For citation purposes: Dan S, Haibo L, Hong L. Pathogenesis and stem cell therapy for premature ovarian failure. OA Stem Cells 2014 Feb 10;2(1):4.

Review

 
Tissue-Specific Stem Cells

Pathogenesis and stem cell therapy for premature ovarian failure

S Dan, L Haibo, L Hong*
 

Authors affiliations

Center for Reproduction and Genetics, Suzhou Municipal Hospital, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou 215002, Jiangsu, China

* Corresponding author Email: hongliszivf@163.com.

Abstract

Introduction

One of the most common significant causes for infertility in women is premature ovarian failure. However, the pathogenesis of premature ovarian failure requires further investigation. Three major causes for premature ovarian failure, including X chromosome-linked genetic defects, are autoimmune disorders and long-term toxicity associated with chemotherapy exposure. Chemotherapy-induced premature ovarian failure is reversible for the infertility of women. Damaged ovarian function can be rescued after stem cell transplantation. Nevertheless, the mechanism behind this still remains unclear. Although these stem cells may potentially differentiate into oocytes or granulosa cells, studies have proved they could not develop into fully functional follicles in vivo. Both the proliferation and apoptosis of granulosa cells are critical in the development of follicles. Greater numbers of studies have revealed stem cells transplanted into the damaged ovary are more inclined to differentiate into granulosa cell-like cells to replenish the lost granulosa cells. Additionally, factors produced by stem cells could inhibit stromal cell apoptosis, thereby playing a part in rescuing damaged ovarian function. This review discusses several kinds of stem cells which have been studied for treating premature ovarian failure, to get comprehensive understanding for the stem cell therapy mechanisms.

Conclusion

Clinical applications of stem cell therapy have become popular for treating premature ovarian failure. Oocyte and granulosa cells regeneration along with the re-establishment of hormone or cytokine profiles supporting stem cell follicular development may be involved in the improvement of both the damaged ovary function and fertility recovery. Increased understanding of this mechanism will promote its wide clinical application.

Introduction

Premature ovarian failure (POF) is an ovarian defect that is characterised by the cessation of ovarian function and premature ovarian follicle depletion before 40 years of age; it is also known as premature menopause. This condition may cause female infertility due to an ovulation, hypoestrogenism, sex steroid deficiencies and elevated gonadotropins in women less than 40 years of age[1]. According to pathogenesis, there are two types of POF: one has a limited number of remaining follicles, and the other has an abundant number of follicles with maturation defects. The POF pathophysiology is believed to differ from normal menopause. The declined ovarian function in the first type of POF is reversible, whereas in the latter one the changes are permanent[2,3].

The aetiology of POF is complex. Genetic pathogenesis is among the most commonly known causes[4]. The X chromosome-linked defects play major roles in these genetic pathogeneses, which include X monosomy (also called Turner’s syndrome)[5,6], trisomy X[7], mosaicism and X chromosome deletions[8].

Immunological pathogenesis has also been studied in POF aetiology[9]. Autoimmune disorders associated with humoral and cellular immunity result in antibody creation or T-cell-mediated injury of ovarian cells such as granulosa cells (GCs), oocytes and the zona pellucida[10,11,12,13].

Chemotherapeutic agents have been widely used to treat cancer patients. Great numbers of studies confirmed that the most commonly seen side effect of chemotherapy is in the reproductive system, most frequently associated with infertility[14,15,16]. According to a study the treatment of busulfan/cyclophosphamide has mostly affected the ovaries, with lesser effects on the spleen, lungs and kidneys, and no effects on heart, liver, stomach or pancreas[17]. One report suggests that the younger females who suffered from chemotherapy-induced POF still retain enough ovarian function with good quality oocytes to support a successful pregnancy[18]. Although previous studies have proven that fertility could be recovered for the women suffering from chemotherapy-induced POF, further research is required.

Studies related to stem cells that are capable of generating oocytes have been undertaken in mice. This outcome brings some hope for new POF treatments. Stem cells derived from different sources may have some effect on the rescue of ovary function, such as recovering ovary sex hormone function, reducing apoptosis of GCs, and increasing the number of follicles. It has been argued that mechanisms involved in these stem cells can restore ovarian function for the following reasons: (1) The in vivo evidence of their ability to develop into fully functional follicles is still rare. (2) The transplanted stem cells have been proven to differentiate into GC-like cells much more easily than into oocytes. (3) The improved ovary after stem cell transplantation is a complex mix of many unclear factors requiring further investigation. (4) Stem cell therapy for the POF may increase ovarian granulosa cell tumour (GCT) occurrence arising from sex-cord stromal cells of the ovary, even though it is an uncommon cancer[19]. Taken together, the work remains controversial for clinical and experimental stem cell therapy and presently has no direct clinical application. The aim of this review was to discuss pathogenesis and stem cell therapy for POF.

