Oguro Hideyuki, McDonald Jeffrey G, Zhao Zhiyu, Umetani Michihisa, Shaul Philip W, Morrison Sean J
Children's Research Institute and.
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
J Clin Invest. 2017 Sep 1;127(9):3392-3401. doi: 10.1172/JCI94027. Epub 2017 Aug 7.
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 α (ERα) 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 ERα ligand 27-hydroxycholesterol (27HC) induced ERα-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. Cyp27a1-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 ERα 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.
孕期会诱导髓外造血（EMH）以支持母体血容量的快速增加。EMH的激活需要造血干细胞（HSC）的增殖和动员，而这些过程依赖于HSCs中的雌激素受体α（ERα）。在此，我们表明，用雌二醇处理小鼠以模拟孕期雌二醇增加的情况，可诱导骨髓中的HSC增殖，但不能诱导HSC动员。用替代的ERα配体27-羟基胆固醇（27HC）处理可诱导依赖于ERα的HSC动员和EMH，但不能诱导骨髓中的HSC分裂。在孕期，由于胆固醇羟化酶CYP27A1的作用，造血干/祖细胞中的27HC水平升高。Cyp27a1基因缺陷型小鼠在孕期的27HC水平、HSC动员和EMH显著降低，但对出血或粒细胞集落刺激因子（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机制诱导EMH。两种不同的ERα配体，雌二醇和27HC，共同作用以促进孕期的EMH，揭示了激素和代谢机制的协同作用以及27HC在正常小鼠中的生理功能。
