Nbs1-mediated DNA damage repair pathway regulates haematopoietic stem cell development and embryonic haematopoiesis.
Nbs1-mediated DNA damage repair pathway regulates haematopoietic stem cell development and embryonic haematopoiesis.
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Nbs1-介导的DNA损伤修复途径调节造血干细胞发育和胚胎造血
DOI：
10.1111/cpr.12972
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发表时间：
2021-03
影响因子：
8.5
通讯作者：
Li T
中科院分区：
文献类型：
--
作者：
Chen Y;Sun J;Ju Z;Wang ZQ;Li T
DNA损伤对造血干细胞（HSC）的维持和造血系统的稳态构成威胁。成年小鼠骨髓中的静止HSC对DNA损伤具有抵抗力，而人脐带血来源的增殖性HSC在电离辐射后易于细胞死亡。小鼠胚胎肝星状细胞在胎肝中增殖，并对称分裂产生肝星状细胞库。小鼠胚胎HSC如何对DNA损伤做出反应尚未明确。建立了胚胎HSC中特异性缺失DNA修复分子Nbs 1或Nbs 1/p53的小鼠模型。使用FACS分析、体外和体内HSC分化测定、qPCR、免疫荧光和蛋白质印迹来描述Nbs 1-p53信号传导在HSC和造血祖细胞中的作用。NBS 1缺陷导致胚胎HSC中持续的DNA断裂，损害胚胎HSC发育，并最终导致小鼠围产期死亡。Nbs 1缺陷的胚胎HSC中持续的DNA断裂导致细胞周期停滞，同时驱动造血祖细胞中更高的细胞死亡率。虽然Nbs 1缺陷促进HSC及其后代中Atm-Chk 2-p53轴的激活，但Nbs 1缺陷HSC中p53的消融加速胚胎致死。我们的研究揭示了DNA双链修复分子Nbs 1在胚胎HSC发育和造血中至关重要。持续的DNA损伤导致HSC和造血祖细胞中不同的细胞命运。Nbs 1无效HSC倾向于通过细胞周期停滞来维持，而Nbs 1无效造血祖细胞则导致细胞死亡。这种差异可能是由不同大小的p53信号介导的。小鼠胚胎造血干细胞（HSC）中DNA双链断裂修复分子Nbs 1的遗传缺失会在HSC及其后代中产生持续性DNA损伤，导致小鼠造血缺陷和围产期致死。Nbs 1缺失的HSC和造血祖细胞表现出不同的细胞命运，这可能是由每个细胞群中p53信号传导的不同幅度介导的。有趣的是，p53缺失加速了HSC中Nbs 1缺失的小鼠的致死率，表明p53信号传导在保护胚胎造血中的重要作用。
DNA damages pose threats to haematopoietic stem cells (HSC) maintenance and haematopoietic system homeostasis. Quiescent HSCs in adult mouse bone marrow are resistant to DNA damage, while human umbilical cord blood‐derived proliferative HSCs are prone to cell death upon ionizing radiation. Murine embryonic HSCs proliferate in foetal livers and divide symmetrically to generate HSC pool. How murine embryonic HSCs respond to DNA damages is not well‐defined. Mice models with DNA repair molecule Nbs1 or Nbs1/p53 specifically deleted in embryonic HSCs were generated. FACS analysis, in vitro and in vivo HSC differentiation assays, qPCR, immunofluorescence and Western blotting were used to delineate roles of Nbs1‐p53 signaling in HSCs and haematopoietic progenitors. Nbs1 deficiency results in persistent DNA breaks in embryonic HSCs, compromises embryonic HSC development and finally results in mouse perinatal lethality. The persistent DNA breaks in Nbs1 deficient embryonic HSCs render cell cycle arrest, while driving a higher rate of cell death in haematopoietic progenitors. Although Nbs1 deficiency promotes Atm‐Chk2‐p53 axis activation in HSCs and their progenies, ablation of p53 in Nbs1 deficient HSCs accelerates embryonic lethality. Our study discloses that DNA double‐strand repair molecule Nbs1 is essential in embryonic HSC development and haematopoiesis. Persistent DNA damages result in distinct cell fate in HSCs and haematopoietic progenitors. Nbs1 null HSCs tend to be maintained through cell cycle arrest, while Nbs1 null haematopoietic progenitors commit cell death. The discrepancies are mediated possibly by different magnitude of p53 signaling. Genetic deletion of Nbs1, a DNA double‐strand break repair molecule, in murine embryonic haematopoietic stem cells (HSCs) generates persistent DNA damages in HSCs and their progenies, contributing to defective haematopoiesis and perinatal lethality in mice. Nbs1 null HSCs and haematopoietic progenitors show different cell fate, which could be mediated by differential magnitude of p53 signaling in each cell population. Intriguingly, p53 loss accelerates lethality of mice with Nbs1 deletion in HSCs, indicating an essential role of p53 signaling safeguarding embryonic haematopoiesis.
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影响因子：
14.9
作者：
Avila AI;Illing A;Becker F;Maerz LD;Morita Y;Philipp M;Burkhalter MD
通讯作者：
Burkhalter MD
影响因子：
10.5
作者：
Bender, CF;Sikes, ML;Petrini, JHJ
通讯作者：
Petrini, JHJ
影响因子：
1.5
作者：
Georgiades, P;Ogilvy, S;Print, CG
通讯作者：
Print, CG
老化的造血干细胞室中 DNA 损伤的积累。
影响因子：
3.6
作者：
Beerman I
通讯作者：
Beerman I
影响因子：
11.8
作者：
Gekas, C;Dieterlen-Lièvre, F;Mikkola, HKA
通讯作者：
Mikkola, HKA