Loss of Endometrial Stem Cells Prior To Conception Raises Miscarriage Risk

Loss of Endometrial Stem Cells Prior To Conception Raises Miscarriage Risk
Portrait of a woman in a striped dress holding her pregnancy bump.

A research team at the University of Warwick in the U.K. has discovered that a depletion of highly proliferative mesenchymal stem cells in the womb lining just before conception is linked to pregnancy loss, as these cells seem to play an important role in early implantation and development of the fetus.

These highly proliferative mesenchymal stem cells (hPMC) are normally present at high numbers in the endometrium lining of the womb at the point in the menstrual cycle where conception is possible. The scientists used single cell transcriptomics to analyze gene expression in these cells and found they were involved in chemotaxis, making sure cells get to right place at right time, and vascular transmigration.

“Our findings indicate that hPMC are derived from circulating bone marrow-derived stem cells and recruited into the lining of the womb at the time of embryo implantation. These cells appear critical in pregnancy to accommodate the rapidly growing placenta,” said Jan Brosens, M.D., Ph.D., a professor at the University of Warwick who led the research.

Brosens and colleagues also discovered that hPMC are present in reduced numbers in women who have experienced recurrent pregnancy loss, suggesting a link with miscarriage. “This raises the possibility that they can be harnessed to prevent pregnancy disorders,” said Brosens.

Endometrial tissue changes frequently during a women’s menstrual cycle and even bigger changes are required for a pregnancy to be successful. In the second half of the cycle, the endometrium begins to remodel itself to make a pregnancy possible. This involves endometrial stem cells changing into specialized decidual cells, which can then support the growth and development of a fertilized egg into a fetus.

The hPMC discovered by the researchers are distinct from other endometrial mesenchymal stem cells and are present at the time of implantation. Single cell transcriptomic analysis of these cells suggests that they play a key role in early pregnancy as they also have a ‘clonogenic’ or proliferative function suggesting they help the fetus to develop successfully.

In a sub analysis of biopsies taken from 15 women with recurrent pregnancy loss (defined as three or more miscarriages) compared with 15 controls, the researchers found that women in the control group had much higher numbers of the specific hPMC population than women in the recurrent pregnancy loss group.

“These are very exciting findings. We have already demonstrated that we can increase these highly proliferative cells in the lining of womb before pregnancy. These new findings explain why these highly proliferative cells are so important for the prevention of miscarriage and possibly spontaneous preterm labor, two devasting pregnancy disorders that affect many women and couples all over the world,” commented Siobhan Quenby, M.D., also a professor at the University of Warwick, co-author of the paper describing the research, which is published in the journal STEM CELLS.

The researchers now plan to continue their work in this important area and investigate ways to increase the numbers of these important cells to improve pregnancy outcomes. For example, the drug sitagliptin, used to managed type 2 diabetes, has been shown to boost the endometrium’s ability to produce proliferative cells in a recent pilot trial.

“It is plausible that treatments aimed at enhancing recruitment, engraftment and differentiation of hPMC in the endometrium prior to, or soon after, conception will not only reduce the risk of miscarriage, but also prevent preterm labor in at risk women,” write the authors.

“The efficacy of sitagliptin, and other potential interventions… warrants further evaluation in clinical trials.”