The gp130 Cytokine Interleukin-11 Regulates Engraftment of Vav1-/- Hematopoietic Stem and Progenitor Cells in Lethally Irradiated Recipients
The gp130 Cytokine Interleukin-11 Regulates Engraftment of Vav1-/- Hematopoietic Stem and Progenitor Cells in Lethally Irradiated Recipients
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DOI：
10.1002/stem.2760
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发表时间：
2018-03-01
期刊：
影响因子：
5.2
通讯作者：
Williams, David A.
中科院分区：
文献类型：
--
作者：
De Vita, Serena;Li, Yanhua;Williams, David A.
在骨髓移植过程中，造血干/祖细胞通过包括Rac在内的Rho GTP酶协同激活分子通路，对来自造血微环境的信号作出反应。我们之前已经证明，RAC的造血特异性激活剂Vav1的缺失会影响成年HSPC移植的植入，而不会影响成年动物的稳态造血。在这里，我们表明Vav1(-/-)胎儿HSPC可以在个体发育过程中适当地种植造血组织，但不能移植到致死性照射的受者体内。我们证明，在没有照射的情况下，Vav1(-/-)HSPC的植入缺陷被消除，并证明Vav1在HSPC对受者骨髓中上调的促炎细胞因子IL-11的反应中起关键作用。Vav1(-/-)HSPC在体外表现出对IL-11的异常增殖反应和对HSPC植入至关重要的通路的异常激活。经抗IL-11抗体治疗的受者，Vav1(-/-)HSPC的植入可被部分挽救。这些数据表明，HSPC可能通过选择性地使用IL-11-Vav-Rac途径来响应不同的功能需求，进一步支持了最近的观点，即移植后能够重建血液系统的HSPC可能不同于在动态平衡条件下支持造血的HSPC。
During bone marrow transplantation, hematopoietic stem and progenitor cells (HSPCs) respond to signals from the hematopoietic microenvironment by coordinately activating molecular pathways through Rho GTPases, including Rac. We have previously shown that deletion of Vav1, a hematopoietic-specific activator of Rac, compromises engraftment of transplanted adult HSPCs without affecting steady-state hematopoiesis in adult animals. Here, we show that Vav1(-/-) fetal HSPCs can appropriately seed hematopoietic tissues during ontogeny but cannot engraft into lethally irradiated recipients. We demonstrate that the engraftment defect of Vav1(-/-) HSPCs is abrogated in the absence of irradiation and demonstrate that Vav1 is critical for the response of HSPCs to the proinflammatory cytokine interleukin-11 (IL-11) that is upregulated in the marrow of irradiated recipients. Vav1(-/-) HSPCs display abnormal proliferative responses to IL-11 in vitro and dysregulated activation of pathways critical to engraftment of HSPCs. The engraftment of Vav1(-/-) HSPCs can be partially rescued in irradiated recipients treated with an anti-IL-11 antibody. These data suggest that HSPCs may respond to different functional demands by selective usage of the IL-11-Vav-Rac pathway, contextualizing further the recent view that HSPCs capable of reconstituting the blood system following transplantation might be distinct from those supporting hematopoiesis during homeostatic conditions.