Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells
Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells
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DOI：
10.1038/nature02994
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发表时间：
2004-10-21
期刊：
影响因子：
64.8
通讯作者：
Orkin, SH
中科院分区：
文献类型：
--
作者：
Hock, H;Hamblen, MJ;Orkin, SH
造血干细胞（HSCs）维持整个生命的血液生产。HSC能够广泛增殖扩增，因为单个HSC可以重建致死性照射的宿主（1）。在稳定状态下，HSC基本上保持静止，并以恒定的低速率自我更新，从而防止它们在成年期间耗尽（2，3）。尽管已经鉴定了促进体内和离体HSC增殖程序的核调节因子（4-6），但限制其循环的转录因子仍然难以捉摸。在这里，我们报道了锌指阻遏物Gfi-1（生长因子非依赖性1），淋巴细胞中的一种协同致癌基因（7，8），意外地限制了HSC的增殖。在Gfi-1缺失后，HSC通过5-溴脱氧尿苷掺入和细胞周期分析显示出升高的增殖率。Gfi-1（-/-）HSC在竞争性再增殖和系列移植试验中功能受损，并且在用Gfi-1（-/-）胚胎干细胞产生的小鼠嵌合体的骨髓中快速竞争。因此，Gfi-1对于限制HSC增殖和保持HSC功能完整性至关重要。
Haematopoietic stem cells (HSCs) sustain blood production throughout life. HSCs are capable of extensive proliferative expansion, as a single HSC may reconstitute lethally irradiated hosts(1). In steady-state, HSCs remain largely quiescent and self-renew at a constant low rate, forestalling their exhaustion during adult life(2,3). Whereas nuclear regulatory factors promoting proliferative programmes of HSCs in vivo and ex vivo have been identified(4-6), transcription factors restricting their cycling have remained elusive. Here we report that the zinc-finger repressor Gfi-1 (growth factor independent 1), a cooperating oncogene in lymphoid cells(7,8), unexpectedly restricts proliferation of HSCs. After loss of Gfi-1, HSCs display elevated proliferation rates as assessed by 5-bromodeoxyuridine incorporation and cell-cycle analysis. Gfi-1(-/-) HSCs are functionally compromised in competitive repopulation and serial transplantation assays, and are rapidly out-competed in the bone marrow of mouse chimaeras generated with Gfi-1(-/-) embryonic stem cells. Thus, Gfi-1 is essential to restrict HSC proliferation and to preserve HSC functional integrity.