Discussion

Mechanisms involved in premature ovarian failure-inducing chemotherapeutic agents

Chemotherapeutic agents are classified into five classes according to their mode of action: alkylating agents, antimetabolites, aneuploidy inducers, radiomimetics and topoisomerase II inhibitors. Antitumour effects of these drugs are often accompanied by their damage on other organs, especially the reproductive system[14]. There are several hypotheses for POF induction by chemotherapy (Figure 1). First, chemical agents can impair follicular stock by driving ovarian cell apoptosis, leading to a finite number of primordial follicles and ensuing POF[20]. Second, some chemical agents interfere with local hormonal regulation related to either follicular recruitment or rest. Third, some chemical agents may interrupt interactions between the oocytes and GCs, which are crucial for follicular growth and maturation[21]. For the above reasons, follicular storage decreases or the follicles do not fully mature, increasing the POF risk.

The hypotheses for POF induction by chemotherapy and the stem cell therapy.

Folliculogenesis is balanced between granulosa cells proliferation and apoptosis

The development and maturation of ovarian follicles includes several stages: primordial, primary, secondary and antral follicles. These processes are classified mainly by GC proliferation. GCs are the primary cell type in the ovary, providing the physical support and microenvironment required for the developing oocyte. The GC provides biosynthesis of some important ovarian steroids. Primary follicles are characterised by an oocyte surrounded by a single layer of seven or more cuboidal GCs. With GC proliferation, the oocyte is surrounded by two to four complete GC layers, described as preantral follicles; antral follicles form when there are five or more complete GC layers with or without a visible antrum. A follicle has one of two paths: ovulation or atresia. Atretic follicles are defined as containing a degenerating oocyte or more than 10% pyknotic GCs, initiated by either oocytes or GC death[22]. Although atresia is the fate for most follicles, excessive follicle atresia represents a follicle developmental defect such as POF, which is caused by the excessive apoptosis of either an oocyte or somatic cells[23].

GCs are one of the most important follicle components; their proliferation, differentiation and apoptosis are all critical for folliculogenesis. In human foetal ovaries, primitive GCs are available for an unlimited number of germ cells entering epithelial cords to form primordial follicles. Meanwhile, in an adult human, a single germ cell with a single epithelial nest of primitive GCs results in excessive germ cell degeneration during the periovulatory periods. This balance between the proliferation and apoptosis of GCs is the key factor deciding the fate of follicles in adult human ovaries[24].

Oocyte–granulosa cells interaction is crucial for the fate of follicles

Study has revealed that the effect of GC apoptosis on oocytes is mediated by reactive oxygen species (ROS). Germ cells appear more susceptible to oxidative stress as compared with somatic cells[25]. Low levels of ROS have no effect on oocyte development, whereas extensive ROS production followed by GCs excess apoptosis has an adverse effect on oocytes. Additionally, even for GCs, they have varying susceptibility to apoptosis according to the different stages of the cell cycle[23,26].

Oocyte–GC or GC–GC cross talk is important for follicular development. Follicles with oocytes have shown a decreased percentage of apoptotic GCs as compared with follicles without oocytes, although the difference is not statistically significant; this finding reveals oocytes protect GCs from apoptosis to some degree[27,28].

Some signal pathways have been proven to participate in the oocyte–GC cross talk, including the Notch signal pathway, a classical pathway involved in cell proliferation, differentiation and apoptosis[29]. The interaction between GC-expressed NOTCH1-2/3 and oocyte-expressed JAG1 plus DLL3 (known as the Notch ligands) inhibits oocyte apoptosis[30] and promotes GCs proliferation[31]. Another proven signal pathway involved in GC–oocyte and GC–GC cross talk is the vascular endothelial growth factor pathway (VEGF). Note that FLT1, as a VEGF receptor, is overexpressed on oocytes. VEGF produced by GCs can protect oocytes from apoptosis through FLT1 and thus protect itself from apoptosis through neuropilin-1 (NRP1) (another VEGF receptor expressed on GCs), thereby helping follicles early against atresia[32,33].

The role of steroidal hormones on follicular development

Both follicle growth and survival are regulated by a variety of steroidal hormones through either paracrine or autocrine mechanisms[34]. Relevant hormones such as gonadotropins, estradiol, luteotropic hormone (LH) and follicle-stimulating hormone (FSH) are produced by either the ovary or hypothalamus. There is a distinct endocrine profile seen with POF, which is partially considered to contribute to the endogenous apoptosis pathways within follicle activation, thereby leading to abnormal follicular atresia. Oestrogen and progesterone are mainly secreted by GCs in the ovary, which is important for stimulating proliferation as well as protecting them against apoptosis by autocrine mechanisms[35,36]. Chemotherapeutic agents would damage GCs production. The ovaries produce little to no oestrogen in ovarian failure (premature or menopause), resulting in loss of the negative feedback system to the hypothalamus and pituitary glands. Thus, the pituitary glands produce elevated levels of FSH. High levels of FSH reduce the number of GC FSH receptors (FSHR). Studies have revealed that oestrogen (as a protocol of hormone replacement therapy (HRT)) may increase both the number and sensitivity of FSHRs on GCs and promote follicular recruitment[37].

