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Table of Contents
REVIEW ARTICLE
Year : 2019  |  Volume : 2  |  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 Submission11-Jun-2019
Date of Acceptance15-Oct-2019
Date of Web Publication31-Jan-2020

Correspondence Address:
Prof. Deepa Bhartiya
Stem Cell Biology Department, ICMR.National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/tofj.tofj_12_19

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  Abstract 


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 Feb 24];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.[1] Fertility experts are now hoping to label this strategy as a method of standard care; however, it remains experimental till now.[2] 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.[3] The mechanism, resulting in pregnancies after heterotopic transplantation needs to be better understood. Oktay[4] 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[5] 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[6],[7] 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.[8],[9] 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.[7] 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.[10],[11],[12] Patel et al.[11] provided first in situ evidence supporting neo-oogenesis and PF assembly in adult sheep ovaries. Recently, Virant-Klun[13] 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.[14],[15] VSELs are relatively quiescent, remain in G0 phase of cell cycle and as a result survive oncotherapy which otherwise targets actively dividing cells.[16],[17] Similarly, VSELs survive chemotherapy in mouse testis[18],[19] and were also detected in azoospermic testicular biopsies of adult men survivors of childhood cancers.[20] 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.[15] The mechanism underlying their quiescence has been studies and reported by Ratajczak's group.[21],[22] 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[23],[24] 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.[25] 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.[18],[26] Niikura et al.[27] 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.[28] Similarly, an abstract has been published by Gabr et al.[29] 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.[30] 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.[31] 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.

Acknowledgments

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

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Jensen AK, Macklon KT, Fedder J, Ernst E, Humaidan P, Andersen CY, et al. 86 successful births and 9 ongoing pregnancies worldwide in women transplanted with frozen-thawed ovarian tissue: Focus on birth and perinatal outcome in 40 of these children. J Assist Reprod Genet 2017;34:325-36.  Back to cited text no. 1
    
2.
Gornet ME, Lindheim SR, Christianson MS. Ovarian tissue cryopreservation and transplantation: What advances are necessary for this fertility preservation modality to no longer be considered experimental? Fertil Steril 2019;111:473-4.  Back to cited text no. 2
    
3.
Oktay K, Türkçüoǧlu I, Rodriguez-Wallberg KA. Four spontaneous pregnancies and three live births following subcutaneous transplantation of frozen banked ovarian tissue: What is the explanation? Fertil Steril 2011;95:804.e7-10.  Back to cited text no. 3
    
4.
Oktay K. Spontaneous conceptions and live birth after heterotopic ovarian transplantation: Is there a germline stem cell connection? Hum Reprod 2006;21:1345-8.  Back to cited text no. 4
    
5.
Kim SS. Revisiting the role of heterotopic ovarian transplantation: Futility or fertility. Reprod Biomed Online 2014;28:141-5.  Back to cited text no. 5
    
6.
Martin JJ, Woods DC, Tilly JL. Implications and current limitations of oogenesis from female germline or oogonial stem cells in adult mammalian ovaries. Cells 2019;8. pii: E93.  Back to cited text no. 6
    
7.
Bhartiya D, Patel H. Ovarian stem cells-resolving controversies. J Assist Reprod Genet 2018;35:393-8.  Back to cited text no. 7
    
8.
Virant-Klun I, Zech N, Rozman P, Vogler A, Cvjeticanin B, Klemenc P, et al. Putative stem cells with an embryonic character isolated from the ovarian surface epithelium of women with no naturally present follicles and oocytes. Differentiation 2008;76:843-56.  Back to cited text no. 8
    
9.
Virant-Klun I, Rozman P, Cvjeticanin B, Vrtacnik-Bokal E, Novakovic S, Rülicke T, et al. Parthenogenetic embryo-like structures in the human ovarian surface epithelium cell culture in postmenopausal women with no naturally present follicles and oocytes. Stem Cells Dev 2009;18:137-49.  Back to cited text no. 9
    
10.
Patel H, Bhartiya D, Parte S, Gunjal P, Yedurkar S, Bhatt M, et al. Follicle stimulating hormone modulates ovarian stem cells through alternately spliced receptor variant FSH-R3. J Ovarian Res 2013;6:52.  Back to cited text no. 10
    
11.
Patel H, Bhartiya D, Parte S. Further characterization of adult sheep ovarian stem cells and their involvement in neo-oogenesis and follicle assembly. J Ovarian Res 2018;11:3.  Back to cited text no. 11
    
12.
Bhartiya D, Patel H, Ganguly R, Shaikh A, Shukla Y, Sharma D, et al. Novel insights into adult and cancer stem cell biology. Stem Cells Dev 2018;27:1527-39.  Back to cited text no. 12
    
