By Stephanie Agbu

The divide between the sexes is attributed to sex hormones, namely estrogen and testosterone. Both hormones are present in men and women, but testosterone predominates in males while estrogen predominates in females. Several organs in the body contain cells whose behavior is modulated by biological sex. For example, female muscle stem cells were found to regenerate muscle cells more efficiently than their male counterparts in a mouse model of muscular dystrophy. Though sex influences cellular behavior in multiple organs, it is generally assumed that cells within organs devoid of sex-specific function behave similarly in both men and women.

A recent report in Nature challenges this notion. Researchers working in Sean Morrison’s lab at the University of Texas have examined sex-specific differences in cell populations that are seemingly unresponsive to sex hormones. Hematopoietic stem cells (HSCs) were among the first such populations to grab the lab’s attention. HSCs reside in the bone marrow and divide to generate red blood cells, which carry oxygen to tissues throughout the body, and immune cells, which recognize and destroy bacteria, viruses, and parasites. These cells often lie dormant until stimulated to divide by external cues, and, at least until recently, there has been no evidence for sex-related differences in their behavior. Data from the Morrison group suggest that HSC behavior is not uniform between males and females. Though HSC number and frequency were comparable between male and female mice, significantly greater HSC division was observed in female mice. Interestingly, HSC division was induced by administration of estrogen to both male and female mice and this phenomenon did not occur in other bone marrow cell populations or in response to testosterone. HSC number, along with red blood cell and immune cell numbers, were increased in pregnant females compared to non-pregnant females. This effect was abolished when estrogen receptor function was compromised, which led Dr. Morrison’s group to conclude that HSCs respond to estrogen and that estrogen can regulate HSC division to accommodate the increased need for oxygen in pregnant females.

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
Haematopoietic stem cells (HSCs) appear to respond to oestrogen signals, which causes female HSCs to divide more frequently than male HSCs. Image from Leeman and Brunet (2014).

If these data mirror HSC activity in humans, I foresee several implications. First, the ability of HSCs to respond to estrogen may be relevant for women’s health. Estrogen levels in women oscillate each month, and estrogen decreases greatly during menopause. Therefore, reduced estrogen production may decrease HSC divisions, causing the immune system to function less efficiently in older women. Second, there is now the possibility that sex hormones can modulate the onset of blood disorders and other diseases. For example, the article’s commentary notes that cytopenias, diseases in which immune cell numbers are greatly reduced, tend to be more common in men. Thus, reduced HSC proliferation in men might contribute to the persistence of these disorders. Third, sex may be an additional variable to consider in the field of personalized medicine, which involves the administration of therapy tailored to an individual’s genetic makeup. In this case, it will be imperative to note the individual’s sex in order to uncover contributing factors to disease and to predict patient prognosis.

It is remarkable that nature may have designed a system that enables HSCs to divide in response to a sex hormone heavily involved in the reproductive process, and it will be fascinating to discover other stem cell populations that function in a similar fashion. Future discoveries of biological differences between the sexes will deepen our understanding of the mechanisms that cells have adopted to meet the changing needs of organisms. Until then, we will dream of additional subtleties in cell behavior that are yet to be discovered.

The Paper

Nakada, D., Oguro, H., Levi, B. P., Ryan, N., Kitano, A., Saitoh, Y., … Morrison, S. J. (2014). Oestrogen increases haematopoietic stem-cell self-renewal in females and during pregnancy. Nature, 505(7484), 555–558. doi:10.1038/nature12932

Further Reading

Barzi, A., & Sekeres, M. a. (2010). Myelodysplastic syndromes: a practical approach to diagnosis and treatment. Cleveland Clinic Journal of Medicine, 77(1), 37–44. doi:10.3949/ccjm.77a.09069

Deasy, B. M., Lu, A., Tebbets, J. C., Feduska, J. M., Schugar, R. C., Pollett, J. B., … Huard, J. (2007). A role for cell sex in stem cell-mediated skeletal muscle regeneration: female cells have higher muscle regeneration efficiency. The Journal of Cell Biology, 177(1), 73–86. doi:10.1083/jcb.200612094

Leeman, D. S., & Brunet, A. (2014). Stem cells: Sex specificity in the blood. Nature, 505(7484), 488–490. doi:10.1038/505488a

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