Researchers have another answer to the question of how females can generate so much blood—enough for two blood systems—during pregnancy.

The answer is stem cells, as is so often the case lately when a question has something to do with underlying biological mechanisms. Hematopoietic (blood) stem cells (HSCs) proliferate more frequently in females than males because their stem cells are highly sensitive to estrogen, according to a new study in Nature.

The work was done in mice, but it is likely to apply to humans.

“It surprised us that tissue stem cells such as HSCs which don’t have obvious sexual dimorphism have sex differences in their regulation,” lead author Daisuke Nakada of the University of Texas Southwestern Medical Center tells Bioscience Technology. “Another surprise was that HSC function is finely integrated into animal physiology and responds rapidly to changes in animal physiology, such as pregnancy.”

The findings are leading the crew to look further into female ovulatory cycles.

“We predict that HSC cycle should increase at phases when estrogen concentration rises,” she says. Given that many blood cancers are thought to arise from HSCs, the research may impact oncology. “It is not clear yet whether we can draw a link between increased HSC division by estrogen in females and the chance of getting blood cancer,” she says. But the team is looking into it.

Sean J. Morrison, Ph.D.

The crew was led by Sean Morrison, director of the university’s Children’s Medical Center Research Institute. In prepared statements, he noted that the discovery explains how red blood cell production is augmented during pregnancy. "Elevated estrogen levels that are sustained during pregnancy induce stem cell mobilization and red cell production in the spleen, which serves as a reserve site for additional red blood cell production."

It has long been known that sex hormones affect tissues—and thus, their tissue-specific stem cells—displaying sex-specific morphological differences. Estrogen and progesterone affect breast stem cells.  Testosterone impacts testicular germ stem cells. In the brain, aging differentially affects the neurogenic properties of male and female neural stem cells in part due to the way they differently respond to estrogen. Estrogen is required for female brain development.

The blood-forming system was thought to be similar between the sexes. But that system is regulated by sex hormones very differently, the Texas team discovered, with estrogen in particular initiating robust proliferation of blood stem cells. The team found that the stem cells were controlled by both systemic hormonal signals and local blood system changes.

Specifically, the team found that estradiol, a form of estrogen produced in the ovaries, caused stem cells to divide faster after administration to both male and female mice. Increased estrogen levels in pregnant mice resulted in a hike in blood stem cell frequency, division, cellularity, and erythropoiesis in the spleen.

The team further discovered that blood stem cells express high levels of estrogen receptor-alpha. When the team blocked that receptor, blood stem cell proliferation decreased in females, not males. In pregnant mice, blocking the receptor reduced hikes in blood stem cell proliferation, frequency, and erythropoiesis.

As noted, many blood cancers contain blood cancer stem cells, particularly virulent cells thought to be the initiators of many cancers. Furthermore, many cancers, from solid tumor cancers to blood cancers, are treated with blood stem cell transplants. If the Nature study’s animal results are repeated in humans, the new knowledge that females’ blood stem cells react differently to estrogen may well impact many different kinds of cancer therapies.

It could also impact how other kinds of blood disorders are treated.

“Can we promote regeneration in the blood-forming system by administering estrogen?” Morrison asked. “Can we reduce the toxicity of chemotherapy to the blood-forming system by taking into account estrogen levels in female patients? Does estrogen promote the growth of some blood cancers? There are numerous clinical opportunities to pursue.”