BOR Papers in Press. Published on February 24, 2016 as DOI:10.1095/biolreprod.115.136374
MINIREVIEW
New Insights into the Role of Autophagy in Ovarian Cryopreservation by Vitrification1 Yanzhou Yang 2,5,6, Hoi Hung Cheung 6, Wai Nok Law 6, Cheng Zhang 7, Wai Yee Chan 6, Xiuying Pei 3,5, Yanrong Wang 4,5 5
Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China
6
The Chinese University of Hong Kong–Shandong University Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, HKSAR
7
College of Life Science, Capital Normal University, Beijing, People’s Republic of China
1
This work was supported by the Natural Science Foundation of China (81560259) and the Ningxia higher school science and technology research project (NGY2015093).
2
Correspondence: Yanzhou Yang, E-mail: [email protected] Correspondence: Xiuying Pei, E-mail, [email protected] 4 Correspondence: Yanrong Wang, E-mail [email protected] 3
ABSTRACT Ovarian cryopreservation by vitrification is a highly useful method for preserving female fertility during radiotherapy and chemotherapy. However, cryo-injury, osmotic stress during vitrification, and ischemia/reperfusion during transplantation lead to losses of ovarian follicles. Ovarian follicle loss may be partially reduced by several methods; however, studies regarding the mechanism of ovarian follicle loss have only investigated cell apoptosis, which comprises type I programmed cell death. Autophagy comprises type II programmed cell death, and cell homeostasis is maintained by autophagy during conditions of stress. The role of autophagy during cryopreservation by vitrification has rarely been reported. The potential role of autophagy during ovarian cryopreservation by vitrification is reviewed in this article. KEYWORDS: Autophagy, Ovarian follicle death, Cryo-injury, Osmotic stress, Ischemia/reperfusion, Ovarian cryopreservation, Ovarian transplantation.
Copyright 2016 by The Society for the Study of Reproduction.
INTRODUCTION The cryopreservation of ovarian tissue by vitrification to preserve fertility for patients with cancer has been investigated for decades. To date, the birth of more than 60 babies from the transplantation of cryopreserved ovarian tissue has demonstrated the clinical success of this method [1], and two of these babies were born from vitrified ovarian tissues/follicles. Following recovery from cancer, patients with ovarian transplantation exhibit a complete return of hormonal function and fertility to baseline [2]. Thus, ovarian tissue cryopreservation by vitrification is considered the most significant method for preserving female fertility, especially for young women undergoing chemotherapy. Ovarian damages are often acquired during the process of chemotherapy; specifically, the number of reserved primordial follicles is reduced, which further triggers POF (premature ovarian failure) [3, 4]. Thus, ovarian vitrification and the transplantation of vitrified/warmed ovaries has emerged as an effective method of preserving ovarian function. However, there are numerous problems with the vitrification process, including follicle loss triggered by cryo-injury, osmotic stress during vitrification, and ischemia/reperfusion during transplantation. Specifically, ischemia/reperfusion causes the death of most primordial follicles [5-7]. However, the mechanism of primordial follicle loss in vitrified ovaries and transplanted ovaries remains completely unknown. Most studies have suggested that the death and loss of ovarian follicles during ovarian vitrification and ovarian grafts is primarily caused by apoptosis. Thus, anti-apoptotic agents are used to preserve the survival of ovarian follicles [8-19]; however, the death of ovarian follicles is only partially decreased with limited follicle survival following anti-apoptotic agent administration. Previous studies have suggested that oocyte death mediated primordial follicle atresia and granulosa cell death mediated primary follicle, secondary follicle, tertiary follicle and mature follicle atresia involve an apoptotic dependent pathway [20-26]. Therefore, the mechanism of ovarian follicle loss during ovarian vitrification and transplantation has been considered to be apoptosis. It remains unknown whether another important pathway is involved in ovarian follicle loss. Autophagy is an intracellular bulk degradation system in which a portion of the cytoplasm is enveloped in double membrane-bound structures referred to as autophagosomes, which undergo maturation and fusion with lysosomes for degradation [27, 28]. At a baseline level, autophagy promotes cellular survival; when activated under stress conditions, such as nutrient deprivation [29], hypoxia [30], and ischemia/reperfusion [31], it may lead to cell