Adult hematopoietic stem cells require NKAP for maintenance and survival
Adult hematopoietic stem cells require NKAP for maintenance and survival
复制标题
DOI：
10.1182/blood-2010-02-268391
复制
发表时间：
2010-10-14
期刊：
影响因子：
20.3
通讯作者：
Shapiro, Virginia Smith
中科院分区：
文献类型：
--
作者：
Pajerowski, Anthony G.;Shapiro, Michael J.;Shapiro, Virginia Smith
稳态造血通过与造血干细胞（HSC）的增殖和自我更新平衡的分化来维持。这种平衡的破坏可导致造血功能衰竭，因为没有自我更新的造血分化导致HSC库的损失。我们发现，条件性基因敲除小鼠，删除转录抑制因子NKAP在造血干细胞和所有造血谱系在胚胎发育过程中表现出围产期的致命性和废除的造血表现为多谱系缺陷淋巴细胞，粒细胞，红细胞和巨核细胞的发展。成年小鼠中NKAP的诱导性缺失导致2周内的致死性，此时骨髓中的造血已经停止并且HSC已经消失。这种造血衰竭和致死性是细胞内在的，因为用诱导型Mx 1-cre NKAP条件性敲除骨髓重建的辐射嵌合体也以类似的时间过程死亡。即使在使用混合辐射嵌合体的完全正常骨髓环境的背景下，NKAP缺失也导致HSC衰竭。NKAP缺失导致HSC增殖减少和凋亡增加，这可能是由于细胞周期蛋白依赖性激酶抑制剂p21 Cip 1/Waf 1和p19 Ink 4d表达增加。这些数据建立NKAP作为一个非常少数的转录调控因子，是绝对需要的成年HSC的维持和生存。（血。2010;116（15）：2684-2693）
Steady-state hematopoiesis is sustained through differentiation balanced with proliferation and self-renewal of hematopoietic stem cells (HSCs). Disruption of this balance can lead to hematopoietic failure, as hematopoietic differentiation without self-renewal leads to loss of the HSC pool. We find that conditional knockout mice that delete the transcriptional repressor NKAP in HSCs and all hematopoietic lineages during embryonic development exhibit perinatal lethality and abrogation of hematopoiesis as demonstrated by multilineage defects in lymphocyte, granulocyte, erythrocyte and megakaryocyte development. Inducible deletion of NKAP in adult mice leads to lethality within 2 weeks, at which point hematopoiesis in the bone marrow has halted and HSCs have disappeared. This hematopoietic failure and lethality is cell intrinsic, as radiation chimeras reconstituted with inducible Mx1-cre NKAP conditional knockout bone marrow also succumb with a similar time course. Even in the context of a completely normal bone marrow environment using mixed radiation chimeras, NKAP deletion results in HSC failure. NKAP deletion leads to decreased proliferation and increased apoptosis of HSCs, which is likely due to increased expression of the cyclin-dependent kinase inhibitors p21Cip1/Waf1 and p19Ink4d. These data establish NKAP as one of a very small number of transcriptional regulators that is absolutely required for adult HSC maintenance and survival. (Blood. 2010;116(15):2684-2693)