The LH surge is an important event for follicle maturation, which occurs following the stimulation of gonadotropin-releasing hormone in the preovulatory stage. Studies have shown that the LH surge appearance would improve GC differentiation and avoid apoptosis in rodents[38]. The progesterone receptor has been proven to be a potential mediator which is induced by the LH surge, therefore promoting GC proliferation and follicular survival.

HRT, in aiming to correct the disordered hormone profile, has been used as one of the most commonly effective treatments for treating POF[37]. However, HRT carries a notably increased risk of vascular disease, osteoporosis and even ovarian cancer and breast cancer for these patients[39,40].

Stem cell therapy for premature ovarian failure

As shown in some clinical reports, stem cell transplantation could help the recovery of ovarian function in some women who suffered premature menopause by chemotherapeutic agents. We will discuss in detail its promise as an ideal potential treatment for POF.

The view of oogenesis being restricted to embryonic life in most mammalian species has been challenged[41]. However, some studies continue to refute this[42]. It is still acceptable to note that the primordial follicle population remains limited during female reproductive life. Once the storage is depleted, females are considered to have entered reproductive senescence or menopause. People have been trying to use stem cell therapy for POF-induced infertility based on the possibility of long-term replenishment for damaged oocytes. These transplanted stem cells could reside in the ovarian tissue and rescue ovarian function, as seen in the preclinical mouse model of chemotherapy-induced POF[43]; however, these mechanisms require further investigation. Other studies showed that stem cells could inhibit stromal cell apoptosis through the secretion of stanniocalcin-1 and some other paracrine factors[44,45,46]. Thus, the recovery of damaged ovarian function in the POF after stem cell transplantation is complex, with transplanted stem cells salvaging the sufficient number of existing oocytes and also helping to repair the damaged ovarian niches. There are several stem cell types that have been investigated in POF treatment. Their recovery of ovary function demonstrates some significant differences from other techniques, some of which are listed in Table 1.

Table 1

The stem cells used in POF therapy

Follicles generated from embryonic and induced pluripotent stem cells

Pluripotent stem cells (PSCs) have the potential to be induced into oocytes: within the past decade, studies have showed that mouse embryonic stem cells (ESCs) can form oocyte-like cells in vitro[47]. Mouse ESCs can be induced into follicle-like structures with a single oocyte-like cell, surrounded by one or more layers of tightly adherent somatic cells[48].

New studies have shown the process of oocyte generation from ESCs[49]. ESCs are first induced into primordial germ cell (PGC)-like cells that are in turn aggregated with somatic cells of female embryonic gonads. These aggregations are transplanted under the ovarian bursa, where it matures and prepares for fertilisation. This reconstitution of oogenesis from ESCs not only has immense applications for both human and animal reproduction, but also has meaningful applications in basic biology[50].

Although multiple studies have focused on the differentiation of ESCs into oocytes[51], this technique has a very low frequency for follicles capable of maturation, fertilisation, embryogenesis and development into live offspring in vitro. Other studies showed evidence rat ESCs that differentiated into ovarian cell types, such as somatic cells. These somatic cells of follicle-like structures have some characteristics of endogenous ovarian-derived GCs[52,53]. Studies have implied that applications of ESC in POF may be based more on development into GCs as the supplement for extensive chemotherapy-induced apoptosis, rather than direct differentiation into a fully functionalfollicle.

Similar to ESC, induced PSCs (iPSCs) are another option for POF stem cells therapy. The iPSCs can also be induced into oocytes in vitro[54]. One study reported that goat iPSCs could be generated into germ cell-like cells and differentiates into goat oocyte-like structures[55]. Hence, studies have demonstrated that culturing with GCs could help to differentiate them into GC-like cells[56]. The rat iPSCs and ESCs could be then differentiated into GC-like cells in vitro, providing evidence of possible cell therapy for POF.

Mesenchymal stem cells in stem cell therapy of premature ovarian failure

Mesenchymal stem cells (MSCs) have been studied for repairing damaged ovaries induced by chemotherapy[57]. Umbilical cord mesenchymal stem cells (UCMSCs) have many advantages over other MSCs. The low expression of human leukocyte antigen major histocompatibility complex I (MHC I) and the absence of MHC II molecules seen in UCMSCs allows them to properly evade immune reaction, even in allogeneic transplantations[58,59,60]. Hence, UCMSCs transplantation often results in little to no immune rejection[61]. Although studies for use in POF treatment remain rare, UCMSCs transplantation could rescue mouse ovary function through the paracrine pathway. For example, UCMSCs could reduce GC apoptosis through effects on its G-protein coupled receptor protein signalling and MAPK pathways, both of which are also important for follicle and oocyte growth.

Adipose-derived stem cells (ADSCs), as another type of MSC, can be differentiated into multiple cell types; however, they have poor immunogenic properties[62]. The ADSCs protective role in POF has been investigated in mice[63]. In labelling these transplanted MSCs, studies found they do not develop into ovarian follicles[64]. However, the follicle and ovulation numbers significantly increase after these stem cells are transplanted into mice. Many growth factors such as VEGF, transforming growth factor-β and placental growth factor can be secreted by ADSCs, which are important for both follicle and oocyte growth. Therefore, we preliminarily concluded that these MSCs function primarily by improving the damaged ovarian niches that are induced by chemotherapy.