death. Therefore, autophagy is often dubbed a “double-edged sword” because it is a necessary process for many cells, but its amplification may lead to cell death [32]. Autophagy comprises type II programmed cell death, and its roles in primordial follicle atresia and granulosa cell apoptosis have been demonstrated [33-37]. Nevertheless, whether autophagy is involved in follicle death during ovarian vitrification and transplantation remains elusive. Thus, the potential roles of autophagy in ovarian vitrification and transplantation are summarized in this article. WHETHER FOLLICLE DEATH OCCURS DURING OVARIAN VITRIFICATION Previous studies that have demonstrated apoptosis is triggered by cryo-injury from liquid nitrogen during the vitrification process remain controversial. Most articles have suggested that apoptosis is initiated during ovarian vitrification; however, the apoptotic rate may be decreased during ovarian vitrification by the administration of several anti-apoptotic reagents [11, 12, 14-16, 38], and apoptosis may be decreased by use of the optimal protocol [39-44]. In contrast, other studies have suggested that there is no apoptosis in ovarian vitrification [45, 46], which is attributed to the application of the optimal protocol. However, it remains unknown whether follicle death is initiated by an apoptosis-independent pathway. Two views exist regarding ovarian vitrification: i) apoptosis is triggered in ovarian follicles during vitrification; and ii) apoptosis is not triggered in ovarian follicles during vitrification with the optimal protocol. Thus, three questions arise: i) If the death of ovarian follicles is initiated by cryo-injury, which pathway comprises the trigger for ovarian follicle death? ii) Is there another cell death pathway in addition to the apoptotic pathway that may be initiated by cryo-injury? iii) If ovarian follicle death is not initiated by cryo-injury, which pathway is initiated to adapt to the stress of cryo-injury? 2
APOPTOSIS IS NOT SOLELY RESPONSIBLE FOR FOLLICLE LOSSES FROM OVARIAN GRAFTS Previous studies have suggested that 60-95% of the follicular reserve is depleted during autografting, which induces the loss of virtually the entire population of growing follicles [5, 47-49]. Ovarian follicle losses occur during the early period of ovarian transplantation, which is caused by tissue ischemia and reperfusion injury [50, 51]. The effects of hypoxia following transplantation decrease the reproductive viability of ovarian transplants [52, 53]. Therefore, angiogenesis, which comprises the formation of new blood vessels, is important for the survival of ovarian transplants and the restoration of ovarian function [52]. The damage of transplanted vitrified/warmed ovaries is reduced by simvastatin [17], which decreases apoptosis and stimulates angiogenesis and endothelial cell migration in ovarian grafts via sphingosine-1-phosphate (S1P) [13]. Erythropoietin (EPO) increases angiogenesis in ovarian grafts [54]. Isoform 165 of vascular endothelial growth factor [55] decreases apoptosis, and oxidative stress is inhibited by N-acetylcysteine (NAC) [18]. The reduction of follicle loss and increasing angiogenesis are two core objectives during ovarian transplantation, and three questions must be resolved: i) Previous studies have suggested that follicle loss is triggered by apoptosis; however, it remains unknown whether other cellular death pathways are also initiated in ovarian grafts. ii) The potential mechanism of angiogenesis during ovarian transplantation must be investigated. iii) Primordial follicle intense activation is another pathway for follicle reserve depletion; thus, whether this pathway is initiated during ovarian transplantation must be investigated, as well as the mechanism of primordial follicle intense activation. IMPORTANCE OF AUTOPHAGY IN OVARIAN FOLLICLE ATRESIA AND FOLLICLE RESERVE DEPLETION Autophagy is an evolutionarily conserved mechanism, and it is indispensable for mammalian reproduction [56, 57] from gametogenesis to parturition [57], including embryogenesis [58], fertilization [59], spermatogenesis [60], and the development of the human placenta [61]. Previous studies have suggested that autophagy is involved in oocyte-death mediated primordial follicle atresia, but not apoptosis [33]. Moreover, autophagy mediated granulosa cell apoptosis is involved in primary follicle, secondary follicle, tertiary follicle and mature follicle atresia [34, 35]. Thus, the importance of autophagy in primordial follicle atresia is supported by several studies. Primordial follicle atresia is not a result of apoptotic pathways [36, 37]; it is attributed to autophagy dependent on pathway [33]. Recent studies have suggested that