The Third Reproductive Organ: Yale Study Reveals the Important of Bone Marrow in Successful Pregnancies

Mouse models are valuable tools for Alzheimer’s researchers. In this study, the Alzheimer’s mice harbored the APP gene, which causes plaque buildup in the brain. Image courtesy of Daniel Wesson.

What if some infertility problems are not just issues with the ovaries or uterus? After decades of groundbreaking research, Yale doctors Hugh S. Taylor and Reshef Tal have discovered that bone marrow might play a part in the success of pregnancy.

The first indication that bone marrow plays a role in uterine function came from studies of the uterine wall’s ability to regenerate as it does with every menstrual cycle or after an injury. Taylor—the Anita O’Keeffe Young Professor of Obstetrics, Gynecology, and Reproductive Services and Chair of the Department of Obstetrics Gynecology and Reproductive Sciences at Yale School of Medicine—studied women who received bone marrow transplants as a treatment for leukemia. Bone marrow contains stem cells that are capable of becoming many other types of cells.  Taylor found that some of the transplanted stem cells ended up repairing uterine injury.

However, the functional role of stem cells during pregnancy as opposed to uterine injury was only speculative until this latest research in mice. It involved a genetic mutation called HoxA11 which causes an unhealthy and defective uterine lining and thus difficulty achieving pregnancy. In order to perform a bone marrow transplant to study the effects of healthy bone marrow on pregnancy, the defective bone marrow first had to be eliminated using chemotherapy. However, the chemotherapy necessary to eliminate bone marrow would also kill the mouse’s eggs in the process, making them the animals sterile.

Reshef Tal, Assistant Professor of Obstetrics and Gynecology and Reproductive Sciences, was influential in overcoming this obstacle. He used five fluorouracil (5FU), a cancer chemotherapy that leaves eggs intact. Taylor, Tal, and the rest of the research team were thus able to study how mice with the HoxA11 genetic mutation responded to healthy bone marrow transplants They were successful. In mice with two copies of the defective HoxA11 gene, the healthy bone marrow transplants helped promote uterine function. They aided in the creation of uterine glands, the enlargement of the uterus, and embryo implantation (although these mice were ultimately unable to carry a pregnancy to term). In mice with only one copy of the defective HoxA11 gene, the transplants allowed these mice to carry and give birth to offspring that would otherwise have been miscarried.

“It really showed that the bone marrow played a crucial functional role in the uterus and in pregnancy by assisting with implantation and maintaining pregnancy,” Taylor said. “Now we’re starting to think…could it be that some infertility problems, cases of miscarriage or pregnancy loss, are really bone marrow problems and not a reproductive tract problem at all? This may be a problem where they can’t make the right bone marrow cells, or they can’t mobilize them, or they can’t recruit them to the uterus, or they can’t graft properly,” Taylor added.

Taylor considers this research to be a “Yale success story,” crediting Tal, the entire research team, and the pioneering work of Diane Krauss, who did early work on bone marrow-derived stem cells, in the discovery.

“Bone marrow really is the missing link…the third reproductive organ,” Taylor said. This new understanding has opened doors to more research and possible clinical applications of anti-metabolite chemotherapy for fertility treatment. Next steps include developing a deeper understanding of stem cell differentiation and its specific applications in the uterus, and applying their findings to women to see which human reproductive issues can be solved through healthy bone marrow transplants.