Cells derived from human amniotic fluid in premature ovarian failure stem cell therapy

Cells derived from human amniotic fluid (hAFCs) exhibit stem cell characteristics, such as high differentiation potential and proliferative activity[65,66]. These kind of stem cells express not only stem cell markers[67,68,69], but also germ cell markers such as BLIMP1 and DAZ in vitro[70,71]. One study reported that implanted hAFCs participate in follicle formation in the chemically damaged murine ovary[72]. Although GFP tracking of transplanted hAFCs demonstrated infiltration into a chemically damaged murine ovarian niche, this portion of hAFCs in the ovary ultimately differentiated into GCs but not germ cells. No evidence has shown that hAFCs recover ovarian function in the POF by restoring folliculogenesis.

CD44 +/CD105 + hAFCs isolated from HuAFCs have shown their special properties in the stem cell transplantation treatment for POF[73]. These stem cells underwent normal cell division and proliferation over the long-term, possibly avoiding the lack of survival and self-renewal seen in other transplanted stem cells located in ovarian tissues.

Bone marrow-derived cells in premature ovarian failure stem cell therapy

Bone marrow transplantation (BMT) has been used to rescue ovarian function and fertility in some reproductive-age women after long-term chemotherapy use[43,74]. Some investigators suggested interactions of bone marrow (BM)-derived cells with ovarian surface epithelium stem cells would give rise to PGCs; some unexplained return of ovarian function after BMT has been attributed to the alternative oogenesis derived from BM stem cells[75,76]. Study has shown that these allogeneic oocytes developed from BMT could not alleviate ovarian infertility[77]. Meanwhile, doubts arose from the report by Johnson that germ cells formed in BM completely disappeared in ovariectomised mice. Moreover, this study showed that BM cells, or any other normally circulating cells travelling to the ovaries through the bloodstream, exhibited properties of committed blood leukocytes instead of mature and ovulated oocytes. Thus, mechanisms involved in BMT treatment of POF require further investigation.

Although these PSCs have different mechanisms in repairing damaged ovarian tissue associated with POF, they have a common treatment goal in re-establishing normal hormonal function, increasing follicle and ovulation number and reducing GC apoptosis. There are many prospects for stem cell therapy mechanisms associated with POF. Among these variations, we elucidated several kinds of stem cells and tried to define the exact way these transplanted stem cells helped to recover the damaged ovary function.

Possible challenges related to premature ovarian failure stem cell therapy

Greater amounts of research about stem cell therapy in POF treatment have been carried out. The survival time associated with these transplanted stem cells is becoming more important. Some stem cells have been proven to have the potential for improving the damaged ovarian niches in vitro. However, the poor survival time in vivo remains a challenge for greater clinical application.

The other challenge relates to tumour occurrence. Inhibiting the GC apoptosis and improving its proliferation have proven to be a common pathway in processing stem cell therapy for POF. Both of these stem cell types, whether they differentiated into GCs or offered a niche supporting GC proliferation, give rise to the GCTs. We should not ignore this evidence although the associated evidence remains minimal.

Conclusion

POF has been considered as one of the most important causes for the infertility of women. The return of ovary function has been seen in many cases after treatments with HRT and stem cell therapy. Clinical applications of stem cell therapy have become popular for treating POF. Oocyte and GC regeneration along with the re-establishment of hormone or cytokine profiles supporting stem cell follicular development may be all involved in the improvement of both the damaged ovary function and fertility recovery. Thus, many complex mechanisms are involved in stem cell POF therapy. Increased understanding of this mechanism will promote its wide clinical application.

Acknowledgement

This review was supported by the science and technology supporting social development fund of Jiangsu Province (BE2012653).

Abbreviations list

ADSCs, adipose-derived stem cells; BM, bone marrow; BMT, bone marrow transplantation; ESCs, embryonic stem cells; FSH, follicle-stimulating hormone; GCs, granulosa cells; GCT, granulosa cell tumour; hAFCs, human amniotic fluid; HRT, hormone replacement therapy; iPSCs, induced pluripotent stem cells; LH, luteotropic hormone; MHC, major histocompatibility complex; MSCs, mesenchymal stem cells; PGCs, putative germ cells; POF, premature ovarian failure; PSCs, pluripotent stem cells; UCMSCs, umbilical cord mesenchymal stem cells; VEGF, vascular endothelial growth factor pathway.

Authors contribution

All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.

Competing interests

None declared.

Conflict of interests

None declared.

A.M.E

All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.