apoptotic and autophagic proteins coexist in fetal oocytes [62]. Furthermore, germline cell death may be apoptotic or non-apoptotic, depending on the stimulus or stage of development [63]. These findings have emphasized the function of autophagy in primordial follicle atresia. Autophagic cell death has not been investigated in ovarian vitrification or ovarian grafts. Another important role of autophagy in follicle reserve has been suggested by several studies in which autophagy is involved in the formation of the primordial follicle pool. Germ cell loss in perinatal mice is caused by the knockout of the autophagic genes BECN1 (Beclin 1) and Atg7 (autophagy related gene 7); there is a 56% germ cell reduction in Becn1+/- mice, and no germ cells are detected in Atg7 -/mice [64]. Germ cell-specific Atg7 knockout results in primary ovarian insufficiency (POI) in female mice, with germ cell over-loss during the neonatal transition period [65]. In addition, premature ovarian failure (POF) is consistently triggered by primordial follicle depletion through knockout of the autophagic activation gene PTEN (phosphatase and tensin homolog deleted on chromosome 10) via negative regulation of PI3K [66], which is a molecule upstream of mTOR. The autophagic activator rapamycin is an inhibitor of mTOR [67]. Inhibition of mTOR pathway activation increases the follicle reserve [68]. Thus, baseline level autophagy is indispensable for the maintenance of the primordial follicle pool, and follicle death is triggered by excess activation of autophagy, whereas the depletion of the primordial follicle pool is triggered by the inhibition of autophagy. IMPORTANCE OF AUTOPHAGY IN OVARIAN VITRIFICATION AND TRANSPLANTATION Autophagy plays a role in ovarian follicle atresia and follicle reserve depletion. Our limited knowledge indicates that autophagy is involved in ovarian vitrification by triggering follicle atresia if 3
ovarian follicle loss occurs in this process or if homeostasis is maintained under the optimal vitrification protocol during cryo-injury. Autophagy is triggered for cell survival in vitrified-warmed mouse oocytes; however, autophagy is not only activated in the cooling process but also the warming stages [69]. Furthermore, Gallardo Bolaños suggests that autophagy is activated for pro-survival in the cryopreservation of stallion spermatozoa; however, apoptosis plays a major role in sperm death during storage [70]. Follicle losses are triggered by ischemia/reperfusion injury [50, 51] and hypoxia injury [51, 52] in ovarian grafts. These findings support the idea that autophagy is involved in the follicle loss of ovarian grafts during ischemia/reperfusion injury, and hypoxia injury triggers follicle atresia or depletion of the primordial follicle pool. Indeed, autophagy mediates follicle atresia [33-37] and depletion of the primordial follicle pool [66, 68]. Furthermore, the importance of autophagy has been investigated during ischemia/reperfusion injury by several studies regarding liver transplantation [71-73] and renal transplantation [74-76]. In addition, a recent novel insight suggests that follicle activation and “burn-out” contribute to post-transplantation follicle loss in ovarian tissue grafts [53, 77]. This phenomenon may be attributable to the vitrification protocol, in which Amorim’s vitrification protocol has a positive impact on the quiescent state of primordial follicles following xenografting and does not activate the resting follicle reserve [78]. It has consistently been hypothesized that massive activation of primordial follicles is a consequence of the ischemic stress that the ovarian graft is subjected to prior to tissue revascularization [14, 79]. Second, the revascularization and vascular remolding of the graft may be the most vital factor for success because it establishes the survival rate of the follicle pool within the graft [2]. The significance of autophagy for vascularization has been demonstrated in recent studies [80, 81]. Microvascular damage is associated with HIF-1-related autophagy [82]. Inhibition of autophagy may significantly enhance the anti-angiogenic activity of the T7 peptide in endothelial cells [83], and macroautophagy (autophagy) is an important factor that affects the function of the vascular endothelial cells (VECs) that must be tightly regulated in these cells [84]. Therefore, autophagy plays an important role in vascularization [85]. Hypoxia is another damage factor for ovarian follicles in ovarian grafts. Hypoxia inducible factor 1 (HIF1) is closely related to ovarian angiogenesis, especially regarding corpus luteum formation and increased expression of VEGF [86-89]; however, hypoxia represents a disadvantage for ovarian grafts. Previous