Can ovarian stem cell technology replenish ovarian reserve?
July 3, 2012Carole 8 Comments »The short answer to the title question is, that Yes!, we are getting considerably closer to achieving therapeutic applications of stem cell technology to replenish ovarian reserve. Dr. Jonathan Tilly and his colleague Dr. Dori Woods recently summarized the dramatic advances in ovarian stem cell technology in their paper “The next (re) generation of ovarian biology and fertility in women: is current science tomorrow’s practice?”
What are stem cells? Stem cells are rare cells that have the capacity to produce more cells identical to themselves. Some of these clones become dedicated to a particular cell type and others remain as stem cells to continually replenish this “starter” population of cells. In a previous blog post, Rejuvenating gonads with stem cells, I discussed Jonathon Tilly’s landmark studies which showed that mouse ovarian stem cells exist well into adulthood. His work was met, as he himself put it, with “considerable skepticism” at first because it upset the accepted dogma that all eggs a female will ever have are present at birth. His work has now been validated by numerous other investigators. In fact, in the mouse model, stem cells recovered from adult mice have been grown in culture for months as cell lines and under in vitro conditions have produced follicles and eggs in culture. Furthermore, the transplantation of these stem cells to recipient mice also results in the in vivo production of oocytes in mice.
Of course, that’s all well and good for mice, but what about humans? Do adult women have these persistant stem cells in their ovaries and do they still have the capacity to produce eggs well into adulthood? Dr. Tilly and his colleagues recently reported that reproductive age women in their 20′s and early 30′s still retain this rare population of stem cells within their ovaries. Stem cells isolated from human ovarian tissue can be grown in culture and produce oocytes in vitro. Furthermore, human ovarian stem cells can be injected into human ovarian substrate tissue and follicles begin to grow in this tissue and produce human eggs when the tissue is transplanted into mice hosts. These studies proved two very important points: first, that reproductive age women have persistent ovarian stem cells and second, these stem cells retain the capacity in adulthood to undergo the process of follicle formation (folliculogenesis) and produce eggs both in vitro and also when transplanted into a host model.
It is important to note that the stem cells used in these studies are ovarian stem cells, not embryonic stem cells. In theory, embryonic stem cells could also be used to produce oocytes but in practice, it has been much more difficult and to date impossible to create a fertilizable oocyte starting with an embryonic stem cell. The developmental road from embryonic stem cell to ovarian stem cell and then to follicle containing an oocyte is even less understood and requires, obviously, more steps. This makes the identification of ovarian stem cells so important and since these ovarian stem cells are recovered from adults, not embryos, the ethical issues associated with embryo use are bypassed.
The next step to advance the ultimate goal of reproductive therapies is to develop reliable in vitro culture systems that take the ovarian stem cell all the way from stem cell to oocyte, without the use of an animal host. Interestingly, there have been promising results with in vitro culture of primordial (early stage) follicles recovered from ovarian tissue which when cultured for a period of months can produce mature follicles containing oocytes. Since isolated ovarian stem cells can produce a primordial follicle, the starting point for the culture system, Tilly and his group would propose combining these two methods (isolation of ovarian stem cells and effective primordial follicle culture) to create the whole culture path.
Tilly envisions several possibilities for future clinical use of ovarian stem cells including:
1. Recovery of human ovarian stem cells for cryopreservation for future use (delay reproduction).
2. In vitro maturation of ovarian stem cells to produce plentiful oocytes for IVF.
3. isolation of ovarian stem cells opens the possibility of introducing bioenergetic enhancers to ovarian stem cells (for example, mitochondrial injection) to improve egg quality. Using donor mitochondria to enhance egg quality has been used with success in studies in which cytoplasm containing “donor” mitochondria from younger women were injected into the eggs of older women, resulting in improved pregnancy rates. These studies were halted by the FDA in 2002 because mitochondria contain DNA from the donor ( a third party) which persisted in the embryo and so represented a “form of genetic manipulation of human germ cells for the purpose of reproduction”. Tilly suggests that a patient’s own ovarian stem cells could be expanded and provide a source of mitochondria for use in “boosting” egg quality that would not involve the use of foreign DNA. Dr. Tilly has coined the term AUGMENT For this strategy which stands for “AUtologous Germline Mitochondrial ENergy Transfer”.
4. Ovarian stem cells could be isolated from a patient, grown in culture and expanded in number, then reintroduced to the patient to increase oocyte numbers to restore or enhance natural fertility.
5. In vitro culture and expansion of ovarian stem cells provides a culture model for identifying other regulators/inducers of ovarian stem cells that could be reintroduced to a patient with reduced ovarian reserve to stimulate their own ovarian stem cells to replenish their ovarian reserve.
