Estrogen increases haematopoietic stem cell self-renewal in females and during pregnancy

Sexually dimorphic mammalian tissues, including sexual organs and the brain, contain stem cells that are directly or indirectly regulated by sex hormones(1-6). An important question is whether stem cells also exhibit sex differences in physiological function and hormonal regulation in tissues that do not exhibit sex-specific morphological differences. The terminal differentiation and function of some haematopoietic cells are regulated by sex hormones(7-10) but haematopoietic stem cell (HSC) function is thought to be similar in both sexes. Here we show that mouse HSCs exhibit sex differences in cell cycle regulation by estrogen. HSCs in females divide significantly more frequently than in males. This difference depended on the ovaries but not the testes. Administration of estradiol, a hormone produced mainly in the ovaries, increased HSC cell division in males and females. Estrogen levels increased during pregnancy, increasing HSC division, HSC frequency, cellularity, and erythropoiesis in the spleen. HSCs expressed high levels of estrogen receptor α (ERα). Conditional deletion of ERα from HSCs reduced HSC division in female, but not male, mice and attenuated the increases in HSC division, HSC frequency, and erythropoiesis during pregnancy. Estrogen/ERα signaling promotes HSC self-renewal, expanding splenic HSCs and erythropoiesis during pregnancy.