studies have demonstrated that a 6-hour fetal ovary culture without hypoxia prior to transplantation improves graft viability and increases the proportion of primordial and preantral follicles [90]. Moreover, hypoxic preconditioning in vitro was not beneficial to grafts and worsened their viability [91]. However, ischemic preconditioning of the ovary improves graft quality [92, 93]. Autophagy is regulated at the molecular level in different hypoxic environments [94]. It is closely related to the apoptosis caused by hypoxia. Autophagy blocks the induction of apoptosis and inhibits the activation of apoptosis-associated caspase, which may reduce cellular injury. Autophagy or autophagy-relevant proteins may facilitate the induction of apoptosis, which may aggravate cell damage in hypoxic conditions [95]. Moreover, hypoxia induces autophagy in human vascular endothelial cells in a hypoxia-inducible factor 1-dependent manner [82]. Ovarian stromal cell fibrosis is another characteristic of ovarian grafts [53, 78], and autophagy has been associated with fibrosis in studies of hepatic fibrosis [96, 97], airway epithelial fibrosis [98], pulmonary fibrosis [99], and myocardial fibrosis [100-102]. However, whether autophagy accelerates or ameliorates fibrosis is dependent on the stimulus, and the role of autophagy in ovarian fibrosis is not known and remains to be elucidated. ANTI-APOPTOSIS IS NOT THE ONLY MECHANISM OF INTERVENTION Although ovarian follicle loss during ovarian vitrification and transplantation may be decreased by several intervention methods, the primary approach assumes that the mechanism of ovarian follicle loss is apoptosis. Ovarian loss has been partially decreased by anti-apoptotic molecules, such as melatonin [8-10], sphingosine-1-phosphate [11-13], Kit ligand [14], catalase [15], necrostatin [16], simvastatin [17], N-acetylcysteine [18], and antifreeze protein [19]. Moreover, several studies have suggested that 4
autophagy is regulated by melatonin [103, 104] and sphingosine-1-phosphate [105-108]. S1P induced autophagy protects cells from death with apoptotic features during nutrient starvation [109], and S1P induces autophagy toward cell survival [110]. These findings further demonstrate that autophagy is activated during ovarian vitrification and transplantation. However, whether apoptosis and autophagy crosstalk with each other remains unknown. Autophagy is an upstream regulator of apoptosis; it blocks the induction of apoptosis and inhibits the activation of apoptosis-associated caspase, which may reduce cellular injury. Autophagy or autophagy-relevant proteins may facilitate the induction of apoptosis, which may aggravate cell damage. In contrast, the activation of the apoptosis-related protein caspase may also degrade autophagy-related proteins, such as Atg3, Atg4, and Beclin1, which inhibits autophagy [95]. These findings suggest that apoptosis is not the only pathway, and autophagy is involved in ovarian vitrification and transplantation. CONCLUSIONS Despite the partial decrease in ovarian follicle loss by several methods and the birth of 2 babies from vitrified ovaries, the mechanisms of ovarian follicle loss during ovarian vitrification and transplantation have not been fully elucidated. A comprehensive understanding of the mechanism of ovarian follicle loss would provide novel insights into the preservation of follicle survival during ovarian vitrification and transplantation and significantly increase the fertility rate for female cancer patients. The importance of autophagy during ovarian vitrification and transplantation was reviewed as follows: i) autophagy is involved in the follicle atresia induced by cryo-injury during ovarian vitrification; ii) autophagy maintains ovarian homeostasis and pro-survival for ovarian follicles during cryo-injury stress if there is no cell death attributable to the use of the optimal protocol; iii) autophagy is involved in follicle loss through follicle atresia, and follicle reserve depletion is induced by ischemia/reperfusion injury and hypoxic injury; and iv) angiogenesis in ovarian grafts is regulated by autophagy. These findings regarding the importance of autophagy in ovarian vitrification and transplantation provide new insights for future studies that will focus on three points: 1) The function of autophagy during cryo-injury in the process of ovarian vitrification, including the maintenance of ovarian homeostasis or involvement follicle atresia. 2) The role of autophagy during ischemia/reperfusion injury and hypoxic injury in the process of transplantation, including the initiation of follicle atresia or follicle reserve depletion. 3) The functions of autophagy in the angiogenesis to ovarian grafts.