References

  • 1. Shelling AN . Premature ovarian failure. Reproduction 2010 Nov;140(5):633-41.
  • 2. Woad KJ, Watkins WJ, Prendergast D, Shelling AN. The genetic basis of premature ovarian failure. Aust N Z J Obstet Gynaecol 2006 Jun;46(3):242-4.
  • 3. Kalantaridou SN, Davis SR, Nelson LM. Premature ovarian failure. Endocrinol Metab Clin North Am 1998 Dec;27(4):989-1006.
  • 4. Davis CJ, Davison RM, Payne NN, Rodeck CH, Conway GS. Female sex preponderance for idiopathic familial premature ovarian failure suggests an X chromosome defect: opinion. Hum Reprod 2000 Nov;15(11):2418-22.
  • 5. Zinn AR, Page DC, Fisher EM. Turner syndrome: the case of the missing sex chromosome. Trends Genet 1993 Mar;9(3):90-3.
  • 6. Zinn AR, Ross JL. Turner syndrome and haploinsufficiency. Curr Opin Genet Dev 1998 Jun;8(3):322-27.
  • 7. Goswami R, Goswami D, Kabra M, Gupta N, Dubey S, Dadhwal V. Prevalence of the triple X syndrome in phenotypically normal women with premature ovarian failure and its association with autoimmune thyroid disorders. Fertil Steril 2003 Oct;80(4):1052-54.
  • 8. Simpson JL, Rajkovic A. Ovarian differentiation and gonadal failure. Am J Med Genet 1999 Dec;89(4):186-200.
  • 9. Wilson C . Autoimmunity: autoimmune Addison disease and premature ovarian failure. Nat Rev Endocrinol 2011 Jul;7(9):498.
  • 10. van Weissenbruch MM, Hoek A, van Vliet-Bleeker I, Schoemaker J, Drexhage H. Evidence for existence of immunoglobulins that block ovarian granulosa cell growth in vitro. A putative role in resistant ovary syndrome? J Clin Endocrinol Metab 1991 Aug;73(2):360-7.
  • 11. Shivers CA, Dunbar BS. Autoantibodies to zona pellucida: a possible cause for infertility in women. Science 1977 Sep;197(4308):1082-4.
  • 12. Rhim SH, Millar SE, Robey F, Luo AM, Lou YH, Yule T. Autoimmune disease of the ovary induced by a ZP3 peptide from the mouse zona pellucida. J Clin Invest 1992 Jan;89(1):28-35.
  • 13. Smith S, Hosid S. Premature ovarian failure associated with autoantibodies to the zona pellucida. Int J Fertil Menopausal Stud 1994 Nov–Dec;39(6):316-19.
  • 14. Meirow D, Nugent D. The effects of radiotherapy and chemotherapy on female reproduction. Hum Reprod Update 2001 Nov–Dec;7(6):535-43.
  • 15. Wenzel L, Dogan-Ates A, Habbal R, Berkowitz R, Goldstein DP, Bernstein M. Defining and measuring reproductive concerns of female cancer survivors. J Natl Cancer Inst Monogr 2005(34):94-8.
  • 16. Lee SJ, Schover LR, Partridge AH, Patrizio P, Wallace WH, Hagerty K. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 2006 Jun;24(18):2917-31.
  • 17. Jiang Y, Zhao J, Qi HJ, Li XL, Zhang SR, Song DW. Accelerated ovarian aging in mice by treatment of busulfan and cyclophosphamide. J Zhejiang Univ Sci B 2013 Apr;14(4):318-24.
  • 18. Ghazeeri G, Awwad J. Two successful pregnancies in a patient with chemotherapy-induced ovarian failure while on hormone replacement therapy. Gynecol Endocrinol 2012 Apr;28(4):286-7.
  • 19. Sekkate S, Kairouani M, Serji B, M’Rabti H, El Ghissassi I, Errihani H. Granulosa cell tumors of the ovary. Bull Cancer 2014 Jan;101(1):93-101(in French).
  • 20. De Vos M, Devroey P, Fauser BC. Primary ovarian insufficiency. Lancet 2010 Sep;376(9744):911-21.
  • 21. Tuttle AM, Stampfli M, Foster WG. Cigarette smoke causes follicle loss in mice ovaries at concentrations representative of human exposure. Hum Reprod 2009 Jun;24(6):1452-9.
  • 22. Driancourt MA, Reynaud K, Cortvrindt R, Smitz J. Roles of KIT and KIT LIGAND in ovarian function. Rev Reprod 2000 Sep;5(3):143-52.
  • 23. Chun SY, Hsueh AJ. Paracrine mechanisms of ovarian follicle apoptosis. J Reprod Immunol 1998 Aug;39(1–2):63-75.
  • 24. Bukovsky A, Caudle MR. Immunoregulation of follicular renewal, selection, POF, and menopause in vivo, vs. neo-oogenesis in vitro, POF and ovarian infertility treatment, and a clinical trial. Reprod Biol Endocrinol 2012 Nov97.
  • 25. Jancar N, Kopitar AN, Ihan A, Virant Klun I, Bokal EV. Effect of apoptosis and reactive oxygen species production in human granulosa cells on oocyte fertilization and blastocyst development. J Assist Reprod Genet 2007 Feb–Mar;24(2–3):91-7.
  • 26. Quirk SM, Cowan RG, Harman RM, Hu CL, Porter DA. Ovarian follicular growth and atresia: the relationship between cell proliferation and survival. J Anim Sci 2004 Jan;82(E-Suppl):E40-52.
  • 27. Lee KS, Joo BS, Na YJ, Yoon MS, Choi OH, Kim WW. Cumulus cells apoptosis as an indicator to predict the quality of oocytes and the outcome of IVF-ET1. J Assist Reprod Genet 2001 Sep;18(9):490.
  • 28. Høst E, Gabrielsen A, Lindenberg S, Smidt-Jensen S. Apoptosis in human cumulus cells in relation to zona pellucida thickness variation, maturation stage, and cleavage of the corresponding oocyte after intracytoplasmic sperm injection. Fertil Steril 2002 Mar;77(3):511-15.
  • 29. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science 1999 Apr;284(5415):770-6.
