|Year : 2019 | Volume
| Issue : 2 | Page : 53-56
Fertility preservation for female cancer patients by manipulating ovarian stem cells that survive oncotherapy
Stem Cell Biology Department, ICMR-National Institute for Research in Reproductive Health, Mumbai, Maharashtra, India
|Date of Submission||11-Jun-2019|
|Date of Acceptance||15-Oct-2019|
|Date of Web Publication||31-Jan-2020|
Prof. Deepa Bhartiya
Stem Cell Biology Department, ICMR.National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
Infertility and premature ovarian failure are unwanted side effects of oncotherapy in females; however, a large number of patients survive cancer due to recent advances in their management. One of the available options to restore fertility in cancer survivors is to transplant ovarian cortical tissue slices at orthotopic sites which has resulted in the birth of 130 babies. Spontaneous pregnancies have also been reported after heterotopic transplantation of cortical tissue slices which can only be explained by the presence of stem cells and paracrine support provided by transplanted ovarian slices to the nonfunctional ovary. The ovary harbors two populations of stem cells, including very small embryonic-like stem cells (VSELs) and slightly bigger ovarian stem cells (OSCs) that divide and undergo clonal expansion to form germ cell nests in adult ovary before undergoing neo-oogenesis and primordial follicle assembly. Being relatively quiescent, VSELs survive oncotherapy and can regenerate the nonfunctional ovary. Stem cells niche gets affected by oncotherapy and transplanting autologous bone marrow mesenchymal stem cells (MSCs, which provide paracrine support) have shown to normalize ovarian function in rodents with the birth of healthy pups. Similarly, transplanting of autologous MSCs in human ovary with premature ovarian failure resulted in the birth of a baby. These advances in the field of OSCs need to be put in proper context before considering making transplantation of ovarian cortical tissue at orthotopic sites as method of standard care. Transplanting autologous MSCs is safe, and efficacy to regenerate nonfunctional ovaries needs to be evaluated in clinical settings.
Keywords: Cancer, fertility, mesenchymal cells, ovary, stem cells, transplantation
|How to cite this article:|
Bhartiya D. Fertility preservation for female cancer patients by manipulating ovarian stem cells that survive oncotherapy. Onco Fertil J 2019;2:53-6
|How to cite this URL:|
Bhartiya D. Fertility preservation for female cancer patients by manipulating ovarian stem cells that survive oncotherapy. Onco Fertil J [serial online] 2019 [cited 2020 Apr 8];2:53-6. Available from: http://www.tofjonline.org/text.asp?2019/2/2/53/277439
Females suffering from cancer have several options available for fertility preservation since cancer therapy (depending on the dose and type of treatment) has adverse effects on the ovaries (supposedly full of life-time supply of follicles), resulting in premature ovarian failure (POF) and infertility. Women can be treated with gonadotropin-releasing hormone agonists to suppress the ovaries before oncotherapy or the ovaries can be shielded and removed from the field of radiotherapy to protect them from the harmful effects. Besides the females can be treated with pituitary gonadotropin (follicle-stimulating hormone [FSH]) to stimulate their ovaries and oocytes can be cryopreserved or fertilized to preserve embryos if they are married before oncotherapy. However, such options are not available for young girls where cryopreservation of ovarian cortical tissues slices is the only option. In general, one whole ovary is removed, and cortical tissue slices are cryopreserved as a source of oocytes for future use to achieve biological parenthood.
When required, the cryopreserved cortical tissue slices are thawed and transplanted at orthotopic sites on the surface of the nonfunctional ovary or in the abdominal wall, whereby the follicles mature, and oocytes could be retrieved/fertilized to achieve pregnancy. This process has resulted in the birth of 130 babies till date. Fertility experts are now hoping to label this strategy as a method of standard care; however, it remains experimental till now. There exists a lack of clarity regarding the source of oocytes after orthotopic transplantation – it is almost impossible to tell whether the follicles are from the transplanted cortical tissue slices or from the intact, nonfunctional ovary.
Live births have also been reported after transplantation of cortical tissues at the heterotopic site which resulted in 4 spontaneous pregnancies and 3 live births. The mechanism, resulting in pregnancies after heterotopic transplantation needs to be better understood. Oktay had earlier discussed a possible stem cell connection, paracrine-endocrine signals from the transplanted slices reach the damaged ovary through circulation and induce generation of oocytes from the resident stem cells in the nonfunctional, menopausal intact ovary. Kim discussed the strategy of transplanting ovarian tissue at heterotopic site and 100% return of ovarian function in all the five patients studied by their group.
