27-Hydroxycholesterol induces hematopoietic stem cell mobilization and extramedullary hematopoiesis during pregnancy
27-Hydroxycholesterol induces hematopoietic stem cell mobilization and extramedullary hematopoiesis during pregnancy
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DOI：
10.1172/jci94027
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发表时间：
2017-09-01
影响因子：
15.9
通讯作者：
Morrison, Sean J.
中科院分区：
文献类型：
--
作者：
Oguro, Hideyuki;McDonald, Jeffrey G.;Morrison, Sean J.
髓外造血（EMH）在妊娠期间被诱导，以支持母体血容量的快速扩张。EMH激活需要造血干细胞（HSC）增殖和动员，这一过程依赖于HSC中的雌激素受体α（ER α）。在这里，我们表明，治疗小鼠与雌二醇模型雌二醇增加在怀孕期间诱导造血干细胞增殖骨髓，但不是造血干细胞动员。用替代ER α配体27-羟基胆固醇（27 HC）处理诱导骨髓中的ER α依赖性HSC动员和EMH，但不诱导HSC分裂。妊娠期间，由于CYP 27 A1（一种胆固醇羟化酶）的作用，造血干/祖细胞中的27 HC水平升高。Cyp 27 α 1缺陷小鼠在妊娠期间27 HC水平、HSC动员和EMH显著降低，但对出血或G-CSF治疗的骨髓造血和EMH正常。因此，不同的造血应激通过不同的机制诱导EMH。两种不同的ER α配体，雌二醇和27 HC，在怀孕期间共同促进EMH，揭示了激素和代谢机制的协作以及27 HC在正常小鼠中的生理功能。
Extramedullary hematopoiesis (EMH) is induced during pregnancy to support rapid expansion of maternal blood volume. EMH activation requires hematopoietic stem cell (HSC) proliferation and mobilization, processes that depend upon estrogen receptor alpha (ER alpha) in HSCs. Here we show that treating mice with estradiol to model estradiol increases during pregnancy induced HSC proliferation in the bone marrow but not HSC mobilization. Treatment with the alternative ERa ligand 27-hydroxycholesterol (27HC) induced ER alpha-dependent HSC mobilization and EMH but not HSC division in the bone marrow. During pregnancy, 27HC levels increased in hematopoietic stem/progenitor cells as a result of CYP27A1, a cholesterol hydroxylase. Cyp27 alpha 1-deficient mice had significantly reduced 27HC levels, HSC mobilization, and EMH during pregnancy but normal bone marrow hematopoiesis and EMH in response to bleeding or G-CSF treatment. Distinct hematopoietic stresses thus induce EMH through different mechanisms. Two different ER alpha ligands, estradiol and 27HC, work together to promote EMH during pregnancy, revealing a collaboration of hormonal and metabolic mechanisms as well as a physiological function for 27HC in normal mice.