Bmi1 confers resistance to oxidative stress on hematopoietic stem cells.
Bmi1 confers resistance to oxidative stress on hematopoietic stem cells.
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DOI：
10.1371/journal.pone.0036209
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Iwama A
中科院分区：
文献类型：
--
作者：
Nakamura S;Oshima M;Yuan J;Saraya A;Miyagi S;Konuma T;Yamazaki S;Osawa M;Nakauchi H;Koseki H;Iwama A
polycomb-group （PcG）蛋白是干细胞的一般调节因子。我们之前报道过逆转录病毒介导的Bmi1的过表达，Bmi1是编码多梳抑制复合体（PRC） 1核心成分的基因，在长期培养过程中维持了造血干细胞（hsc）的自我更新。然而，体内Bmi1过表达对hsc的影响仍有待明确。在这项研究中，我们建立了一个小鼠系，其中Bmi1可以在内源性Rosa26启动子的控制下以造血细胞特异性的方式有条件地过表达（Tie2-Cre;R26StopFLBmi1）。虽然Bmi1的过表达对稳态造血没有显著影响，但它在离体培养过程中促进了功能性造血干细胞的扩增，并有效地保护了造血干细胞在连续移植过程中免受自我更新能力的丧失。Bmi1过表达对电离辐射引发的DNA损伤反应无影响。相比之下，Tie2-Cre；R26StopFLBmi1造血干细胞在氧化应激下保持多能状态，总体上耐受氧化应激优于对照组。出乎意料的是，Bmi1的过表达对细胞内活性氧（ROS）水平没有影响。我们的研究结果表明，Bmi1的过度表达赋予造血干细胞抵抗应激，特别是氧化应激的能力。这增强了它们的再生能力，表明Bmi1位于ROS信号的下游，并受其负调控。
The polycomb-group (PcG) proteins function as general regulators of stem cells. We previously reported that retrovirus-mediated overexpression of Bmi1, a gene encoding a core component of polycomb repressive complex (PRC) 1, maintained self-renewing hematopoietic stem cells (HSCs) during long-term culture. However, the effects of overexpression of Bmi1 on HSCs in vivo remained to be precisely addressed. In this study, we generated a mouse line where Bmi1 can be conditionally overexpressed under the control of the endogenous Rosa26 promoter in a hematopoietic cell-specific fashion (Tie2-Cre;R26StopFLBmi1). Although overexpression of Bmi1 did not significantly affect steady state hematopoiesis, it promoted expansion of functional HSCs during ex vivo culture and efficiently protected HSCs against loss of self-renewal capacity during serial transplantation. Overexpression of Bmi1 had no effect on DNA damage response triggered by ionizing radiation. In contrast, Tie2-Cre;R26StopFLBmi1 HSCs under oxidative stress maintained a multipotent state and generally tolerated oxidative stress better than the control. Unexpectedly, overexpression of Bmi1 had no impact on the level of intracellular reactive oxygen species (ROS). Our findings demonstrate that overexpression of Bmi1 confers resistance to stresses, particularly oxidative stress, onto HSCs. This thereby enhances their regenerative capacity and suggests that Bmi1 is located downstream of ROS signaling and negatively regulated by it.
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影响因子：
2.1
作者：
Iwama, A;Oguro, H;Nakauchi, H
通讯作者：
Nakauchi, H
DOI：
10.1073/pnas.1014263108
发表时间：
2011-03-29
影响因子：
11.1
作者：
Chagraoui, Jalila;Hebert, Josee;Sauvageau, Guy
通讯作者：
Sauvageau, Guy
影响因子：
2.7
作者：
Kisanuki, YY;Hammer, RE;Yanagisawa, M
通讯作者：
Yanagisawa, M
影响因子：
5.3
作者：
Ginjala, Vasudeva;Nacerddine, Karim;Ganesan, Shridar
通讯作者：
Ganesan, Shridar
影响因子：
32.4
作者：
Sasaki, Yoshiteru;Derudder, Emmanuel;Schmidt-Supprian, Marc
通讯作者：
Schmidt-Supprian, Marc