27-Hydroxycholesterol induces hematopoietic stem cell mobilization and extramedullary hematopoiesis during pregnancy

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.