Future Therapies?: Endometrial reconstruction from stem cells.

In my last Q from U post, I answered a patient’s question about how significant a factor “thin” endometrium was in hindering embryo implantation. As a rule of thumb, the endometrium must regenerate after menses to at least 7mm thickness (in excess of 9 mm is preferred) in order to provide an optimal implantation site for the hatching embryo. For a frozen embryo transfer cycle, estrogen is given for more than a week  to stimulate the endometrium to grow in preparation for the embryo transfer procedure. The increasing thickness of the endometrium is monitored by ultrasound in the physician’s office to determine when the endometrium is “ready” for a transfer. To date, there is little to be done if the lining refuses to grow and the pregnancy rate is usually poor with a thin endometrium. An inadequate uterine lining can also result from a medical condition called Asherman’s Syndrome in which the uterine lining does not regenerate normally without scarring, but instead forms scars and fibrous tissue which is not hospitable to embryo implantation. Understanding how stem cells give rise to normal uterine tissue may be the key to future treatments for these infertility-causing conditions.

The July issue of Fertility and Sterility takes up the topic of regenerative medicine, a term for a new field of medicine that uses stem cells to repair or reconstruct damaged or missing organs. Generally speaking, stem cells are “starter” cells, similar to the starter yeast cells that “seed” the population of cells that form the active yeast culture when you make bread. Some of the cells that originate from a stem cell differentiate or become specific to their task and others return to the stem cell population, much as you might take some of the starter yeast and put it back in the fridge so that you can make more bread tomorrow.

The human embryo is made up of these starter “stem” cells. If you remove the inner cell mass of an embryo after about five days post fertilization, you have a population of cells that are all stem cells and will give rise to all the different tissue types and organs in the human body. If these cells are disaggregated, specific cell lines can be produced that are identical and can be induced to have the same “mission” or function– to be a nerve cell–or a uterine cell-  for example. Even long past the embryonic stage, some of our cells still enjoy this regenerative capacity. For instance the cells that line the inside of your mouth or that form the outside layer of your skin are constantly being replaced by newer cells that arise from residual stem cells that reside in the deeper cell layers.

Stem cells can be identified in a population of cells or in prepared tissue sections by specific “markers’ that they produce, perhaps a specific protein molecule. These markers have shown that the human uterine endometrium, the layer of cells that line the uterus, also have stem cells and these are most likely responsible for allowing the lining to regenerate monthly after the top layer is lost through menstruation. Furthermore, evidence suggests that the absence or scarcity of functional stem cells may explain why some infertile women have a “thin”endometrium that can’t adequately support embryo implantation. It might also explain the inability of the lining to regenerate normal epithelium in Asherman’s syndrome, creating large areas of scar tissue that also can’t support implantation.

Trauma to the uterine lining can occur from curettage (scraping) of the uterine lining to treat excessive postpartum bleeding or after a spontaneous miscarriage.  The uterine lining normally regenerates in response to trauma. Increasingly, the scientific evidence suggests that normal regeneration is due to stem cells and thus, regeneration may fail if there are insufficient functional stem cells to initiate recovery. Some studies in the literature suggest that slight damage to the lining may actually stimulate quiet stem cells into more aggressive proliferation to restore the normal endometrium.

Cells derived from human endometrium (both epithelial and underlying stromal cells) have been cultured in vitro and have responded like stem cells, namely giving rise to colonies of identical cells that can differentiate into specialized uterine cells with specific functions. In mouse studies, human donor uterine stem cells were transplanted into a mouse and proceeded to grow and function like uterine cells, producing a reconstructed human endometrium which cycled in response to hormones and bled. This study demonstrated that adult human stem cells could be isolated, cultured, transplanted and could survive and thrive after transplantation. Although encouraging, these mouse studies are the first baby steps toward using donor stem cells to treat insufficient normal uterine lining cells in human patients.

In theory, embryonic stem cells recovered from excess IVF embryos could be induced to produce uterine endometrium for clinical applications but work with embryonic stem cells has proceeded with extreme caution.  This cautious approach is not just due to the ethical concerns regarding using human embryos for medical applications or research, but also because embryonic cells if not completely understood, could transform into undesirable cell types, such as tumors. Because of this caution, the FDA has only approved two applications of human embryonic stem cell derived clinical treatments, neither of which has been for reproductive medicine. In theory, use of a patient’s own stem cells, expanded in vitro and then returned to the patient may ultimately be the safest and ethically simplest approach, but autologous cell therapies are years away from clinical testing, much less routine implementation. Interestingly, menstrual blood has been shown to be another source of mesenchymal/stromal cells (MSC) which form the bottom layer of the endometrial lining. These MSC cells, mixed with epithelial stem cells has been proposed by some as a mixture that could be used  in the  future to clinically restore or regenerate thin or insufficient endometrium.

The bone marrow is another rich source of all kinds of stem cells. In one case study, a mixture of fibroblast, MSC and epithelial stem cells were  recovered from a patient’s bone marrow and this mixture was returned to the uterine cavity of the same patient who suffered from a thin dysfunctional endometrium that failed to respond to estrogen. High doses of estrogen were given to the patient to stimulate the growth of stem cell-induced endometrium during four artificial cycles and then a clinical pregnancy was achieved for this patient using in vitro fertilization and embryo transfer. Unfortunately, the case report did not discuss whether the patient gave birth and only followed the patient to 8 weeks of pregnancy. The original article can be read here. Although an exciting case study, this is a single report and much more rigorous scientific research is needed to repeat this clinical experiment and show that these results are repeatable and due to the infusion of stem cells.

In summary, continuing research to advance our understanding of how stem cells work is exceedingly important and may eventually provide clinical treatments that can restore reproductive function for infertility patients with inadequate endometrium.

 

Reference:

Endometrial reconstruction from stem cells. Caroline E Gargett, PhD and Louie Ye, PhD. Fertility and Sterility. Vol. 98. No 1. July 2012. pp 11-20.

© 2012, Carole. All rights reserved.

©2012 Fertility Lab Insider. All Rights Reserved.

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