RhoA GTPase controls cytokinesis and programmed necrosis of hematopoietic progenitors.
RhoA GTPase controls cytokinesis and programmed necrosis of hematopoietic progenitors.
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DOI：
10.1084/jem.20122348
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发表时间：
2013-10-21
期刊：
影响因子：
--
通讯作者：
Zheng Y
中科院分区：
文献类型：
--
作者：
Zhou X;Florian MC;Arumugam P;Chen X;Cancelas JA;Lang R;Malik P;Geiger H;Zheng Y
GTPase RhoA 是造血祖细胞适当分裂和存活所必需的。造血祖细胞 (HPC) 是造血的核心，因为它们提供维持血液稳态所需的大量谱系定义的血细胞。它们是循环最活跃的体细胞之一，它们的精确控制对于造血稳态至关重要。小 GTP 酶 RhoA 是一种细胞内分子开关，它整合细胞因子、趋化因子和粘附信号以协调多个上下文依赖性细胞过程。通过使用 RhoA 条件性基因敲除小鼠模型，我们发现 RhoA 缺陷会导致多谱系造血功能衰竭，并与多能 HPC 缺陷相关。有趣的是，RhoA−/− 造血干细胞保留了长期植入潜力，但未能产生多能 HPC 和谱系定义的血细胞。通过将野生型 RhoA 重建到 RhoA−/− Lin−Sca-1+c-Kit+ 室中，可以挽救这种多谱系造血衰竭。从机制上讲，RhoA 调节肌动球蛋白信号传导、胞质分裂和 HPC 的程序性坏死，RhoA 的缺失会导致 HPC 的胞质分裂失败，表现为末期后卵裂沟脱落失败导致多核细胞的积累。与此同时，HPC 显示出与 TNF-RIP 介导的坏死增加相关的死亡急剧增加。这些结果表明，RhoA 是胞质分裂过程中多能 HPC 的关键且特异性调节剂，因此对于多系造血至关重要。
The GTPase RhoA is required for the appropriate division and survival of hematopoietic progenitor cells. Hematopoietic progenitor cells (HPCs) are central to hematopoiesis as they provide large numbers of lineage-defined blood cells necessary to sustain blood homeostasis. They are one of the most actively cycling somatic cells, and their precise control is critical for hematopoietic homeostasis. The small GTPase RhoA is an intracellular molecular switch that integrates cytokine, chemokine, and adhesion signals to coordinate multiple context-dependent cellular processes. By using a RhoA conditional knockout mouse model, we show that RhoA deficiency causes a multilineage hematopoietic failure that is associated with defective multipotent HPCs. Interestingly, RhoA−/− hematopoietic stem cells retained long-term engraftment potential but failed to produce multipotent HPCs and lineage-defined blood cells. This multilineage hematopoietic failure was rescued by reconstituting wild-type RhoA into the RhoA−/− Lin−Sca-1+c-Kit+ compartment. Mechanistically, RhoA regulates actomyosin signaling, cytokinesis, and programmed necrosis of the HPCs, and loss of RhoA results in a cytokinesis failure of HPCs manifested by an accumulation of multinucleated cells caused by failed abscission of the cleavage furrow after telophase. Concomitantly, the HPCs show a drastically increased death associated with increased TNF–RIP-mediated necrosis. These results show that RhoA is a critical and specific regulator of multipotent HPCs during cytokinesis and thus essential for multilineage hematopoiesis.
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