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9
MINIREVIEW
New Insights into the Role of Autophagy in Ovarian Cryopreservation by Vitrification1 Yanzhou Yang 2,5,6, Hoi Hung Cheung 6, Wai Nok Law 6, Cheng Zhang 7, Wai Yee Chan 6, Xiuying Pei 3,5, Yanrong Wang 4,5 5
Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China
6
The Chinese University of Hong Kong–Shandong University Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, HKSAR
7
College of Life Science, Capital Normal University, Beijing, People’s Republic of China
1
This work was supported by the Natural Science Foundation of China (81560259) and the Ningxia higher school science and technology research project (NGY2015093).
2
Correspondence: Yanzhou Yang, E-mail: [email protected] Correspondence: Xiuying Pei, E-mail, [email protected] 4 Correspondence: Yanrong Wang, E-mail [email protected] 3
ABSTRACT Ovarian cryopreservation by vitrification is a highly useful method for preserving female fertility during radiotherapy and chemotherapy. However, cryo-injury, osmotic stress during vitrification, and ischemia/reperfusion during transplantation lead to losses of ovarian follicles. Ovarian follicle loss may be partially reduced by several methods; however, studies regarding the mechanism of ovarian follicle loss have only investigated cell apoptosis, which comprises type I programmed cell death. Autophagy comprises type II programmed cell death, and cell homeostasis is maintained by autophagy during conditions of stress. The role of autophagy during cryopreservation by vitrification has rarely been reported. The potential role of autophagy during ovarian cryopreservation by vitrification is reviewed in this article. KEYWORDS: Autophagy, Ovarian follicle death, Cryo-injury, Osmotic stress, Ischemia/reperfusion, Ovarian cryopreservation, Ovarian transplantation.
Copyright 2016 by The Society for the Study of Reproduction.
INTRODUCTION The cryopreservation of ovarian tissue by vitrification to preserve fertility for patients with cancer has been investigated for decades. To date, the birth of more than 60 babies from the transplantation of cryopreserved ovarian tissue has demonstrated the clinical success of this method [1], and two of these babies were born from vitrified ovarian tissues/follicles. Following recovery from cancer, patients with ovarian transplantation exhibit a complete return of hormonal function and fertility to baseline [2]. Thus, ovarian tissue cryopreservation by vitrification is considered the most significant method for preserving female fertility, especially for young women undergoing chemotherapy. Ovarian damages are often acquired during the process of chemotherapy; specifically, the number of reserved primordial follicles is reduced, which further triggers POF (premature ovarian failure) [3, 4]. Thus, ovarian vitrification and the transplantation of vitrified/warmed ovaries has emerged as an effective method of preserving ovarian function. However, there are numerous problems with the vitrification process, including follicle loss triggered by cryo-injury, osmotic stress during vitrification, and ischemia/reperfusion during transplantation. Specifically, ischemia/reperfusion causes the death of most primordial follicles [5-7]. However, the mechanism of primordial follicle loss in vitrified ovaries and transplanted ovaries remains completely unknown. Most studies have suggested that the death and loss of ovarian follicles during ovarian vitrification and ovarian grafts is primarily caused by apoptosis. Thus, anti-apoptotic agents are used to preserve the survival of ovarian follicles [8-19]; however, the death of ovarian follicles is only partially decreased with limited follicle survival following anti-apoptotic agent administration. Previous studies have suggested that oocyte death mediated primordial follicle atresia and granulosa cell death mediated primary follicle, secondary follicle, tertiary follicle and mature follicle atresia involve an apoptotic dependent pathway [20-26]. Therefore, the mechanism of ovarian follicle loss during ovarian vitrification and transplantation has been considered to be apoptosis. It remains unknown whether another important pathway is involved in ovarian follicle loss. Autophagy is an intracellular bulk degradation system in which a portion of the cytoplasm is enveloped in double membrane-bound structures referred to as autophagosomes, which undergo maturation and fusion with lysosomes for degradation [27, 28]. At a baseline level, autophagy promotes cellular survival; when activated under stress conditions, such as nutrient deprivation [29], hypoxia [30], and ischemia/reperfusion [31], it may lead to cell death. Therefore, autophagy is often