CD24 expression identifies teratogen-sensitive fetal neural stem cell subpopulations: evidence from developmental ethanol exposure and orthotopic cell transfer models.
CD24 expression identifies teratogen-sensitive fetal neural stem cell subpopulations: evidence from developmental ethanol exposure and orthotopic cell transfer models.
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DOI：
10.1371/journal.pone.0069560
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Miranda RC
中科院分区：
文献类型：
--
作者：
Tingling JD;Bake S;Holgate R;Rawlings J;Nagsuk PP;Chandrasekharan J;Schneider SL;Miranda RC
乙醇是一种强致畸剂。其不良神经效应部分是通过干扰胎儿神经发生来介导的。致畸过程知之甚少，脆弱的神经源性阶段尚未确定。识别这些是治疗干预措施的先决条件，以减轻致畸剂暴露的影响。我们使用流式细胞术和qRT-PCR筛选胎鼠来源的神经球培养物中乙醇敏感的神经干细胞（NSC）亚群，以研究NSC的更新和分化。使用母体乙醇暴露模型，在体内验证了脆弱的NSC群体的身份。最后，在超声引导下过继转移后，评估了乙醇暴露对脆弱NSC亚群整合到胎儿神经源性环境中的能力的影响。乙醇降低了c-kit、Musashi-1和GFAP mRNA的表达。乙醇可选择性降低CD 24 + NSC群，特别是CD 24 + CD 15+双阳性亚群。母体乙醇暴露也导致胎儿前脑CD 24表达降低。乙醇预暴露的CD 24+细胞表现出增殖增加，细胞自主和线索导向的神经元分化的缺陷，原位移植到幼稚胎儿后，不能整合到神经原性龛。CD 24耗竭的细胞保留了神经球再生能力，但在乙醇暴露后，相对于对照组产生了更多的CD 24+细胞。神经元谱系定向CD 24+细胞表现出特定的脆弱性，乙醇暴露持续损害这一群体的细胞自主分化能力。CD 24+细胞可能还充当神经原性龛内的群体传感器;它们的丢失导致补偿性NSC激活，可能耗尽更新能力。这些数据共同提出了一个畸形机制假说，导致小脑畸形。
Ethanol is a potent teratogen. Its adverse neural effects are partly mediated by disrupting fetal neurogenesis. The teratogenic process is poorly understood, and vulnerable neurogenic stages have not been identified. Identifying these is a prerequisite for therapeutic interventions to mitigate effects of teratogen exposures. We used flow cytometry and qRT-PCR to screen fetal mouse-derived neurosphere cultures for ethanol-sensitive neural stem cell (NSC) subpopulations, to study NSC renewal and differentiation. The identity of vulnerable NSC populations was validated in vivo, using a maternal ethanol exposure model. Finally, the effect of ethanol exposure on the ability of vulnerable NSC subpopulations to integrate into the fetal neurogenic environment was assessed following ultrasound guided, adoptive transfer. Ethanol decreased NSC mRNAs for c-kit, Musashi-1and GFAP. The CD24+ NSC population, specifically the CD24+CD15+ double-positive subpopulation, was selectively decreased by ethanol. Maternal ethanol exposure also resulted in decreased fetal forebrain CD24 expression. Ethanol pre-exposed CD24+ cells exhibited increased proliferation, and deficits in cell-autonomous and cue-directed neuronal differentiation, and following orthotopic transplantation into naïve fetuses, were unable to integrate into neurogenic niches. CD24depleted cells retained neurosphere regeneration capacity, but following ethanol exposure, generated increased numbers of CD24+ cells relative to controls. Neuronal lineage committed CD24+ cells exhibit specific vulnerability, and ethanol exposure persistently impairs this population’s cell-autonomous differentiation capacity. CD24+ cells may additionally serve as quorum sensors within neurogenic niches; their loss, leading to compensatory NSC activation, perhaps depleting renewal capacity. These data collectively advance a mechanistic hypothesis for teratogenesis leading to microencephaly.
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