  • 30. Xu J, Gridley T. Notch2 is required in somatic cells for breakdown of ovarian germ-cell nests and formation of primordial follicles. BMC Biol 2013 Feb;1113.
  • 31. Zhang CP, Yang JL, Zhang J, Li L, Huang L, Ji SY. Notch signaling is involved in ovarian follicle development by regulating granulosa cell proliferation. Endocrinology 2011 Jun;152(6):2437-47.
  • 32. Yang MY, Fortune JE. Vascular endothelial growth factor stimulates the primary to secondary follicle transition in bovine follicles in vitro. Mol Reprod Dev 2007 Sep;74(9):1095-104.
  • 33. Greenaway J, Connor K, Pedersen HG, Coomber BL, LaMarre J, Petrik J. Vascular endothelial growth factor and its receptor, Flk-1/KDR, are cytoprotective in the extravascular compartment of the ovarian follicle. Endocrinology 2004 Jun;145(6):2896-905.
  • 34. Tilly JL, Kowalski KI, Johnson AL, Hsueh AJ. Involvement of apoptosis in ovarian follicular atresia and postovulatory regression. Endocrinology 1991 Nov;129(5):2799-801.
  • 35. Rosenfeld CS, Wagner JS, Roberts RM, Lubahn DB. Intraovarian actions of oestrogen. Reproduction 2001 Aug;122(2):215-26.
  • 36. Peluso JJ, Pappalardo A, Losel R, Wehling M. Expression and function of PAIRBP1 within gonadotropin-primed immature rat ovaries: PAIRBP1 regulation of granulosa and luteal cell viability. Biol Reprod 2005 Aug;73(2):261-70.
  • 37. Stangel-Wojcikiewicz K, Zdebik A, Jach R, Huras H, Wadowska-Jaszczynska K, Radon-Pokracka M. Hormone replacement therapy regimens in chemotherapy-induced premature ovarian failure and the subsequent correction of hormone levels. Neuro Endocrinol Lett 2012;33(7):697-702.
  • 38. Porter DA, Harman RM, Cowan RG, Quirk SM. Susceptibility of ovarian granulosa cells to apoptosis differs in cells isolated before or after the preovulatory LH surge. Mol Cell Endocrinol 2001 May;176(1–2):13-20.
  • 39. Chen H, Li J, Cui T, Hu L. Adjuvant gonadotropin-releasing hormone analogues for the prevention of chemotherapy induced premature ovarian failure in premenopausal women. Cochrane Database Syst Rev 2011 Nov(11):CD008018.
  • 40. Ginsburg J, Isaacs AJ, Gore MB, Havard CW. Use of clomiphene and luteinizing hormone/follicle stimulating hormone-releasing hormone in investigation of ovulatory failure. Br Med J 1975 Jul;3(5976):130-3.
  • 41. Gougeon A . Is neo-oogenesis in the adult ovary, a realistic paradigm?. Gynecol Obstet Fertil 2010 Jun;38(6):398-401 (in French).
  • 42. Eggan K, Jurga S, Gosden R, Min IM, Wagers AJ. Ovulated oocytes in adult mice derive from non-circulating germ cells. Nature 2006 Jun;441(7097):1109-14.
  • 43. Lee HJ, Selesniemi K, Niikura Y, Niikura T, Klein R, Dombkowski DM. Bone marrow transplantation generates immature oocytes and rescues long-term fertility in a preclinical mouse model of chemotherapy-induced premature ovarian failure. J Clin Oncol 2007 Aug;25(22):3198-204.
  • 44. Souidi N, Stolk M, Seifert M. Ischemia-reperfusion injury: beneficial effects of mesenchymal stromal cells. Curr Opin Organ Transplant 2013 Feb;18(1):34-43.
  • 45. Lin H, Xu R, Zhang Z, Chen L, Shi M, Wang FS. Implications of the immunoregulatory functions of mesenchymal stem cells in the treatment of human liver diseases. Cell Mol Immunol 2011 Jan;8(1):19-22.
  • 46. Yan Y, Xu W, Qian H, Si Y, Zhu W, Cao H. Mesenchymal stem cells from human umbilical cords ameliorate mouse hepatic injury in vivo. Liver Int 2009 Mar;29(3):356-65.
  • 47. Hübner K, Fuhrmann G, Christenson LK, Kehler J, Reinbold R, De La Fuente R. Derivation of oocytes from mouse embryonic stem cells. Science 2003 May;300(5623):1251-6.
  • 48. Salvador LM, Silva CP, Kostetskii I, Radice GL, Strauss JF 3rd. The promoter of the oocyte-specific gene, Gdf9, is active in population of cultured mouse embryonic stem cells with an oocyte-like phenotype. Methods 2008 Jun;45(2):172-81.
  • 49. Nicholas CR, Haston KM, Grewall AK, Longacre TA, Reijo Pera RA. Transplantation directs oocyte maturation from embryonic stem cells and provides a therapeutic strategy for female infertility. Hum Mol Genet 2009 Nov;18(22):4376-89.
  • 50. Hayashi K, Saitou M. Generation of eggs from mouse embryonic stem cells and induced pluripotent stem cells. Nat Protoc 2013 Aug;8(8):1513-24.
  • 51. Pelosi E, Forabosco A, Schlessinger D. Germ cell formation from embryonic stem cells and the use of somatic cell nuclei in oocytes. Ann N Y Acad Sci 2011 Mar;1221(1):18-26.
  • 52. Psathaki OE, Hübner K, Sabour D, Sebastiano V, Wu G, Sugawa F. Ultrastructural characterization of mouse embryonic stem cell-derived oocytes and granulosa cells. Stem Cells Dev 2011 Dec;20(12):2205-15.
  • 53. Novak I, Lightfoot DA, Wang H, Eriksson A, Mahdy E, Höög C. Mouse embryonic stem cells form follicle-like ovarian structures but do not progress through meiosis. Stem Cells 2006 Aug;24(8):1931-6.
