NADPH oxidase 2 regulates bone marrow microenvironment following hindlimb ischemia: role in reparative mobilization of progenitor cells.
NADPH oxidase 2 regulates bone marrow microenvironment following hindlimb ischemia: role in reparative mobilization of progenitor cells.
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DOI：
10.1002/stem.1048
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发表时间：
2012-05
期刊：
影响因子：
5.2
通讯作者：
Ushio-Fukai, Masuko
中科院分区：
文献类型：
--
作者：
Urao, Norifumi;McKinney, Ronald D.;Fukai, Tohru;Ushio-Fukai, Masuko
骨髓微环境受缺氧和蛋白水解酶的调节，对干/祖细胞的功能和动员参与出生后新生血管形成至关重要。我们证明，NADPH氧化酶2（Nox 2）衍生的活性氧（ROS）参与缺血后骨髓细胞的动员和血管重建。然而，Nox 2在调节缺血性损伤后BM微环境中的作用仍不清楚。在这里，我们表明，小鼠后肢缺血增加ROS的生产在骨内膜和中央区域的BM组织原位，这是几乎完全废除在Nox 2基因敲除（KO）小鼠。这种Nox 2依赖性ROS的产生主要来源于BM中的Gr-1+髓样细胞。在体注射低氧探针显示，基础状态下，BM骨内膜缺氧，HIF-1α高表达。后肢缺血后，缺氧区域和HIF-1α表达在整个BM中扩大，这在Nox 2 KO小鼠中受到抑制。这种缺血诱导的Nox 2依赖性BM微环境的改变与BM组织中VEGF表达和Akt磷酸化的增加相关，从而促进Lin-祖细胞存活和扩增，导致其从BM动员。此外，后肢缺血增加BM中的蛋白水解酶MT 1-MMP表达和MMP-9活性，这在Nox 2 KO小鼠中被抑制。总之，Nox 2依赖性的ROS增加在调节组织缺血时BM微环境中的缺氧扩展和蛋白水解活性中起关键作用。这反过来又促进祖细胞扩增和从BM的修复性动员，导致缺血后新血管形成和组织修复。
Bone marrow (BM) microenvironment, which is regulated by hypoxia and proteolytic enzymes, is crucial for stem/progenitor cell function and mobilization involved in postnatal neovascularization. We demonstrated that NADPH oxidase2 (Nox2)-derived reactive oxygen species (ROS) are involved in post-ischemic mobilization of BM cells and revascularization. However, role of Nox2 in regulating BM microenvironment in response to ischemic injury remains unknown. Here we show that hindlimb ischemia of mice increases ROS production in both the endosteal and central region of BM tissue in situ, which is almost completely abolished in Nox2 knockout (KO) mice. This Nox2-dependent ROS production is mainly derived from Gr-1+ myeloid cells in BM. In vivo injection of hypoxyprobe reveals that endosteum at the BM is hypoxic with high expression of HIF-1α in basal state. Following hindlimb ischemia, hypoxic areas and HIF-1α expression are expanded throughout the BM, which is inhibited in Nox2 KO mice. This ischemia-induced alteration of Nox2-dependent BM microenvironment is associated with an increase in VEGF expression and Akt phosphorylation in BM tissue, thereby promoting Lin− progenitor cell survival and expansion, leading to their mobilization from BM. Furthermore, hindlimb ischemia increases proteolytic enzymes MT1-MMP expression and MMP-9 activity in BM, which is inhibited in Nox2 KO mice. In summary, Nox2-dependent increase in ROS play a critical role in regulating hypoxia expansion and proteolytic activities in BM microenvironment in response to tissue ischemia. This in turn promotes progenitor cell expansion and reparative mobilization from BM, leading to post-ischemic neovascularization and tissue repair.
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DOI：
10.1016/j.bbrc.2006.12.148
发表时间：
2007-02-23
影响因子：
3.1
作者：
Piccoli, Claudia;D'Aprile, Annamaria;Capitanio, Nazzareno
通讯作者：
Capitanio, Nazzareno
影响因子：
4.8
作者：
Choi, Yoon Kyung;Kim, Chun-Ki;Kim, Young-Myeong
通讯作者：
Kim, Young-Myeong
影响因子：
20.3
作者：
Rehn, Matilda;Olsson, Andre;Cammenga, Jorg
通讯作者：
Cammenga, Jorg
影响因子：
4.1
作者：
Fan, Jinli;Cai, Haibo;Tan, Wen-Song
通讯作者：
Tan, Wen-Song
影响因子：
37.8
作者：
Galis, ZS;Asanuma, K;Meng, XP
通讯作者：
Meng, XP