27-Hydroxycholesterol induces hematopoietic stem cell mobilization and extramedullary hematopoiesis during pregnancy
Hideyuki Oguro, Jeffrey G. McDonald, Zhiyu Zhao, Michihisa Umetani, Philip W. Shaul, Sean J. Morrison
Hideyuki Oguro, Jeffrey G. McDonald, Zhiyu Zhao, Michihisa Umetani, Philip W. Shaul, Sean J. Morrison
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Research Article

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

Abstract

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.

Authors

Hideyuki Oguro, Jeffrey G. McDonald, Zhiyu Zhao, Michihisa Umetani, Philip W. Shaul, Sean J. Morrison

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Figure 6

Pregnancy increases Cyp27a1 expression and 27HC levels in primitive hematopoietic stem and progenitor cells.

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Pregnancy increases Cyp27a1 expression and 27HC levels in primitive hema...
(A and B) Cyp27a1 deficiency did not affect the numbers of hematopoietic stem and progenitor cells in the bone marrow (femurs and tibias; A) or spleen (B) of mice that had been repeatedly bled (a total of 5–6 mice/treatment from 3 independent experiments). (C and D) Cyp27a1 deficiency did not affect the numbers of hematopoietic stem and progenitor cells in the bone marrow (femurs and tibias; C) or spleen (D) of mice treated with G-CSF for 6 days (a total of 3 mice/treatment from 2 independent experiments). (E, G, and H) Cyp27a1 (E) or Cxcr4 (G and H) transcript levels were quantified by qRT-PCR in the indicated bone marrow cell populations (a total of 3–5 mice from 3–4 independent experiments). Expression values were normalized to beta-Actin and presented relative to those in control WBM cells. (F) Intracellular 27HC levels in 107 lineage-depleted bone marrow cells from non-pregnant and pregnant WT mice (a total of 5 mice/treatment from 4 independent experiments). Statistical significance was assessed using 1-way ANOVA with Šídák’s multiple comparisons tests, with the exception of E, F, and H, where we used 2-tailed unpaired Student’s t tests using the FDR method to correct for multiple comparisons (*P < 0.05, ‡P < 0.01, #P < 0.001). All data represent mean ± SD.