  • 54. Hayashi K, Ogushi S, Kurimoto K, Shimamoto S, Ohta H, Saitou M. Offspring from oocytes derived from in vitro primordial germ cell-like cells in mice. Science 2012 Nov;338(6109):971-5.
  • 55. Goyal A, Chavez SL, Reijo Pera RA. Generation of human induced pluripotent stem cells using epigenetic regulators reveals a germ cell-like identity in partially reprogrammed colonies. PLoS One 2013 Dec;8(12):e82838.
  • 56. Zhang J, Li H, Wu Z, Tan X, Liu F, Huang X. Differentiation of rat iPS cells and ES cells into granulosa cell-like cells in vitro. Acta Biochim Biophys Sin (Shanghai) 2013 Apr;45(4):289-95.
  • 57. Kilic S, Pinarli F, Ozogul C, Tasdemir N, Naz Sarac G, Delibasi T. Protection from cyclophosphamide-induced ovarian damage with bone marrow-derived mesenchymal stem cells during puberty. Gynecol Endocrinol 2014 Feb;30(2):13540.
  • 58. Yan M, Sun M, Zhou Y, Wang W, He Z, Tang D. Conversion of human umbilical cord mesenchymal stem cells in Wharton’s jelly to dopamine neurons mediated by the Lmx1a and neurturin in vitro: potential therapeutic application for Parkinson’s disease in a rhesus monkey model. PLoS One 2013 May;8(5):e64000.
  • 59. Liu Y, Mu R, Wang S, Long L, Liu X, Li R. Therapeutic potential of human umbilical cord mesenchymal stem cells in the treatment of rheumatoid arthritis. Arthritis Res Ther 2010 Nov;12(6):R210.
  • 60. Bieback K, Brinkmann I. Mesenchymal stromal cells from human perinatal tissues: from biology to cell therapy. World J Stem Cells 2010 Aug;2(4):81-92.
  • 61. Tipnis S, Viswanathan C, Majumdar AS. Immunosuppressive properties of human umbilical cord-derived mesenchymal stem cells: role of B7-H1 and IDO. Immunol Cell Biol 2010 Nov–Dec;88(8):795-806.
  • 62. Varma MJ, Breuls RG, Schouten TE, Jurgens WJ, Bontkes HJ, Schuurhuis GJ. Phenotypical and functional characterization of freshly isolated adipose tissue-derived stem cells. Stem Cells Dev 2007 Feb;16(1):91-104.
  • 63. Sun M, Wang S, Li Y, Yu L, Gu F, Wang C. Adipose-derived stem cells improved mouse ovary function after chemotherapy-induced ovary failure. Stem Cell Res Ther 2013 Jul;4(4):80.
  • 64. Wang S, Yu L, Sun M, Mu S, Wang C, Wang D. The therapeutic potential of umbilical cord mesenchymal stem cells in mice premature ovarian failure. Biomed Res Int 2013 Aug;2013690491.
  • 65. Prusa AR, Marton E, Rosner M, Bernaschek G, Hengstschläger M. Oct-4-expressing cells in human amniotic fluid: a new source for stem cell research?. Hum Reprod 2003 Jul;18(7):1489-93.
  • 66. In‘t Anker PS, Scherjon SA, Kleijburg-van der Keur C, Noort WA, Claas FH, Willemze R. Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation. Blood 2003 Aug;102(4):1548-9.
  • 67. Kim J, Lee Y, Kim H, Hwang KJ, Kwon HC, Kim SK. Human amniotic fluid-derived stem cells have characteristics of multipotent stem cells. Cell Prolif 2007 Feb;40(1):75-90.
  • 68. Bossolasco P, Montemurro T, Cova L, Zangrossi S, Calzarossa C, Buiatiotis S. Molecular and phenotypic characterization of human amniotic fluid cells and their differentiation potential. Cell Res 2006 Apr;16(4):329-36.
  • 69. Tsai MS, Hwang SM, Tsai YL, Cheng FC, Lee JL, Chang YJ. Clonal amniotic fluid-derived stem cells express characteristics of both mesenchymal and neural stem cells. Biol Reprod 2006 Mar;74(3):545-51.
  • 70. Stefanidis K, Loutradis D, Koumbi L, Anastasiadou V, Dinopoulou V, Kiapekou E. Deleted in Azoospermia-Like (DAZL) gene-expressing cells in human amniotic fluid: a new source for germ cells research?. Fertil Steril 2008 Sep;90(3):798-804.
  • 71. Cheng X, Chen S, Yu X, Zheng P, Wang H. BMP15 gene is activated during human amniotic fluid stem cell differentiation into oocyte-like cells. DNA Cell Biol 2012 Jul;31(7):1198-204.
  • 72. Lai D, Wang F, Chen Y, Wang L, Wang Y, Cheng W. Human amniotic fluid stem cells have a potential to recover ovarian function in mice with chemotherapy-induced sterility. BMC Dev Biol 2013 Sep;1334.
  • 73. Liu T, Huang Y, Guo L, Cheng W, Zou G. CD44+/CD105+ human amniotic fluid mesenchymal stem cells survive and proliferate in the ovary long-term in a mouse model of chemotherapy-induced premature ovarian failure. Int J Med Sci 2012 Sep;9(7):592-602.
  • 74. Hershlag A, Schuster MW. Return of fertility after autologous stem cell transplantation. Fertil Steril 2002 Feb;77(2):419-21.
  • 75. Bukovsky A, Ayala ME, Dominguez R, Svetlikova M, Selleck-White R. Bone marrow derived cells and alternative pathways of oogenesis in adult rodents. Cell Cycle 2007 Sep;6(18):2306-9.
  • 76. Bukovsky A, Caudle MR, Svetlikova M, Upadhyaya NB. Origin of germ cells and formation of new primary follicles in adult human ovaries. Reprod Biol Endocrinol 2004 Apr;220.
  • 77. Bukovsky A . Can ovarian infertility be treated with bone marrow- or ovary-derived germ cells?. Reprod Biol Endocrinol 2005 Aug;336.
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The stem cells used in POF therapy