In spite of the amazing clinical potential of ovarian stem cells, the routine use of ovarian stem cells to treat problems with egg quality and quantity is still years away, even in the estimation of the enthusiastic Dr. Tilly. The possibilities for new treatments are there but whether as a society, we will support the research and clinical studies necessary to prove their safety and efficacy is not entirely clear. Stay tuned.
References:
The next (re)generation of ovarian biology and fertility in women:is current science tomorrow’s practice? by Dori C Woods PhD and Jonathon L. Tilly PhD, published in Fertility and Sterility. vol 98. no 1. July 2012 pp 3-10
© 2012, Carole. All rights reserved.
July 8th, 2012 at 6:52 am
Thank you Drs. Woods and Tilly, for doing this research. Scientific community – please support getting this research to clinical application. So many people are hurting because of infertility, this research could really make a difference.
September 27th, 2012 at 11:45 am
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November 8th, 2012 at 6:13 pm
Did they look for stem cells in women older than 30?
November 8th, 2012 at 8:26 pm
Hi A,
In the full length paper, the authors (Woods and Tilly) describe finding similar ovarian stem cells in older women-older meaning in their 30s, 40s, and 50s who were undergoing ovarian removal for benign reasons. Also at the recent ASRM meeting, it was discussed that stem cells have been found in post-menopausal women. Finding stem cells proves it is possible but validating the safety and efficacy of stem cell rejuvenation will take much more research. Check out the work of Ovascience http://www.ovascience.com/ This company, founded by Tilly among others, is working on using stem cells as a source of mitochondria (cellular organelles that power cells) which can be amplified by invitro culture and used as an “egg stimulant” of sorts at the time of ICSI. See more about the technology here http://www.ovascience.com/technology/ I believe they are gearing up to do clinical trials. Best wishes, Carole
November 11th, 2012 at 11:20 pm
If Ovascience is in the midst or on the cusp of starting trials for Augment does that mean that this may be an available treatment next year (per their website)? Or are the trials just that, and it may really be a few years before Augment could be available? Also, their trial was for women between 38 – 42, does that mean that Augment will be for that age group? Or will it be a fit for the 42+ crowd.
November 12th, 2012 at 8:08 am
Hi LuLu,
If Augment were a drug, it would have to be approved by the FDA after the clinical trials were completed and before it could be sold to the public. Augment is a treatment, a procedure, a process so I honestly don’t know what approval hurdles apply–I don’t know if the FDA will weigh in here with an approval. I suspect the bar is lower for approving what physicians can offer their patients in terms of procedures but I really don’t know. I would refer your questions to the contact person at Ovascience because I am sure they know how and when they can offer this treatment legally-assuming that it is shown to be effective and safe in their clinical trials. Good Luck! Carole
November 15th, 2012 at 9:43 am
Carole:
Thank you for your response. One additional question. If Augment becomes available, to the best of your knowledge, how much does this treamtment change the age factor for women pursing ivf over 40? Their website discusses how the mitochondria boosts embryos that seem to stall, but I haven’t see them address the issue if that eggs over 40 – mid 40 have fundamental chromosonal issues, will a mitochonrial boost mitigate this? I am not a dr. or technical, just a long time ivf patient. I just can’t tell if, asumming by 44 most eggs are chromosonally compromised, this treatment (Augment) would change anything, or if this is intended to get chromosonaly eggs that are “tired” (for lack of a better word) a jump start to get to the next stage where they should continue to grow, where otherwise they wouldn’t. I know their site discusses using stem cells to make new eggs which would seem to take the chromosonal issue out, but I suspect that is a few years out and their site talks of the Augment treatment being available possibly next year.
Thank you. Sorry this seems long.
November 15th, 2012 at 10:20 am
Hi LuLu,
If an egg is chromosomally abnormal, the Augment treatment will not fix it. But by restoring the power source to the egg, it might be able to have the egg function more normally as an embryo when it also has to expand its DNA and divide the cell. Some of these chromosomal abnormalities arise later as the embryo goes about its business of dividing so some of these post-fertilization errors might be avoided. But except for that small possible overlap, the two problems (aneuploidy and suboptimal mitochondria) are two separate issues. You are also correct that using stem cells as pre-cursor cell for producing “fresh” eggs in vitro is further down the pipeline. The Augment approach is to use stem cells as a source of mitochondria that can be amplified and “harvested” to get a patient-specific supply of supplemental mitochondria for the patients own eggs. Hope this helps. Best wishes, Carole