p190-B RhoGAP and intracellular cytokine signals balance hematopoietic stem and progenitor cell self-renewal and differentiation.
p190-B RhoGAP and intracellular cytokine signals balance hematopoietic stem and progenitor cell self-renewal and differentiation.
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DOI：
10.1038/ncomms14382
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发表时间：
2017-02-08
影响因子：
16.6
通讯作者：
Filippi MD
中科院分区：
文献类型：
--
作者：
Hinge A;Xu J;Javier J;Mose E;Kumar S;Kapur R;Srour EF;Malik P;Aronow BJ;Filippi MD
调控造血干细胞和祖细胞（HSPC）命运选择的机制仍然不明确。在这里，我们发现p190-B RhoGAP-ROS-TGF-β-p38 MAPK信号网络平衡HSPC自我更新和分化。移植后，HSPC表达大量生物活性TGF-β1蛋白，这与体内高水平的p38 MAPK活性和HSC自我更新的丧失有关。生物活性TGF-β1水平升高与体外单个HSPC中通过p38 MAPK活性的不对称命运选择相关，这与活化的p38 MAPK的不对称分布相关。相比之下，RhoGT抑制剂p190-B的缺失使HSPC中的TGF-β水平和p38 MAPK活性正常化，并且与体内HSC自我更新增加相关。p190-B的缺失也促进了单一HSPC骨髓细胞培养物中多谱系能力的对称保留，进一步表明了HSPC分化中p190-B-RhoGAP与非经典TGF-β信号传导之间的联系。因此，细胞内细胞因子信号传导可作为HSPC用于调节其活性的“命运决定因子”。造血干细胞（HSC）移植的成功依赖于了解是什么调控了自我更新的命运决定。在这里，作者使用体外试验和体内移植表明，RhoGAP p190-B的缺失通过抑制TGFβ/p38信号传导来增强自我更新。
The mechanisms regulating hematopoietic stem and progenitor cell (HSPC) fate choices remain ill-defined. Here, we show that a signalling network of p190-B RhoGAP-ROS-TGF-β-p38MAPK balances HSPC self-renewal and differentiation. Upon transplantation, HSPCs express high amounts of bioactive TGF-β1 protein, which is associated with high levels of p38MAPK activity and loss of HSC self-renewal in vivo. Elevated levels of bioactive TGF-β1 are associated with asymmetric fate choice in vitro in single HSPCs via p38MAPK activity and this is correlated with the asymmetric distribution of activated p38MAPK. In contrast, loss of p190-B, a RhoGTPase inhibitor, normalizes TGF-β levels and p38MAPK activity in HSPCs and is correlated with increased HSC self-renewal in vivo. Loss of p190-B also promotes symmetric retention of multi-lineage capacity in single HSPC myeloid cell cultures, further suggesting a link between p190-B-RhoGAP and non-canonical TGF-β signalling in HSPC differentiation. Thus, intracellular cytokine signalling may serve as ‘fate determinants' used by HSPCs to modulate their activity. The success of hematopoietic stem cell (HSC) transplantation relies on understanding what regulates the fate decision to self-renew. Here, the authors show using both in vitro assays and in vivo transplantation that loss of the RhoGAP p190-B enhances self-renewal by inhibiting TGFβ/p38 signalling.