Stem cells types References Stem cells and germ cells markers Chemotherapy Morphologically of ovary after stem cells transplanted Hormone or cytokines profile changes Tracking of stem cells Survival time
Bone marrow transplantation Lee et al.43 / / / BMP15­, FMR1­, FSHR­, INHA­, AMH­, NOBOX­, FOXO3­, EIF2B­, FIGLA­and GDF9­ Reactivate host oogenesis; not generate oocytes /
CD44 +/CD105 + human amniotic fluid mesenchymal stem cells Liu et al.73 CD29, CD44, CD73, CD90, CD105 and CD166 Intraperitoneal injection of cyclophosphamide / / / Survive and proliferate over the long-term in the ovarian tissues.
Adipose-derived stem cells Sun et al.63 / Intraperitoneal injection of cyclophosphamide Follicle number ­, ovulation number­ and apoptotic GCs¯ HGF ­, VEGF­, PGF­ and TGF-β­ Not participate in follicle regeneration A large number of engrafted cells died within 1 month after transplantation.
Umbilical cord mesenchymal stem cells Wang et al.64 CD29, CD44,CD90 and CD105 Intraperitoneal injection of cyclophosphamide Apoptosis of GC¯, number of follicles­and oocyte containing follicles­ E2 ­ Not develop into follicles /
Human amniotic fluid cells Lai et al.72 BLIMP1, STELLA, DAZL, VASA, STRA8, SCP3, SCP1 and GDF9 Intraperitoneal injection of cyclophosphamide and busulphan Oocytes at all stages ­ AMH­and FSHR ­ Differentiated into GCs; not germ cell /

AMH, antimüllerian hormone; BMP15, bone morphogenetic protein15; FSHR, follicle-stimulating hormone receptor; HGF, hepatocyte growth factor; PGF, placental growth factor; POF, premature ovarian failure; VEGF, vascular endothelial growth factor; TGF-β, transforming growth factor-β; E2, oestrogen; INHA, inhibin alpha; FIGLA, factor in the germline alpha GC, granulosa cell.The mark of ‘/’represent that there is no report by now.

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