Mich John K, Signer Robert Aj, Nakada Daisuke, Pineda André, Burgess Rebecca J, Vue Tou Yia, Johnson Jane E, Morrison Sean J
Department of Pediatrics, Children's Research Institute, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
Elife. 2014 May 7;3:e02669. doi: 10.7554/eLife.02669.
Neurosphere formation is commonly used as a surrogate for neural stem cell (NSC) function but the relationship between neurosphere-initiating cells (NICs) and NSCs remains unclear. We prospectively identified, and isolated by flow cytometry, adult mouse lateral ventricle subventricular zone (SVZ) NICs as Glast(mid)EGFR(high)PlexinB2(high)CD24(-/low)O4/PSA-NCAM(-/low)Ter119/CD45(-) (GEPCOT) cells. They were highly mitotic and short-lived in vivo based on fate-mapping with Ascl1(CreERT2) and Dlx1(CreERT2). In contrast, pre-GEPCOT cells were quiescent, expressed higher Glast, and lower EGFR and PlexinB2. Pre-GEPCOT cells could not form neurospheres but expressed the stem cell markers Slc1a3-CreER(T), GFAP-CreER(T2), Sox2(CreERT2), and Gli1(CreERT2) and were long-lived in vivo. While GEPCOT NICs were ablated by temozolomide, pre-GEPCOT cells survived and repopulated the SVZ. Conditional deletion of the Bmi-1 polycomb protein depleted pre-GEPCOT and GEPCOT cells, though pre-GEPCOT cells were more dependent upon Bmi-1 for Cdkn2a (p16(Ink4a)) repression. Our data distinguish quiescent NSCs from NICs and make it possible to study their properties in vivo.DOI: http://dx.doi.org/10.7554/eLife.02669.001.
神经球形成通常被用作神经干细胞（NSC）功能的替代指标，但神经球起始细胞（NIC）与NSC之间的关系仍不清楚。我们通过流式细胞术前瞻性地鉴定并分离出成年小鼠侧脑室室下区（SVZ）的NIC，其为Glast（中等）EGFR（高）PlexinB2（高）CD24（- /低）O4 / PSA - NCAM（- /低）Ter119 / CD45（-）（GEPCOT）细胞。基于用Ascl1（CreERT2）和Dlx1（CreERT2）进行的命运图谱分析，它们在体内具有高度的有丝分裂活性且寿命较短。相比之下，前GEPCOT细胞处于静止状态，表达较高的Glast，以及较低的EGFR和PlexinB2。前GEPCOT细胞不能形成神经球，但表达干细胞标志物Slc1a3 - CreER（T）、GFAP - CreER（T2）、Sox2（CreERT2）和Gli1（CreERT2），并且在体内寿命较长。虽然替莫唑胺可消除GEPCOT NIC，但前GEPCOT细胞存活并重新填充了SVZ。Bmi - 1多梳蛋白的条件性缺失使前GEPCOT和GEPCOT细胞减少，尽管前GEPCOT细胞在抑制Cdkn2a（p16（Ink4a））方面对Bmi - 1的依赖性更强。我们的数据区分了静止的NSC和NIC，并使得在体内研究它们的特性成为可能。DOI：http://dx.doi.org/10.7554/eLife.02669.001 。
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