Single-cell profiling of human subventricular zone progenitors identifies SFRP1 as a target for stimulating progenitor activation.. Single-cell profiling of human subventricular zone progenitors identifies SFRP1 as a target for stimulating progenitor activation.

Following the decline of neurogenesis at birth, progenitors of the subventricular zone (SVZ) remain mostly in a quiescent state in the adult human brain. The mechanisms that regulate this quiescent state are still unclear. Here, we isolated CD271+ progenitors from the aged human SVZ for single-cell RNA sequencing analysis. Our transcriptome data revealed the identity of progenitors of the aged human SVZ as late oligodendrocyte progenitor cells. We identified the Wnt pathway antagonist SFRP1 as a possible signal that promotes quiescence of progenitors from the aged human SVZ. Administration of WAY-316606, a small molecule that inhibits SFRP1 function, stimulates activation of neural stem cells both in vitro and in vivo under homeostatic conditions. Our data unravel a possible mechanism through which progenitors of the adult human SVZ are maintained in a quiescent state and a potential target for stimulating progenitors to re-activate. Overall design: Single-cell transcriptome data from the aged human SVZ. Progenitors, astrocytes, and microglia were isolated by FACS. Sort-seq was run on single-cells as described in Muraro et al., 2016.

随着出生后神经发生的衰退，成年人类大脑脑室下区（subventricular zone, SVZ）的祖细胞大多处于静息状态。调控该静息状态的具体机制目前仍不明确。本研究从老年人类脑室下区中分离出CD271阳性祖细胞，用于单细胞RNA测序分析。我们的转录组数据揭示，老年人类脑室下区祖细胞的身份为晚期少突胶质细胞祖细胞。我们鉴定出Wnt信号通路拮抗剂SFRP1是一种可能促进老年人类脑室下区祖细胞静息的信号分子。给予可抑制SFRP1功能的小分子WAY-316606后，可在稳态条件下的体外及体内环境中促进神经干细胞的激活。本研究数据阐明了成年人类脑室下区祖细胞维持静息状态的潜在机制，同时也找到了刺激祖细胞重新激活的潜在靶点。
总体实验设计：采集老年人类脑室下区的单细胞转录组数据。通过荧光激活细胞分选（fluorescence-activated cell sorting, FACS）分离祖细胞、星形胶质细胞（astrocytes）与小胶质细胞（microglia）。按照Muraro等人2016年发表的研究方法，对单细胞进行Sort-seq测序。