Nfix is a novel regulator of murine hematopoietic stem and progenitor cell survival
Nfix is a novel regulator of murine hematopoietic stem and progenitor cell survival
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DOI：
10.1182/blood-2013-04-493973
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发表时间：
2013-10-24
期刊：
影响因子：
20.3
通讯作者：
McKinney-Freeman, Shannon
中科院分区：
文献类型：
--
作者：
Holmfeldt, Per;Pardieck, Jennifer;McKinney-Freeman, Shannon
造血干细胞对于维持脊椎动物的完整血液系统既是必要的也是充分的。在此我们表明，Nfix作为转录因子核因子I（Nfi）家族的一员，在小鼠成年骨髓的造血干细胞和祖细胞（HSPCs）中高度表达。尽管短发夹RNA介导的对谱系（-）Sca - 1（+）c - Kit（+）HSPCs中Nfix表达的敲低对体外细胞生长或活力没有影响，但Nfix缺失的HSPCs显示出集落形成潜能的显著丧失，以及短期和长期的体内造血重建活性的丧失。对移植后4到20天的受体小鼠的分析显示，Nfix缺失的HSPCs能在骨髓中定植，但由于凋亡细胞死亡增加而无法持续存在。对Nfix缺失的HSPCs的基因表达谱分析表明，HSPCs中Nfix表达的缺失伴随着多个已知对HSPCs存活重要的基因表达的降低，例如Erg、Mecom和Mpl。这些数据表明，Nfix是移植后HSPCs存活的一种新型调节因子，并确立了Nfi基因在调节这一细胞亚群中的作用。
Hematopoietic stem cells are both necessary and sufficient to sustain the complete blood system of vertebrates. Here we show that Nfix, a member of the nuclear factor I (Nfi)family of transcription factors, is highly expressed by hematopoietic stem and progenitor cells (HSPCs) of murine adult bone marrow. Although short hairpin RNA-mediated knockdown of Nfix expression in Lineage(-)Sca-1(+)c-Kit(+) HSPCs had no effect on in vitro cell growth or viability, Nfix-depleted HSPCs displayed a significant loss of colony-forming potential, as well as short-and long-term in vivo hematopoietic repopulating activity. Analysis of recipient mice at 4 to 20 days posttransplant revealed that Nfix-depleted HSPCs are established in the bone marrow, but fail to persist due to increased apoptotic cell death. Gene expression profiling of Nfix-depleted HSPCs reveals that loss of Nfix expression in HSPCs is concomitant with a decrease in the expression of multiple genes known to be important for HSPCs survival, such as Erg, Mecom, and Mpl. These data reveal that Nfix is a novel regulator of HSPCs survival posttransplantation and establish a role for Nfi genes in the regulation of this cellular compartment.