Thursday, March 31, 2016

Uterine stem cells deficiency linked to Recurrent Pregnancy Loss (RPL).



Stem cells have the potential to treat a myriad of diseases and have acted as a powerful tool to treat many life threatening diseases. Researchers have opened up a new avenue in stem cell therapy by tying stem cell deficiency in endometrium to recurrent pregnancy loss.

According to a recent paper published in February issue of Stem cells by Lucas E S et al researchers postulated that stem cell deficiency in the endometrial tissue and accelerated stromal aging is responsible for RPL by limiting the endometrial capacity to decidualize. Most miscarriages are sporadic and are due to chromosomal aberration in the conceptus, but RPL is a distinct entity.  In about 50% of RPL, the etiology is not defined. It is estimated that roughly 5% of women suffer from 2 clinical miscarriage and 1% ending up with 3 or more losses. While many factors seems to play role in RPL, the underlying endometrial pathology is not yet explored.

It is indicated that RPL is associated with impaired differentiation of endometrial stromal cells (HESCs) into specialized decidual cells. The differentiation termed as decidualization, predicts the end of implantation window and confers endometrium the ability to recognize, respond to and eliminate implanting compromised embryos, theory of natural selection. The theory suggests that it is the response of the decidualized endometrium to embryonic signals, which decides the future implantation and development of the  embryo or its rapid demise through menstruation-like shedding. Current evidence suggests that it is the abnormal decidualization which causes the loss of selectivity leading to implantation without further progress leading to pregnancy loss. So, the endometrium acts as a ‘biosensor’ detecting the embryo derived signal and deciding the fate of the embryo.

It is already known that decidualization of the endometrium in not dependent on embryo. It happens in post ovulatory phase of every cycle due to increase in progesterone levels and cAMP. It is because of cyclic activation of mesenchymal stem cells which differentiate into stromal cells in regenerating endometrium.

The authors hypothesized that defect in cyclic regeneration of endometrium in RPL patients is impacted due to defect in DNA methylation status of human endometrial stromal cells (HESCs).

A total of 183 endometrial biopsies were taken from patients with  normal women and those with RPL, except 8 random samples, all other were timed between 6 and 10 days after the preovulatory luteinizing hormone surge.  HESCs were isolated from the samples and cultured in laboratory. They were further tested for epigenetic markers for recurrent pregnancy loss.

It was seen that endometrial lining in patients with RPL showed loss of plasticity, with included increased senescence, deficiency and limited capacity to differentiate. Epigentic signature was lacking in women who experienced RPL as compared to their normal counterparts.

The endometrium also had decreased number of stem cells that had limited capacity to renew the endometrium, resulting in aging. Aging cells mount an inflammatory response that is enough for implantation but not for development and sustaining the embryo.

In an interview with medscape  Dr. Brosens said “"We also found that the greater the number of miscarriages a woman had experienced...the more depleted the lining was."

"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," Dr. Brosens notes.

He futher explained hat medicine usually regards recurrent miscarriage as being associated with an underlying disease, and normal practice is to investigate clotting abnormalities, hormonal imbalances, or immune responses. In the United States, patients are referred to specialist care after two consecutive losses; patients are referred after three losses in the United Kingdom. "It is often stated that a cause for recurrent miscarriage can be found in 50% of patients. However, for every woman with an apparent known 'cause' of miscarriage, there will be 50 to 100 women who have the same disorder but do not experience miscarriage. So current tests completely lack specificity."

With sporadic miscarriages, the majorities are caused by chromosomal abnormalities in the fetus, but with recurrent miscarriages, the majority involves normal fetuses. The more miscarriages a woman has, the greater the likelihood pregnancy loss involves a fetus with normal chromosomes. "Also, as the number of miscarriages increases, there is a higher chance of recurrent miscarriage," Dr. Brosens added.

According to Dr. Brosens, the real challenge lies in translating these findings into something clinically meaningful. He believes that this could further lead to development of some sort of screening tests, eventually ending up with some sort of treatment for women at risk. "The abnormalities we have identified all precede pregnancy, so it is possible to test the uterine lining for these markers and help predict if a patient is at risk of recurrent miscarriages."

He also pointed that stem cells in the uterine lining were highly dynamic and active pool, that are undergoing  cyclic shedding and regeneration, so intermittently the defects in the uterine lining could undergo self-repair, changing from an unsupportive environment to a supportive one. This explains why many women have a successful pregnancy even after recurrent miscarriages.

The authors concluded that “These findings open up new avenues to screen women prior to pregnancy for the risk of miscarriage and point to the potential of cell-based therapies in the prevention of RPL.”



References:
Lucas, E. S., Dyer, N. P., Murakami, K., Hou Lee, Y., Chan, Y.-W., Grimaldi, G., Muter, J., Brighton, P. J., Moore, J. D., Patel, G., Chan, J. K.Y., Takeda, S., Lam, E. W.-F., Quenby, S., Ott, S. and Brosens, J. J. (2016), Loss of Endometrial Plasticity in Recurrent Pregnancy Loss. STEM CELLS, 34: 346–356. doi: 10.1002/stem.2222
http://www.ncbi.nlm.nih.gov/pubmed/20847090


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