A woman’s bone marrow may determine her ability to start and sustain a pregnancy


A woman’s bone marrow may determine her ability to start and sustain a pregnancy, report Yale researchers in PLOS Biology.

The study shows that when an egg is fertilized, stem cells leave the bone marrow and travel via the bloodstream to the uterus, where they help transform the uterine lining for implantation.

If the lining fails to go through this essential transformation, the embryo cannot implant, and the body terminates the pregnancy.

“We have always known that two kind of things were necessary for pregnancy,” says Dr. Hugh Taylor, senior author and the Anita O’Keeffe Young Professor of Obstetrics, Gynecology, and Reproductive Sciences at Yale.

“You must have ovaries to make eggs, and you must also have a uterus to receive the embryo. But knowing that bone marrow has a significant role is a paradigm shift.”

Previous research has indicated that, in small numbers, bone marrow-derived stem cells contribute to the non-immune environment of the non-pregnant uterus, but it’s remained unknown if and how stem cells affect a pregnant uterus.

In this study, the researchers were able to prove the physiological relevance of stem cells to pregnancy.

“Some of these bone marrow-derived mesenchymal stem cells travel to the uterus and become decidual cells, which are the cells that are essential for the process of implantation and pregnancy maintenance,” explains Dr. Reshef Tal, first author of the study and assistant professor of obstetrics, gynecology and reproductive sciences at Yale.

In two mouse models with the Hoxa11 gene defect, which presents in mice as a defective endometrium, the researchers found that a bone marrow transplant from a healthy donor could improve fertility by promoting sufficient decidualization of the endometrium.

An immunofluorescent section of a pregnant mouse uterus on embryonic day E9.5 showing the distribution of bone marrow-derived cells, labeled with green fluorescent protein (GFP). Cell nuclei are labeled with DAPI (blue). Numerous bone marrow-derived cells are recruited to the pregnant uterus where they contribute to embryo implantation and pregnancy. Credit: Reshef Tal

In mice with only one copy of the defective gene, the transplant saved pregnancies that would otherwise have been lost and increased litter sizes, while in the mice with two bad copies of the gene, which were thus entirely infertile, the transplant caused growth and repair of the defective endometria.

This study was made possible by a methods breakthrough that Tal and Taylor made a few years ago.

For more than two decades, Taylor and his team had been trying to restore fertility in mice with these genetic mutations, but until recently, they didn’t have a form of chemotherapy strong enough to allow an effective bone marrow transplant without killing all the eggs of the mice. (Before a bone marrow transplant, chemotherapy or radiation is used to clear the body of the existing bone marrow, so that the donor bone marrow can take its place.)

“We used an anti-metabolite drug, which is still considered a chemotherapy, but it doesn’t harm the ovary, and therefore the mice are still able to get pregnant, allowing us to track the transplanted bone marrow cells and investigate their role in reproduction,” says Tal.

“We are currently translating these findings into humans to better understand the role that these bone marrow-derived stem cells play in recurrent implantation failure and recurrent pregnancy loss, two conditions that are unexplained in the majority of women and have no effective treatment.”

Though more research is needed prior to clinical trials, Tal and Taylor see hope for the patients they treat for infertility on the clinical side of their practice in this latest advance.

“These are frustrating medical conditions,” says Taylor. “When you have a damaged endometrium leading to infertility or repeated pregnancy loss, all too frequently we have not been able to correct it. Bone marrow can be considered another critical reproductive organ. This finding opens up a new potential avenue for treatment of a condition that has been untreatable in the past.”

The first 1000 days post conception are regarded as a sensitive window of time that can define the childʼs health and in which the risk of later non-transmissible diseases can be modified 1 . The importance of a healthy lifestyle with a balanced diet and exercise in this phase of life is an important building block for the prevention of these diseases and is underlined by, amongst others, the national health goal “Before and after birth” of 2017 2 .

In Germany, about a third of women of childbearing age are overweight or obese 5 . Obesity reduces the likelihood of conception 6 and is associated, amongst others, with a higher risk of pregnancy and birth complications, birth defects, premature births and miscarriages, a high infant birth weight and later obesity of the child 6 ,  7 . In 2014/15 gestational diabetes was diagnosed in 13% of pregnant women during a screening programme 8 . About 11% of mothers of 0- to 6-year-old children reported in the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) that they had smoked during pregnancy 11 . It is estimated that about 0.2 – 8 out of 1000 neonates in Germany are born annually with fetal alcohol syndrome. Far more children are affected by a fetal alcohol spectrum disorder 12 .

A healthy lifestyle prevents risks of pregnancy complications and helps maintain the health of mother and child. In this phase of life in particular expectant parents are often highly motivated to optimise their lifestyle and are receptive to appropriate recommendations. Women and couples wishing to have children are less aware that their lifestyle affects fertility, the course of the pregnancy and also the childʼs later health.

The recommendations of the Healthy Start – Young Family Network (Netzwerk Gesund ins Leben) are intended to help contribute to a health-promoting lifestyle and thus to promote the health of mothers and children and prevent long-term overweight and its associated diseases. In 2012 the Germany-wide Practical Recommendations for Nutrition in Pregnancy of the Healthy Start – Young Family Network were first published 13 . The updated version presented here has been extended to include recommendations covering the period before pregnancy and around the time of conception.

They are intended to provide gynaecologists, midwives, paediatricians and members of other health professions with a basis for counselling a healthy lifestyle.

Healthy Start – Young Family is a network of institutions, learned societies and associations that are concerned with young families. The aim is to provide parents with uniform messages about nutrition and exercise so that they and their children live healthy lives and grow up healthy.

The Healthy Start – Young Family Network is part of the IN FORM initiative and is accommodated in the Federal Centre for Nutrition (BZfE), an institution that comes within the sphere of responsibility of the Federal Ministry of Food and Agriculture (BMEL).

More information: Tal R, Shaikh S, Pallavi P, Tal A, López-Giráldez F, Lyu F, et al. (2019) Adult bone marrow progenitors become decidual cells and contribute to embryo implantation and pregnancy. PLoS Biol 17(9): e3000421. doi.org/10.1371/journal.pbio.3000421

Journal information: PLoS Biology
Provided by Yale University


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