The strategy of obtaining live births by transplanting cortical tissue slices needs to be also understood taking in account the recent advances that ovary harbors stem cells in the surface epithelium, which possibly result in neo-oogenesis and primordial follicle (PF) assembly continuously throughout reproductive phase of life similar to spermatogenesis in the testes. Virant-Klun's group reported stem cells with embryonic characteristics in human ovaries (20 postmenopausal and 5 women with POF) with no naturally present follicles/oocytes which differentiated in culture into oocytes of about >95 μm diameter and into parthenotes., Two distinct types of stem cells are clearly visualized on scraping OSE cells in a dish, including small-sized, spherical very small embryonic-like stem cells (VSELs) with high nucleo-cytoplasmic ratio, and ovarian stem cells (OSCs) which are slightly bigger in size and have more cytoplasm. VSELs undergo rare self-renewal and give rise to the OSCs by undergoing asymmetrical cell divisions and the OSCs in turn undergo symmetrical cell divisions and form germ cell nests.,, Patel et al. provided first in situ evidence supporting neo-oogenesis and PF assembly in adult sheep ovaries. Recently, Virant-Klun showed that the eggs that develop in vitro on culture of OSCs on fertilization show cortical reaction.
Unlike embryonic and induced pluripotent stem cells, VSELs do not grow teratomas in vivo and do not proliferate in vitro if cultured without feeder-layer support. However, they differentiate into three germ layers and into germ cells under appropriate conditions., VSELs are relatively quiescent, remain in G0 phase of cell cycle and as a result survive oncotherapy which otherwise targets actively dividing cells., Similarly, VSELs survive chemotherapy in mouse testis, and were also detected in azoospermic testicular biopsies of adult men survivors of childhood cancers. VSELs are developmentally equivalent to the primordial germ cells (PGCs) which survive in few numbers throughout life in adult tissues and serve as a backup pool of stem cells to give rise to tissue-specific progenitors. The mechanism underlying their quiescence has been studies and reported by Ratajczak's group., Like the PGCs, VSELs show bilateral erasure of imprinted genes, including the Igf2-H19 locus on both the chromosomes which leads to downregulation of Igf2 (autocrine/paracrine mitogen) and upregulation of H19 (gives rise to noncoding mRNA that is a precursor of several microRNAs that negatively affect cell proliferation) expression.
It is very likely that the VSELs in nonfunctional ovaries become functional in the presence of improved paracrine support provided by the transplanted cortical tissue slices to undergo PF assembly and the oocytes thus produced result in pregnancies and birth of babies. Several groups across the world have shown that direct transplantation of mesenchymal stromal/stem cells in the nonfunctional, chemoablated ovaries can normalize their function and result in the birth of fertile offspring. Reviews have been recently published, on the use of mesenchymal stem cells (MSCs) therapy (from various sources including human MSCs) for the recovery of fertility in rodents and rabbits. Lai et al. transplanted human endometrial MSCs in chemoablated mouse ovaries that resulted in improved estrus cycles and ovarian function.
These transplanted MSCs are a source of growth factors for the surviving VSELs in the chemoablated ovaries, to result in neo-oogenesis and primordial follicle assembly. We have reported extensively on similar functional ability of surviving VSELs in chemoablated testes to undergo spermatogenesis., Niikura et al. showed that aged mouse ovaries have premeiotic germ cells that can produce oocytes when the aged ovarian tissue was grafted on a young ovary.
Thus, all that is required is transplantation of autologous mesenchymal cells in nonfunctional ovaries as well as in azoospermic testes of cancer survivors to restore fertility. There may be no need to counsel patients of infertility as a possible side-effect after oncotherapy or banking of gonadal tissue before therapy. Let the cancer patients undergo oncotherapy, and once they have won the battle against cancer, transplantation of autologous MSCs directly in their gonads can restore ovarian/testicular function. There is one case report where a baby girl has been born on transplanting autologous MSCs in ovary with POF. Similarly, an abstract has been published by Gabr et al. who transplanted autologous bone marrow MSCs in 30 women with POF. Twenty-six of their study participants showed lowering of FSH levels, increase in E and anti-Müllerian hormone levels and 18 of 26 women showed ovulation, one spontaneous pregnancy and three patients were subjected to in vitro fertilization.
This concept of regenerating nonfunctional/aged ovary is superior to rejuvenating aged eggs. The strategy of providing a healthy niche to the surviving VSELs in the otherwise nonfunctional gonads (by transplanting autologous mesenchymal cells) holds a lot of promise for cancer survivors, will simplify the approach to preserve fertility, there may be no need to bank gonadal tissue and will prove to be more practical. This was recently discussed elsewhere also. Well-designed pilot clinical studies need to be undertaken to support the concept. Cell therapy is safe, but efficacy needs to be demonstrated in the clinics.
The author acknowledges the work done by her Ph.D. students and project staff. Funding was provided over the years by various funding agencies DST, DBT, and ICMR. NIRRH accession number is IR/773/05-2019.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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