Haploinsufficiency of GATA-2 perturbs adult hematopoietic stem-cell homeostasis
Haploinsufficiency of GATA-2 perturbs adult hematopoietic stem-cell homeostasis
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DOI：
10.1182/blood-2004-08-2989
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发表时间：
2005-07-15
期刊：
影响因子：
20.3
通讯作者：
Scadden, DT
中科院分区：
文献类型：
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作者：
Rodrigues, NP;Janzen, V;Scadden, DT
锌指转录因子加塔-2在哺乳动物发育中造血干细胞的产生中起着重要作用。不太明确的是加塔-2是否参与成人干细胞调节，我们使用造血细胞中表达水平降低的加塔-2的加塔-2杂合子小鼠来解决这个问题。虽然加塔-2（+/-）小鼠表现出一些集落形成祖细胞的减少，但在干细胞区室中观察到最显著的变化。杂合子骨髓的Lin（-）c-kit（+）Sca-1（+）CD 34（-）细胞丰度较低，在竞争性移植和定量第5周鹅卵石区域形成细胞（CAFC）测定中表现较差。此外，从GATA 1（+/-）骨髓干细胞富集的人口是更多的静止，并表现出更大的频率与抗凋亡基因Bcl-xL的表达降低相关的凋亡细胞。然而，根据连续移植的判断，+/-干细胞室的自我更新潜力没有改变。这些数据表明，在较低加塔-2基因剂量的情况下，原始细胞增殖和存活受损，而剩余干细胞的分化或自我更新能力没有变化。因此，加塔-2剂量通过影响干细胞功能的选择方面来调节成体干细胞稳态。
The zinc finger transcription factor GATA-2 plays a fundamental role in generating hematopoietic stem-cells in mammalian development. Less well defined is whether GATA-2 participates in adult stem-cell regulation, an issue we addressed using GATA-2 heterozygote mice that express reduced levels of GATA-2 in hematopoietic cells. While GATA-2(+/-) mice demonstrated decreases in some colony-forming progenitors, the most prominent changes were observed within the stem-cell compartment. Heterozygote bone marrow had a lower abundance of Lin(-) c-kit(+)Sca-1(+)CD34(-) cells and performed poorly in competitive transplantation and quantitative week-5 cobblestone area-forming cell (CAFC) assays. Furthermore, a stem-cell-enriched population from GATA1(+/-) marrow was more quiescent and exhibited a greater frequency of apoptotic cells associated with decreased expression of the antiapoptotic gene Bcl-xL. Yet the self-renewal potential of the +/- stem-cell compartment, as judged by serial transplantations, was unchanged. These data indicate compromised primitive cell proliferation and survival in the setting of a lower GATA-2 gene dose without a change in the differentiation or self-renewal capacity of the stem-cells that remain. Thus, GATA-2 dose regulates adult stem-cell homeostasis by affecting select aspects of stem cell function.