dubbed a “double-edged sword” because it is a necessary process for many cells, but its amplification may lead to cell death [32]. Autophagy comprises type II programmed cell death, and its roles in primordial follicle atresia and granulosa cell apoptosis have been demonstrated [33-37]. Nevertheless, whether autophagy is involved in follicle death during ovarian vitrification and transplantation remains elusive. Thus, the potential roles of autophagy in ovarian vitrification and transplantation are summarized in this article. WHETHER FOLLICLE DEATH OCCURS DURING OVARIAN VITRIFICATION Previous studies that have demonstrated apoptosis is triggered by cryo-injury from liquid nitrogen during the vitrification process remain controversial. Most articles have suggested that apoptosis is initiated during ovarian vitrification; however, the apoptotic rate may be decreased during ovarian vitrification by the administration of several anti-apoptotic reagents [11, 12, 14-16, 38], and apoptosis may be decreased by use of the optimal protocol [39-44]. In contrast, other studies have suggested that there is no apoptosis in ovarian vitrification [45, 46], which is attributed to the application of the optimal protocol. However, it remains unknown whether follicle death is initiated by an apoptosis-independent pathway. Two views exist regarding ovarian vitrification: i) apoptosis is triggered in ovarian follicles during vitrification; and ii) apoptosis is not triggered in ovarian follicles during vitrification with the optimal protocol. Thus, three questions arise: i) If the death of ovarian follicles is initiated by cryo-injury, which pathway comprises the trigger for ovarian follicle death? ii) Is there another cell death pathway in addition to the apoptotic pathway that may be initiated by cryo-injury? iii) If ovarian follicle death is not initiated by cryo-injury, which pathway is initiated to adapt to the stress of cryo-injury? 2
APOPTOSIS IS NOT SOLELY RESPONSIBLE FOR FOLLICLE LOSSES FROM OVARIAN GRAFTS Previous studies have suggested that 60-95% of the follicular reserve is depleted during autografting, which induces the loss of virtually the entire population of growing follicles [5, 47-49]. Ovarian follicle losses occur during the early period of ovarian transplantation, which is caused by tissue ischemia and reperfusion injury [50, 51]. The effects of hypoxia following transplantation decrease the reproductive viability of ovarian transplants [52, 53]. Therefore, angiogenesis, which comprises the formation of new blood vessels, is important for the survival of ovarian transplants and the restoration of ovarian function [52]. The damage of transplanted vitrified/warmed ovaries is reduced by simvastatin [17], which decreases apoptosis and stimulates angiogenesis and endothelial cell migration in ovarian grafts via sphingosine-1-phosphate (S1P) [13]. Erythropoietin (EPO) increases angiogenesis in ovarian grafts [54]. Isoform 165 of vascular endothelial growth factor [55] decreases apoptosis, and oxidative stress is inhibited by N-acetylcysteine (NAC) [18]. The reduction of follicle loss and increasing angiogenesis are two core objectives during ovarian transplantation, and three questions must be resolved: i) Previous studies have suggested that follicle loss is triggered by apoptosis; however, it remains unknown whether other cellular death pathways are also initiated in ovarian grafts. ii) The potential mechanism of angiogenesis during ovarian transplantation must be investigated. iii) Primordial follicle intense activation is another pathway for follicle reserve depletion; thus, whether this pathway is initiated during ovarian transplantation must be investigated, as well as the mechanism of primordial follicle intense activation. IMPORTANCE OF AUTOPHAGY IN OVARIAN FOLLICLE ATRESIA AND FOLLICLE RESERVE DEPLETION Autophagy is an evolutionarily conserved mechanism, and it is indispensable for mammalian reproduction [56, 57] from gametogenesis to parturition [57], including embryogenesis [58], fertilization [59], spermatogenesis [60], and the development of the human placenta [61]. Previous studies have suggested that autophagy is involved in oocyte-death mediated primordial follicle atresia, but not apoptosis [33]. Moreover, autophagy mediated granulosa cell apoptosis is involved in primary follicle, secondary follicle, tertiary follicle and mature follicle atresia [34, 35]. Thus, the importance of autophagy in primordial follicle atresia is supported by several studies. Primordial follicle atresia is not a result of apoptotic pathways [36, 37]; it is attributed to autophagy dependent on pathway [33]. Recent studies have suggested that apoptotic and autophagic proteins coexist in