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Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells

机译:Gfi-1限制增殖并保留造血干细胞的功能完整性

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摘要

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.
机译:造血干细胞(HSC)终生维持血液生产。 HSC具有广泛的增殖能力,因为单个HSC可能会重建致死性辐射的宿主(1)。在稳定状态下,HSC基本上保持静止状态并以较低的恒定速率自我更新,从而阻止了成年后的疲惫(2,3)。尽管已经确定了促进体内和离体HSC增殖程序的核调节因子(4-6),但是限制其循环的转录因子仍然难以捉摸。在这里我们报道锌指阻遏物Gfi-1(独立于生长因子1),是淋巴样细胞中的协同致癌基因(7,8),出乎意料地限制了HSC的增殖。 Gfi-1丢失后,HSC表现出较高的增殖速率,这是通过5-溴脱氧尿苷掺入和细胞周期分析来评估的。 Gfi-1(-/-)HSCs在竞争性种群重建和系列移植试验中功能受损,并且在由Gfi-1(-/-)胚胎干细胞产生的小鼠嵌合体的骨髓中迅速竞争。因此,Gfi-1对于限制HSC增殖和保持HSC功能完整性至关重要。

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