Stem cells

Sex specificity in the blood

Haematopoietic stem cells, from which blood cells originate, are shown to respond to oestrogen and divide more frequently in female mice than in males, probably preparing females for the increased demand for blood in pregnancy. See Letter p.555

Males and females exhibit differences not only in reproductive organs, but also in sexually dimorphic tissues such as the mammary gland, brain and muscle. In such tissues, the activity of stem cells, which self-renew and produce differentiated cells for tissue maintenance and repair, differs between males and females1,2,3,4. A fundamental yet unexplored question is whether the stem cells of tissues without conspicuous sex differences, such as the blood or gut, also exhibit sexually dimorphic function. On page 555 of this issue, Nakada et al.5 find that haematopoietic stem cells (HSCs), which form the blood and immune system, do differ between male and female mice. The authors show that female HSCs respond to long-range oestrogen signals in a manner that seems to help mothers meet the haematopoietic demands of pregnancy.

HSCs reside in the bone marrow and produce all blood cells, which in turn mediate processes ranging from immunity to clotting to oxygen transport. Nakada and colleagues find that, under basal conditions, female HSCs and their immediate progeny, multipotent progenitor cells (MPPs), divide more frequently than male HSCs, and generate more erythroid progenitors (the cells that give rise to red blood cells).

Despite the increased frequency of division in female HSCs, males and females have the same basal number of HSCs and a similar cellular composition in the bone marrow and spleen (an organ colonized by haematopoietic cells). The authors suggest that female HSCs undergo more asymmetric divisions in which one daughter cell remains a stem cell and the other differentiates along the red blood cell lineage, and that these newly produced erythroid progenitors undergo cell death at a higher frequency (Fig. 1). These differences may explain why the sexual dimorphism of HSCs has not previously been observed.

Figure 1: Oestrogen regulates stem-cell cycling.
figure1

Nakada et al.5 report that haematopoietic stem cells (HSCs) respond to oestrogen signals, causing female HSCs to divide (circular arrows) more frequently than male HSCs, and produce more erythroid progenitors, which give rise to red blood cells. Despite this difference, the composition of the male and female bone marrow and spleen remains similar under basal conditions, because in females a higher percentage of erythroid progenitors undergo cell death. During pregnancy, however, oestrogen levels increase, leading to an expansion of the HSC population in the bone marrow and spleen, and more erythroid cells in the spleen. This response seems to play a key part in meeting the haematopoietic demands of pregnant females.

During pregnancy, however, the authors observed a further increase in HSC proliferation, an expansion of the number of HSCs in the bone marrow and spleen, and more erythroid cells in the spleen. Thus, it seems that female HSCs may be 'primed' for the increased demand for blood during pregnancy.

Nakada et al. identify oestrogen as the causal agent for HSC sexual dimorphism (Fig. 1). They find that ovariectomy or pharmacological inhibition of aromatase (an enzyme necessary for oestrogen synthesis) reduced the percentage of proliferating HSCs and MPPs in females, whereas injection of oestradiol (the predominant oestrogen in females) increased HSC proliferation and drove erythropoiesis in normal and ovariectomized females, as well as in males. Although oestradiol injection was recently reported to induce cell proliferation in a subset of bone-marrow cells6, Nakada and colleagues' study extends this observation by showing that physiological levels of oestrogen are sufficient to specifically influence HSCs. The authors also show that Esr1, the gene encoding oestrogen receptor-α (ERα), is highly expressed in HSCs and is necessary for the enhanced proliferation of female HSCs under steady-state conditions and during pregnancy. Furthermore, they find that oestradiol increases proliferation of wild-type HSCs, but not of Esr1-deleted HSCs, strongly suggesting that HSCs respond to oestrogen through ERα.

These findings raise the exciting possibility that the sensing of sex hormones by organs that are not sexually dimorphic may be necessary to orchestrate biological functions such as pregnancy. A key remaining question is whether this oestrogen-induced haematopoietic expansion is necessary for successful pregnancy or for maternal or fetal health. The mechanisms of action and target genes of ERα in HSCs are also not known, and their elucidation will contribute to our understanding of oestrogen-induced HSC proliferation and how it compares with oestrogen-induced responses in other stem cells.

Many genetically modified and naturally occurring mouse strains that have increased HSC proliferation exhibit premature exhaustion of HSC pools7, so it will be interesting to investigate whether females show more HSC depletion than do males over long periods of time. HSCs are relatively quiescent cells, and this state is thought to protect them from the damage caused by cellular respiration and DNA-replication errors. However, it has also been suggested that DNA repair is more effective in cycling HSCs than in quiescent ones8,9. It would be worth testing whether HSCs exhibit sex-specific protection or repair mechanisms that allow female HSCs to sustain increased proliferation. Such exploration could reveal mechanisms by which HSCs might sustain increased proliferation without premature exhaustion or transformation.

Several studies have begun to address the questions of when and how tissue-specific stem cells are mobilized and coordinated by long-range signals in response to the body's systemic needs. Stem-cell function is affected by systemic signals, including those resulting from diet, circadian rhythm, exercise, mating and pregnancy2. During pregnancy, for example, increases in oestrogen and progesterone levels coordinate an expansion of mammary stem cells, which is required for remodelling of the mammary gland3. And increases in the hormone prolactin stimulate the production of pancreatic β-cells10 and the proliferation of neural stem cells4, which may have roles in responding to the increased metabolic load of the pregnant female and in maternal recognition of offspring, respectively. Nakada et al. have now introduced the concept that long-range signals act not only in response to specific systemic needs, but also under basal conditions to keep stem cells in a primed state, ready to act when pregnancy is initiated.

Sexual dimorphism in stem cells is understudied, and many stem-cell studies have been performed on only one sex or analysed without distinguishing between sexes. Nakada and colleagues' work suggests that attention to sex differences will be essential for understanding basic stem-cell biology, diseases associated with stem cells, and regenerative medicine. It is tempting to speculate that the authors' findings could provide explanations for sex differences that are poorly understood. For example, the enhanced engraftment of human HSC transplants in female compared to male mice11 could be attributable to oestrogen. In addition, the slower erosion of telomeres (specific sequences at the ends of chromosomes that shorten with each cell division) observed in human bone-marrow transplants from female donors12 might reflect a greater requirement of female HSCs to guard against exhaustion.

Further studies of sexually dimorphic regulation of stem cells could also provide insight into why some human diseases have a sex bias. Myelodysplastic syndromes and cytopenias, for example, which are characterized by reduced production of mature blood cells, often erythroid cells13, have a higher incidence in men. This bias is interesting in light of Nakada and colleagues' identification of lower basal levels of HSC proliferation and erythropoiesis in male mice. Thus, their study imparts the unexpected lesson that consideration of sex in the context of disease pathogenesis and therapeutics may prove valuable even in diseases of seemingly non-sexually dimorphic organs.

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Correspondence to Anne Brunet.

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Leeman, D., Brunet, A. Sex specificity in the blood. Nature 505, 488–489 (2014). https://doi.org/10.1038/505488a

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