For women and their partners who are trying to conceive, seeing those two lines appear on a positive pregnancy test is a surreal thrill.

The two lines of a positive pregnancy test. Image: Wikipedia.

But for 15 to 25% of known pregnancies, that initial excitement ends in disappointment due to miscarriage, a spontaneous loss of the fetus typically within the first 20 weeks. Even worse, about 1% of women experience three or more consecutive miscarriages, or recurrent pregnancy loss (RPL).

The psychological toll of miscarriage

While the odds are still good that women with RPL will go on to have a successful, full-term pregnancy, the psychological toll of multiple miscarriages can be devastating, leading to clinical depression and extreme anxiety in many. Currently there aren’t definitive ways to predict or treat RPL.

On Monday, UK researchers at the University of Warwick

reported in the journal, Stem Cell, that a lack of stem cells in the uterus may be a culprit in recurring miscarriages.

To carry out their study, the team obtained biopsies of endometrium, the tissue which lines the uterus, from healthy women and those with RPL. In the lab, human endometrial stromal cells (HESC, not to be confused with hESC, or human embryonic stem cells) were isolated from these samples and grown in petri dishes.

The endometrium, the inner cellular lining of the uterus.
Image: Wikimedia commons.

Human endometrial stromal cells (HESCs): a key player in successful pregnancy

So why the focus on HESCs? With each menstrual cycle, mesenchymal stem cells from the blood migrate into the lining of the uterus and give rise to the HESCs which specialize further to rebuild the endometrium. It’s in this tissue that the fertilized embryo implants and is supported as the pregnancy progresses.

Comparing DNA from RPL and non-RPL HESCs, the team identified distinct differences in the patterns of methylation, which is a chemical tag found on DNA that can affect gene activity. In particular, a methylation pattern associated with stem cells was present in the non-RPL HESC DNA but was missing in the RPL HESC DNA. This result suggested a reduction in the number of stem cells in the RPL tissue samples. Sure enough, fewer mesenchymal stem cells were seen in the RPL patient samples compared to non-RPL samples. Additional examination of the RPL samples found that the lack of stem cells was associated with premature aging of the HESC cells which was marked by a loss of cell division and growth.

Reduced stem cells -> Defective uterus cell lining -> multiple miscarriages

Altogether, the lack of stem cells and decreased HESC cell growth in recurring miscarriages points to a scenario in which the embryo is lacking proper support from the endometrial lining of the uterus. Jan Brosens, a professor of obstetrics and gynecology who led the team, summed it up this way in an interview with The Guardian:

Jan Brosens, Professor of Obstetrics & Gynaecology at Warwick Medical School at the University of Warwick

“After an embryo has implanted, the lining of the uterus develops into a specialized structure called the decidua, and this process can be replicated when cells from the uterus are cultured in the lab. Cultured cells from women who had had three or more consecutive miscarriages showed that aging cells in the lining of the womb don’t have the ability to prepare adequately for pregnancy.”

Now the real work begins

The lab is now focused on turning these insights into tangible help for women suffering with RPL:

Siobhan Quenby, Professor of Obstetrics, Siobhan Quenby

“The real challenge now is to develop strategies to increase the function of stem cells in the womb lining”, Siobhan Quenby, a co-author of the study and University of Warwick professor of obstetrics, told The Guardian. “First, we wish to improve the screening of women at risk of recurrent miscarriage by developing new endometrial tests. Second, there are a number of drugs and other interventions, such as endometrial ‘scratch’, a procedure used to help embryos implant more successfully, that have the potential to increase the stem cell populations in the womb lining.”