Deepa BhartiyaDr., Stem Cell biology Department, ICMR-National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai 400 012,
- Stem Cell biology Department, ICMR-National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai 400 012,
Surgical advance for robot-assisted orthotopic/heterotopic ovarian tissue transplantation technique by Oktay’s group is indeed praise-worthy. However, using this advance to discuss what more is needed to make ovarian tissue cryopreservation (OTC) with subsequent orthotopic transplantation as a potential treatment option for women a method of standard care was not compelling. In addition to citing Oktay’s 2000 article, we also need to discuss their article of 2011 (1) where four spontaneous pregnancies were reported and three live births following heterotopic transplantation of ovarian tissue. They had discussed a role of stem cells and their niche.
There are stem cells in the ovary as well as in the testis which survive oncotherapy (2,3) and can regenerate non-functional gonads on transplantation of niche cells (mesenchymal stromal cells). This has been shown by several groups in mice resulting in live births which was compiled as a systematic review (4) and our group has further shown that although stem cells survive oncotherapy, their niche gets affected by oncotherapy (5).
It may be best to undertake few clinical studies to study the effect of transplanting autologus mesenchymal stromal cells in non-functional ovary/testis before planning to make OCT followed by orthotopic transplantation a method of standard care. We have discussed this earlier also (6).
- Oktay K, Türkçüoğlu 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(2):804.e7-10.
- 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(7):884-903.
- 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. 2016;12(6):682-697.
- Fazeli Z, Abedindo A, Omrani MD, Ghaderian SMH. Mesenchymal stem cells (MSCs) therapy for recovery of fertility: a systematic review. Stem Cell Rev. 2017; doi:10.1007/s12015-017-9765-x.
- Bhartiya D, Anand S. Effects of oncotherapy on testicular stem cells and niche. Mol Hum Reprod. 2017;23(9):654-655.
- Bhartiya D. Use of very small embryonic-like stem cells to avoid legal, ethical, and safety issues associated with oncofertility. JAMA Oncol 2016; 2 : 689.
The studies, reported by Herraiz et al (2018) published in Fertility and Sterility and commented upon by Prof Bates, clearly tells us that stem cells in human BM get mobilized into the peripheral blood on injecting G-CSF which are lacking in PBMNCs that help improve ovarian function in chemoablated mice. Further experiments involving the xenografted human cortical tissue pieces in mice shows that these stem cells have better regenerative potential compared to CD133+ sorted cells. Earlier CD133+ cells were used to treat thin endometrium with marginal benefit. Thanks to Prof Bates for acknowledging our work on VSELs. We have reported that a novel population of pluripotent stem cells exists in adult ovaries, testes and uterus [https://www.ncbi.nlm.nih.gov/pubmed/27614362] – they survive oncotherapy [https://www.ncbi.nlm.nih.gov/pubmed/25779995] – and can restore non-functional ovary/testis/uterus when a healthy niche is provided by transplanting mesenchymal cells [https://www.ncbi.nlm.nih.gov/pubmed/29128912; https://www.ncbi.nlm.nih.gov/pubmed/28342456; https://www.ncbi.nlm.nih.gov/pubmed/27663915; https://www.ncbi.nlm.nih.gov/pubmed/28911213]. Most probably it is the MSCs that got mobilized have provided beneficial effects and allowed endogenous VSELs in the chemoablated mouse ovary and xenografted human cortical tissue with poor follicular reserve to undergo neo-oogenesis and follicle assembly. Since human mobilized cells were transplanted in mice – MSCs numbers were perhaps enough to result in beneficial effect. But G-CSF mobilization of cells in patients with poor ovarian reserve may not suffice to result in beneficial effects in humans. Best approach will be to expand autologus MSCs and transplant directtly in non-functional ovaries, testes and also in thin endometrium. Stem cells lodged in ovary surface epithelium can bring about neo-oogenesis and follicle assembly [https://www.ncbi.nlm.nih.gov/pubmed/29304868; https://www.ncbi.nlm.nih.gov/pubmed/26635884]. Being a basic scientist, I cannot conduct clinical trials but wait for someone to follow this approach. It will be an international breakthrough and revolutionize reproductive medicine for the common man including cancer survivors.
Deepa Bhartiya, PhD; ICMR-National Institute for Research in Reproductive Health, Parel, Mumbai, INDIA www.nirrh.res.in
Dear Prof Goldberg. Very nice compilation of the field. Besides facilitating decidualization or activation of immune response or helping to improve synchrony - endometrial scratching may also lead to increased mobilization of stem cells to the site of injury where they undergo differentiation and improve endometrial cells population comprising the receptive site. Stem cells are known to get mobilized in response to stress in an attempt to restore homeostasis. However, this needs to be demonstrated in animal models. Is there any mouse model to study this?