Embryo implantation in the uterus: the role of bone marrow in implantation failures

For a pregnancy to begin, a sperm must meet an egg, fertilization must occur, and, once in the uterus, the resulting blastocyst must implant (nest) in the uterine wall. If one of these stages is not possible or is hindered, the pregnancy will not start or will not continue.

The conditions that favor or prevent the implantation of the blastocyst in the uterus are not fully known, and many of the implantation failures that occur after a natural conception or after an assisted fertilization treatment still fall into the field of unexplained infertility.

Research in recent years has focused on shedding light on one of the most important and fascinating mechanisms of pregnancy and on the causes that can prevent implantation.

In particular, a very recent study has shown that when an oocyte is fertilized, bone marrow stem cells are recalled and recruited from the uterus, in order to prepare a favorable environment for the implantation of the embryo .

The role of the bone marrow in the implantation of the embryo in the uterus

Research published in September 2019 in the journal PLOS Biology highlighted how bone marrow-derived cells play a role in changes in the mouse uterus before and during pregnancy, allowing for implantation of the embryo and reducing miscarriages. Although the study was conducted in mice, a dysfunction in this mechanism is thought to contribute to implantation failure and pregnancy loss in women as well.

Bone marrow stem cells can become blood or tissue cells. It was already known that they differentiate into endometrial tissue cells in the uterus, but until now it was not known whether they also had a specific function during pregnancy.

Authors of the study, Reshef Tal and colleagues at the Yale School of Medicine developed a bone marrow transplant protocol that preserved ovarian and reproductive function by allowing them for the first time to track these marrow cells during pregnancy. The authors demonstrated that after reaching the uterus, marrow stem cells proliferate and become so-called decidua cells , specialized uterine cells that are critical to nourishing the embryo and supporting its implantation.

The role of the Hoxa11 protein in mice

In their research, the authors used female mice lacking Hoxa11, a protein found in cells of the uterus but also in bone marrow-derived cells; these mice are known to have defects in the lining of the uterus and are unable to become pregnant.

Partially Hoxa11-deficient female mice can become pregnant but have recurrent miscarriages. The authors found that after receiving bone marrow transplants from healthy mice, the Hoxa11-deficient mice turned on genes involved in preparing the uterine lining for pregnancy and became pregnant. In mice with partial Hoxa11 deficiency, transplantation of bone marrow from healthy mice prevented pregnancy loss and allowed for a normal number of offspring.

The role of Hoxa 11 in women

Unexplained recurrent miscarriages occur in 1-2% of couples. Hoxa11 production has been related to implantation in the uterus and several studies have shown that Hoxa11 protein levels are lower in infertile conditions such as endometriosis, submucous fibroids and recurrent miscarriages.

The study results unveiled a critical role of stem cells from bone marrow and suggest further research to investigate the role of these cells in human implantation and pregnancy.

“ The common thought about bone marrow, when it is related to pregnancy ” the authors explained, “ is that it is only involved in the production of immune cells that play fundamental roles in the maternal-fetal interface to allow pregnancy to take place. This study shows for the first time that adult bone marrow is also a source of non-immune cells for the uterus, which become decidua cells .”

“ We are currently translating these findings to humans to better understand the role these cells play in recurrent implantation failure and recurrent pregnancy loss , two conditions that go unexplained in the majority of cases, and yet have no effective treatment.” . The findings of this study open up exciting new avenues for researching the causes of these conditions and developing new treatments for women who suffer from them . ”