13.
Virant-Klun I. Functional testing of primitive oocyte-like cells developed in ovarian surface epithelium cell culture from small VSEL-like stem cells: Can they be fertilized one day? Stem Cell Rev Rep 2018;14:715-21.  Back to cited text no. 13
    
14.
Shaikh A, Anand S, Kapoor S, Ganguly R, Bhartiya D. Mouse bone marrow VSELs exhibit differentiation into three embryonic germ lineages and germ and amp; hematopoietic cells in culture. Stem Cell Rev Rep 2017;13:202-16.  Back to cited text no. 14
    
15.
Ratajczak MZ, Ratajczak J, Kucia M. Very small embryonic-like stem cells (VSELs). Circ Res 2019;124:208-10.  Back to cited text no. 15
    
16.
Sriraman K, Bhartiya D, Anand S, Bhutda S. Mouse ovarian very small embryonic-like stem cells resist chemotherapy and retain ability to initiate oocyte-specific differentiation. Reprod Sci 2015;22:884-903.  Back to cited text no. 16
    
17.
Bhartiya D. Stem cells survive oncotherapy and amp; can regenerate non-functional gonads: A paradigm shift for oncofertility. Indian J Med Res 2018;148:S38-49.  Back to cited text no. 17
    
18.
Anand S, Bhartiya D, Sriraman K, Mallick A. Underlying mechanisms that restore spermatogenesis on transplanting healthy niche cells in busulphan treated mouse testis. Stem Cell Rev Rep 2016;12:682-97.  Back to cited text no. 18
    
19.
Patel H, Bhartiya D. Testicular stem cells express follicle-stimulating hormone receptors and are directly modulated by FSH. Reprod Sci 2016;23:1493-508.  Back to cited text no. 19
    
20.
Kurkure P, Prasad M, Dhamankar V, Bakshi G. Very small embryonic-like stem cells (VSELs) detected in azoospermic testicular biopsies of adult survivors of childhood cancer. Reprod Biol Endocrinol 2015;13:122.  Back to cited text no. 20
    
21.
Shin DM, Zuba-Surma EK, Wu W, Ratajczak J, Wysoczynski M, Ratajczak MZ, et al. Novel epigenetic mechanisms that control pluripotency and quiescence of adult bone marrow-derived oct4(+) very small embryonic-like stem cells. Leukemia 2009;23:2042-51.  Back to cited text no. 21
    
22.
Ratajczak MZ. Igf2-H19, an imprinted tandem yin-yanggene and its emerging role in development, proliferation of pluripotent stem cells, senescence and cancerogenesis. J Stem Cell Res Ther 2012;2. pii: 108.  Back to cited text no. 22
    
23.
Yoon SY. Mesenchymal stem cells for restoration of ovarian function. Clin Exp Reprod Med 2019;46:1-7.  Back to cited text no. 23
    
24.
Fazeli Z, Abedindo A, Omrani MD, Ghaderian SMH. Mesenchymal stem cells (MSCs) therapy for recovery of fertility: A systematic review. Stem Cell Rev Rep 2018;14:1-2.  Back to cited text no. 24
    
25.
Lai D, Wang F, Yao X, Zhang Q, Wu X, Xiang C, et al. Human endometrial mesenchymal stem cells restore ovarian function through improving the renewal of germline stem cells in a mouse model of premature ovarian failure. J Transl Med 2015;13:155.  Back to cited text no. 25
    
26.
Bhartiya D, Anand S. Effects of oncotherapy on testicular stem cells and niche. Mol Hum Reprod 2017;23:654-5.  Back to cited text no. 26
    
27.
Niikura Y, Niikura T, Tilly JL. Aged mouse ovaries possess rare premeiotic germ cells that can generate oocytes following transplantation into a young host environment. Aging (Albany NY) 2009;1:971-8.  Back to cited text no. 27
    
28.
Edessy M, Hosni HN, Shady Y, Waf Y, Bakr S, Kamel M. Autologous stem cells therapy, the first baby of idiopathic premature ovarian failure. Acta Med Int 2016;3:19-23.  Back to cited text no. 28
  [Full text]  
29.
Gabr H, Elkheir WA, El-Gazzar A. Autologous stem cell transplantation in patients with idiopathic premature ovarian failure. J Tissue Sci Eng 2016;7 Suppl 3:27.  Back to cited text no. 29
    
30.
Bhartiya D. Letter to the editor: Rejuvenate eggs or regenerate ovary? Mol Cell Endocrinol 2017;446:111-3.  Back to cited text no. 30
    
31.
Bhartiya D. Stem cells survive oncotherapy & can regenerate non-functional gonads: A paradigm shift for oncofertility. Indian J Med Res 2018;148(Suppl):S38-S49.  Back to cited text no. 31
    




 

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