Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells
Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells
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DOI：
10.1038/nature01587
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发表时间：
2003-05-15
期刊：
影响因子：
64.8
通讯作者：
Clarke, MF
中科院分区：
文献类型：
--
作者：
Park, IK;Qian, DL;Clarke, MF
干细胞生物学的一个核心问题是了解调节造血干细胞（HSC）自我更新的机制，造血干细胞是动物一生中持续造血所必需的（1）。我们发现，成年和胎儿小鼠和成年人HSC表达原癌基因Bmi-1。Bmi-1（-/-）小鼠胎肝中的HSC数量正常（2）。在出生后的Bmi-1（-/-）小鼠中，HSC的数量显著减少。从Bmi-1（-/-）小鼠获得的移植胎肝和骨髓细胞只能短暂地促进造血。成年HSC没有可检测到的自我更新，表明Bmi-1（-/-）小鼠存在细胞自主缺陷。基因表达分析显示，干细胞相关基因（3）、细胞存活基因、转录因子和调节增殖的基因（包括p16（Ink 4a）和p19（Arf））的表达在Bmi-1（-/-）小鼠的骨髓细胞中发生了改变。正常HSC中p16（Ink 4a）和p19（Arf）的表达分别导致增殖停滞和p53依赖性细胞死亡。我们的研究结果表明，Bmi-1是必不可少的自我更新的成人HSC的产生。
A central issue in stem cell biology is to understand the mechanisms that regulate the self-renewal of haematopoietic stem cells (HSCs), which are required for haematopoiesis to persist for the lifetime of the animal(1). We found that adult and fetal mouse and adult human HSCs express the proto-oncogene Bmi-1. The number of HSCs in the fetal liver of Bmi-1(-/-) mice(2) was normal. In postnatal Bmi-1(-/-) mice, the number of HSCs was markedly reduced. Transplanted fetal liver and bone marrow cells obtained from Bmi-1(-/-) mice were able to contribute only transiently to haematopoiesis. There was no detectable self-renewal of adult HSCs, indicating a cell autonomous defect in Bmi-1(-/-) mice. A gene expression analysis revealed that the expression of stem cell associated genes(3), cell survival genes, transcription factors, and genes modulating proliferation including p16(Ink4a) and p19(Arf) was altered in bone marrow cells of the Bmi-1(-/-) mice. Expression of p16(Ink4a) and p19(Arf) in normal HSCs resulted in proliferative arrest and p53-dependent cell death, respectively. Our results indicate that Bmi-1 is essential for the generation of self-renewing adult HSCs.