27-Hydroxycholesterol induces hematopoietic stem cell mobilization and extramedullary hematopoiesis during pregnancy
Hideyuki Oguro, … , Philip W. Shaul, Sean J. Morrison
Hideyuki Oguro, … , Philip W. Shaul, Sean J. Morrison
Published August 7, 2017
Citation Information: J Clin Invest. 2017;127(9):3392-3401. https://doi.org/10.1172/JCI94027.
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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 1

Estradiol promotes HSC division in the bone marrow and 27HC promotes mobilization to the spleen.

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Estradiol promotes HSC division in the bone marrow and 27HC promotes mob...
(A and B) The numbers of hematopoietic stem and progenitor cells in the bone marrow (femurs and tibias; A) and spleen (B) of male mice treated with estradiol (E2), 27HC, or G-CSF daily for 6 days (a total of 4–5 mice/treatment from 5 independent experiments). The vehicle for E2 was corn oil, and the vehicle for 27HC was 2-hydroxypropyl-β-cyclodextrin. The markers used to identify each cell population are shown in Methods. (C) BrdU incorporation into hematopoietic stem and progenitor cells in the bone marrow of male mice treated with E2, 27HC, or G-CSF for 6 days. The mice received BrdU for the last 3 days (a total of 4–5 mice/treatment from 4 independent experiments). (D) The frequency of annexin V+ cells in the indicated hematopoietic stem and progenitor cell populations in the bone marrow of male mice treated with vehicle, E2, or 27HC daily for 6 days (a total of 3–4 mice/treatment from 2 independent experiments). (E) Plasma 27HC levels in male mice treated with vehicle or 27HC daily for 6 days (a total of 5 mice/treatment from 5 independent experiments). (F) BrdU incorporation into hematopoietic stem and progenitor cells in the spleens of male mice treated with 27HC daily for 6 days. The mice received BrdU for the last 3 days (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 E, where we used Welch’s test (‡P < 0.01) and F, where we used 2-tailed unpaired Student’s t tests using the false discovery rate (FDR) method to correct for multiple comparisons (*P < 0.05, ‡P < 0.01, #P < 0.001). See Methods for details. All data represent mean ± SD.