Ovariectomy expands murine short-term hemopoietic stem cell function through T cell expressed CD40L and Wnt10B
Ovariectomy expands murine short-term hemopoietic stem cell function through T cell expressed CD40L and Wnt10B
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DOI：
10.1182/blood-2013-03-487801
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发表时间：
2013-10-03
期刊：
影响因子：
20.3
通讯作者：
Pacifici, Roberto
中科院分区：
文献类型：
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作者：
Li, Jau-Yi;Adams, Jonathan;Pacifici, Roberto
雌激素缺乏扩大造血干细胞和祖细胞（HSPCs）和成熟血液谱系，但涉及的机制和受影响的HSPC群体大多未知。在这里，我们发现卵巢切除术（ovx）通过t细胞共刺激分子CD40配体（CD40L）的双重作用扩大了短期HSPCs (ST-HSPCs)，并改善了骨髓移植后的血细胞植入和宿主存活。ovx需要这种表面受体来刺激t细胞产生Wnt10b， Wnt10b是一种Wnt配体，可激活HSPCs和基质细胞（SCs）中的Wnt信号传导。此外，ovx需要CD40L来增加造血细胞因子白细胞介素(IL)-6、IL-7和粒细胞巨噬细胞集落刺激因子的SC生成。证明CD40L和Wnt10b的相关性，ovx不能在CD40L缺失的小鼠和缺乏Wnt10b全局或t细胞表达的动物中扩增ST-HSPCs。综上所述，T细胞表达CD40L，由此导致T细胞和SCs分别增加Wnt10b和造血细胞因子的产生，在ovx调节造血的机制中起关键作用。这些数据表明，抗雌激素可能是通过激活微环境来改善ST-HSPC功能的药理靶点。
Estrogen deficiency expands hemopoietic stem and progenitor cells (HSPCs) and mature blood lineages, but the involved mechanism and the affected HSPC populations are mostly unknown. Here we show that ovariectomy (ovx) expands short-term HSPCs (ST-HSPCs) and improves blood cell engraftment and host survival after bone marrow (BM) transplantation through a dual role of the T-cell costimulatory molecule CD40 ligand (CD40L). This surface receptor is required for ovx to stimulate T-cell production of Wnt10b, a Wnt ligand that activates Wnt signaling in HSPCs and stromal cells (SCs). Moreover, CD40L is required for ovx to increase SC production of the hemopoietic cytokines interleukin (IL)-6, IL-7, and granulocyte macrophage-colony-stimulating factor. Attesting to the relevance of CD40L and Wnt10b, ovx fails to expand ST-HSPCs in CD40L-null mice and in animals lacking global or T-cell expression of Wnt10b. In summary, T cells expressed CD40L, and the resulting increased production of Wnt10b and hemopoietic cytokines by T cells and SCs, respectively, plays a pivotal role in the mechanism by which ovx regulates hemopoiesis. The data suggest that antiestrogens may represent pharmacological targets to improve ST-HSPC function through activation of the microenvironment.