normally make neuroblasts. These data support a model where gliogenesis versus neurogenesis is determined by the local NSC neighborhood and where injury-induced niche alterations promote NSC activation, local oligodendrogenesis, and likely contribute to myelin repair. High-throughput single cell transcriptomic profiles of the adult mouse brain (V-SVZ) cells, from CD-1 and lineage tracing NesCreERT2;EYFP animals exposed to either 6 weeks of cuprizone-rapamycin or vehicle control with 3 weeks recovery, generated by single cell RNA sequencing using the 10X Genomics platform.

本研究采用单细胞RNA测序（single cell RNA-sequencing）与单细胞空间转录组（single cell spatial transcriptomics）技术，对稳态与损伤条件下的前脑神经干细胞（NSC, Neural Stem Cell）微环境进行了表征。
我们将背侧与外侧脑室下区（V-SVZ, ventricular-subventricular zones）定义为两个独立的微环境区域，并证实：在白质损伤后，背侧NSCs会被局部激活，分化为少突胶质细胞以完成髓鞘再生。
该激活过程与背侧V-SVZ微环境中转录特征独特的小胶质细胞的大量扩增同步发生。
我们对该动态变化的微环境内的配体-受体相互作用进行了建模分析，鉴定出两种与髓鞘再生相关的小胶质细胞配体——胰岛素样生长因子1（IGF1）与抑瘤素M（OSM），二者在体外培养中可促进前体细胞增殖与少突胶质细胞生成。
将任一配体注入侧脑室后，即便在通常由NSCs生成神经母细胞的外侧V-SVZ中，少突胶质细胞生成过程也得到了增强。
上述数据支持如下模型：神经胶质细胞生成与神经元生成的命运选择由局部NSC微环境区域决定，而损伤诱导的微环境改变可促进NSC激活、局部少突胶质细胞生成，并可能助力髓鞘修复。
本数据集包含采用10X Genomics平台通过单细胞RNA测序获得的成年小鼠大脑脑室下区（V-SVZ）细胞的高通量单细胞转录组图谱。实验对象为CD-1品系小鼠以及经谱系示踪的NesCreERT2;EYFP小鼠，这些小鼠分别接受了6周的铜嗪-雷帕霉素处理或赋形剂对照处理，并在处理结束后恢复3周。