fetal oocytes [62]. Furthermore, germline cell death may be apoptotic or non-apoptotic, depending on the stimulus or stage of development [63]. These findings have emphasized the function of autophagy in primordial follicle atresia. Autophagic cell death has not been investigated in ovarian vitrification or ovarian grafts. Another important role of autophagy in follicle reserve has been suggested by several studies in which autophagy is involved in the formation of the primordial follicle pool. Germ cell loss in perinatal mice is caused by the knockout of the autophagic genes BECN1 (Beclin 1) and Atg7 (autophagy related gene 7); there is a 56% germ cell reduction in Becn1+/- mice, and no germ cells are detected in Atg7 -/mice [64]. Germ cell-specific Atg7 knockout results in primary ovarian insufficiency (POI) in female mice, with germ cell over-loss during the neonatal transition period [65]. In addition, premature ovarian failure (POF) is consistently triggered by primordial follicle depletion through knockout of the autophagic activation gene PTEN (phosphatase and tensin homolog deleted on chromosome 10) via negative regulation of PI3K [66], which is a molecule upstream of mTOR. The autophagic activator rapamycin is an inhibitor of mTOR [67]. Inhibition of mTOR pathway activation increases the follicle reserve [68]. Thus, baseline level autophagy is indispensable for the maintenance of the primordial follicle pool, and follicle death is triggered by excess activation of autophagy, whereas the depletion of the primordial follicle pool is triggered by the inhibition of autophagy. IMPORTANCE OF AUTOPHAGY IN OVARIAN VITRIFICATION AND TRANSPLANTATION Autophagy plays a role in ovarian follicle atresia and follicle reserve depletion. Our limited knowledge indicates that autophagy is involved in ovarian vitrification by triggering follicle atresia if 3
ovarian follicle loss occurs in this process or if homeostasis is maintained under the optimal vitrification protocol during cryo-injury. Autophagy is triggered for cell survival in vitrified-warmed mouse oocytes; however, autophagy is not only activated in the cooling process but also the warming stages [69]. Furthermore, Gallardo Bolaños suggests that autophagy is activated for pro-survival in the cryopreservation of stallion spermatozoa; however, apoptosis plays a major role in sperm death during storage [70]. Follicle losses are triggered by ischemia/reperfusion injury [50, 51] and hypoxia injury [51, 52] in ovarian grafts. These findings support the idea that autophagy is involved in the follicle loss of ovarian grafts during ischemia/reperfusion injury, and hypoxia injury triggers follicle atresia or depletion of the primordial follicle pool. Indeed, autophagy mediates follicle atresia [33-37] and depletion of the primordial follicle pool [66, 68]. Furthermore, the importance of autophagy has been investigated during ischemia/reperfusion injury by several studies regarding liver transplantation [71-73] and renal transplantation [74-76]. In addition, a recent novel insight suggests that follicle activation and “burn-out” contribute to post-transplantation follicle loss in ovarian tissue grafts [53, 77]. This phenomenon may be attributable to the vitrification protocol, in which Amorim’s vitrification protocol has a positive impact on the quiescent state of primordial follicles following xenografting and does not activate the resting follicle reserve [78]. It has consistently been hypothesized that massive activation of primordial follicles is a consequence of the ischemic stress that the ovarian graft is subjected to prior to tissue revascularization [14, 79]. Second, the revascularization and vascular remolding of the graft may be the most vital factor for success because it establishes the survival rate of the follicle pool within the graft [2]. The significance of autophagy for vascularization has been demonstrated in recent studies [80, 81]. Microvascular damage is associated with HIF-1-related autophagy [82]. Inhibition of autophagy may significantly enhance the anti-angiogenic activity of the T7 peptide in endothelial cells [83], and macroautophagy (autophagy) is an important factor that affects the function of the vascular endothelial cells (VECs) that must be tightly regulated in these cells [84]. Therefore, autophagy plays an important role in vascularization [85]. Hypoxia is another damage factor for ovarian follicles in ovarian grafts. Hypoxia inducible factor 1 (HIF1) is closely related to ovarian angiogenesis, especially regarding corpus luteum formation and increased expression of VEGF [86-89]; however, hypoxia represents a disadvantage for ovarian grafts. Previous studies have demonstrated that a 6-hour fetal