Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Research Foundation, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Nat Commun. 2017 Feb 8;8:14382. doi: 10.1038/ncomms14382.
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-p38 balances HSPC self-renewal and differentiation. Upon transplantation, HSPCs express high amounts of bioactive TGF-β1 protein, which is associated with high levels of p38 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.
调节造血干/祖细胞（HSPC）命运选择的机制仍不清楚。在这里，我们表明，p190-B RhoGAP-ROS-TGF-β-p38 信号网络平衡 HSPC 的自我更新和分化。在移植后，HSPC 表达大量具有生物活性的 TGF-β1 蛋白，这与体内高水平的 p38 活性和 HSC 自我更新丧失有关。在体外单个 HSPC 中，通过 p38MAPK 活性，升高的生物活性 TGF-β1 水平与不对称命运选择相关，这与激活的 p38MAPK 的不对称分布相关。相比之下，RhoGTPase 抑制剂 p190-B 的缺失可使 HSPC 中的 TGF-β 水平和 p38MAPK 活性正常化，并与体内 HSC 自我更新增加相关。p190-B 的缺失也促进了单个 HSPC 髓系细胞培养物中多谱系能力的对称保留，这进一步表明 p190-B-RhoGAP 和 HSPC 分化中非经典 TGF-β 信号之间存在联系。因此，细胞内细胞因子信号可能作为 HSPC 用来调节其活性的“命运决定因素”。
