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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