ovary culture without hypoxia prior to transplantation improves graft viability and increases the proportion of primordial and preantral follicles [90]. Moreover, hypoxic preconditioning in vitro was not beneficial to grafts and worsened their viability [91]. However, ischemic preconditioning of the ovary improves graft quality [92, 93]. Autophagy is regulated at the molecular level in different hypoxic environments [94]. It is closely related to the apoptosis caused by hypoxia. Autophagy blocks the induction of apoptosis and inhibits the activation of apoptosis-associated caspase, which may reduce cellular injury. Autophagy or autophagy-relevant proteins may facilitate the induction of apoptosis, which may aggravate cell damage in hypoxic conditions [95]. Moreover, hypoxia induces autophagy in human vascular endothelial cells in a hypoxia-inducible factor 1-dependent manner [82]. Ovarian stromal cell fibrosis is another characteristic of ovarian grafts [53, 78], and autophagy has been associated with fibrosis in studies of hepatic fibrosis [96, 97], airway epithelial fibrosis [98], pulmonary fibrosis [99], and myocardial fibrosis [100-102]. However, whether autophagy accelerates or ameliorates fibrosis is dependent on the stimulus, and the role of autophagy in ovarian fibrosis is not known and remains to be elucidated. ANTI-APOPTOSIS IS NOT THE ONLY MECHANISM OF INTERVENTION Although ovarian follicle loss during ovarian vitrification and transplantation may be decreased by several intervention methods, the primary approach assumes that the mechanism of ovarian follicle loss is apoptosis. Ovarian loss has been partially decreased by anti-apoptotic molecules, such as melatonin [8-10], sphingosine-1-phosphate [11-13], Kit ligand [14], catalase [15], necrostatin [16], simvastatin [17], N-acetylcysteine [18], and antifreeze protein [19]. Moreover, several studies have suggested that 4
autophagy is regulated by melatonin [103, 104] and sphingosine-1-phosphate [105-108]. S1P induced autophagy protects cells from death with apoptotic features during nutrient starvation [109], and S1P induces autophagy toward cell survival [110]. These findings further demonstrate that autophagy is activated during ovarian vitrification and transplantation. However, whether apoptosis and autophagy crosstalk with each other remains unknown. Autophagy is an upstream regulator of apoptosis; it blocks the induction of apoptosis and inhibits the activation of apoptosis-associated caspase, which may reduce cellular injury. Autophagy or autophagy-relevant proteins may facilitate the induction of apoptosis, which may aggravate cell damage. In contrast, the activation of the apoptosis-related protein caspase may also degrade autophagy-related proteins, such as Atg3, Atg4, and Beclin1, which inhibits autophagy [95]. These findings suggest that apoptosis is not the only pathway, and autophagy is involved in ovarian vitrification and transplantation. CONCLUSIONS Despite the partial decrease in ovarian follicle loss by several methods and the birth of 2 babies from vitrified ovaries, the mechanisms of ovarian follicle loss during ovarian vitrification and transplantation have not been fully elucidated. A comprehensive understanding of the mechanism of ovarian follicle loss would provide novel insights into the preservation of follicle survival during ovarian vitrification and transplantation and significantly increase the fertility rate for female cancer patients. The importance of autophagy during ovarian vitrification and transplantation was reviewed as follows: i) autophagy is involved in the follicle atresia induced by cryo-injury during ovarian vitrification; ii) autophagy maintains ovarian homeostasis and pro-survival for ovarian follicles during cryo-injury stress if there is no cell death attributable to the use of the optimal protocol; iii) autophagy is involved in follicle loss through follicle atresia, and follicle reserve depletion is induced by ischemia/reperfusion injury and hypoxic injury; and iv) angiogenesis in ovarian grafts is regulated by autophagy. These findings regarding the importance of autophagy in ovarian vitrification and transplantation provide new insights for future studies that will focus on three points: 1) The function of autophagy during cryo-injury in the process of ovarian vitrification, including the maintenance of ovarian homeostasis or involvement follicle atresia. 2) The role of autophagy during ischemia/reperfusion injury and hypoxic injury in the process of transplantation, including the initiation of follicle atresia or follicle reserve depletion. 3) The functions of autophagy in the angiogenesis to ovarian grafts.
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