Park In-kyung, Qian Dalong, Kiel Mark, Becker Michael W, Pihalja Michael, Weissman Irving L, Morrison Sean J, Clarke Michael F
Division of Hematology/Oncology, Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
Nature. 2003 May 15;423(6937):302-5. doi: 10.1038/nature01587. Epub 2003 Apr 20.
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. 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 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, cell survival genes, transcription factors, and genes modulating proliferation including p16Ink4a and p19Arf was altered in bone marrow cells of the Bmi-1-/- mice. Expression of p16Ink4a and p19Arf 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.
干细胞生物学的一个核心问题是了解调控造血干细胞（HSC）自我更新的机制，造血作用需要造血干细胞在动物的整个生命周期中持续存在。我们发现成年和胎儿小鼠以及成年人类的造血干细胞表达原癌基因Bmi-1。Bmi-1基因敲除小鼠胎肝中的造血干细胞数量正常。在出生后的Bmi-1基因敲除小鼠中，造血干细胞数量显著减少。从Bmi-1基因敲除小鼠获得的移植胎肝和骨髓细胞仅能短暂地参与造血作用。成年造血干细胞没有可检测到的自我更新，这表明Bmi-1基因敲除小鼠存在细胞自主性缺陷。基因表达分析显示，在Bmi-1基因敲除小鼠的骨髓细胞中，与干细胞相关的基因、细胞存活基因、转录因子以及包括p16Ink4a和p19Arf在内的调节增殖的基因表达发生了改变。正常造血干细胞中p16Ink4a和p19Arf的表达分别导致增殖停滞和p53依赖性细胞死亡。我们的结果表明，Bmi-1对于产生自我更新的成年造血干细胞至关重要。
