Mitochondria as a tool for oocyte rejuvenation
2019; Elsevier BV; Volume: 111; Issue: 2 Linguagem: Inglês
10.1016/j.fertnstert.2018.10.036
ISSN1556-5653
AutoresElena Labarta, María José de los Santos, Marı́a José Escribá, António Pellicer, Sonia Herraiz,
Tópico(s)Renal and related cancers
ResumoOvarian aging leads to a decrease in the quantity and quality of oocytes. Aged oocytes have significantly reduced amounts of mitochondria, the energy factories of cells, leading to lower fertilization rates and poor embryonic development. Various techniques have tried to use heterologous or autologous sources of mitochondria to reestablish oocyte health by providing more energy. However, heterologous sources are no longer used owing to the known risk of heteroplasmy. Although autologous methods have recently been tested in humans, they have not shown a clear improvement in embryo quality. In this review, we describe the techniques that have been tested in recent years to provide a state of the art on oocyte rejuvenation through extra injection of mitochondria. Ovarian aging leads to a decrease in the quantity and quality of oocytes. Aged oocytes have significantly reduced amounts of mitochondria, the energy factories of cells, leading to lower fertilization rates and poor embryonic development. Various techniques have tried to use heterologous or autologous sources of mitochondria to reestablish oocyte health by providing more energy. However, heterologous sources are no longer used owing to the known risk of heteroplasmy. Although autologous methods have recently been tested in humans, they have not shown a clear improvement in embryo quality. In this review, we describe the techniques that have been tested in recent years to provide a state of the art on oocyte rejuvenation through extra injection of mitochondria. Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/40541-27075 Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/40541-27075 Advanced maternal age is considered to be the major cause of infertility in developed countries. Women have delayed the age to desired motherhood, bringing along an associated decline in oocyte yield and euploid embryo rates (1Munné S. Cohen J. Sable D. Preimplantation genetic diagnosis for advanced maternal age and other indications.Fertil Steril. 2002; 78: 234-236Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 2Franasiak J.M. Forman E.J. Hong K.H. Werner M.D. Upham K.M. 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Zhuang G.L. et al.Low mitochondrial DNA and ATP contents contribute to the absence of birefringent spindle imaged with Polscope in in vitro matured human oocytes.Hum Reprod. 2007; 22: 1681-1686Crossref PubMed Scopus (111) Google Scholar, 5Zhang X. Wu X.Q. Lu S. Guo Y.L. Ma X. Deficit of mitochondria-derived ATP during oxidative stress impairs mouse MII oocyte spindles.Cell Res. 2006; 16: 841-850Crossref PubMed Scopus (187) Google Scholar). Therefore, insufficiency in cell energetics due to low mitochondrial adenosine triphosphate (ATP) synthesis could be considered a cause of chromosomal aberrations and could determine both oocyte and embryo quality (6Wiernsperger N. Nivoit P. de Aguiar L.G. Bouskela E. Microcirculation and the metabolic syndrome.Microcirculation. 2007; 14: 403-438Crossref PubMed Scopus (65) Google Scholar), because ATP levels have been correlated with improved in vitro fertilization (IVF) outcomes in human oocytes (7van Blerkom J. Davis P.W. Lee J. ATP content of human oocytes and developmental potential and outcome after in-vitro fertilization and embryo transfer.Hum Reprod. 1995; 10: 415-424Crossref PubMed Scopus (541) Google Scholar). Increasing age is associated with reduced mitochondrial endowment in granulosa cells (8Seifer D.B. DeJesus V. Hubbard K. Mitochondrial deletions in luteinized granulosa cells as a function of age in women undergoing in vitro fertilization.Fertil Steril. 2002; 78: 1046-1048Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar) and more numerous deletions in ovarian mitochondrial DNA (9Suganuma N. Kitagawa T. Nawa A. Tomoda Y. Human ovarian aging and mitochondrial DNA deletion.Horm Res. 1993; 39: 16-21Crossref PubMed Scopus (29) Google Scholar). Moreover, mitochondrial DNA copy number in oocytes from patients with previous fertilization failure due to unknown causes is significantly lower than in patients with fertilization failure due to severe sperm factor (10Reynier P. May-Panloup P. Chretien M.F. Morgan C.J. Jean M. Savagner F. et al.Mitochondrial DNA content affects the fertilizability of human oocytes.Mol Hum Reprod. 2001; 7: 425-429Crossref PubMed Scopus (386) Google Scholar). Due to the relevance of aging in infertility, methods to rejuvenate and improve oocyte quality have been developed by introducing new sources of energy (11Bentov Y. Casper R.F. The aging oocyte—can mitochondrial function be improved?.Fertil Steril. 2013; 99: 18-22Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). Nonhuman animal studies show that impaired mitochondrial function leads to reduced preimplantation development of bovine oocytes and that mitochondrial supplementation into those oocytes restores embryo developmental capability, producing healthy calves (12Chiaratti M.R. Ferreira C.R. Perecin F. Meo S.C. Sangalli J.R. Mesquita L.G. et al.Ooplast-mediated developmental rescue of bovine oocytes exposed to ethidium bromide.Reprod Biomed Online. 2011; 22: 172-183Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar). In humans (13Barritt J.A. Brenner C.A. Malter H.E. Cohen J. Mitochondria in human offspring derived from ooplasmic transplantation.Hum Reprod. 2001; 16: 513-516Crossref PubMed Scopus (265) Google Scholar, 14Cohen J. Scott R. Alikani M. Schimmel T. Munne S. Levron J. et al.Ooplasmic transfer in mature human oocytes.Mol Hum Reprod. 1998; 4: 269-280Crossref PubMed Scopus (280) Google Scholar, 15Lanzendorf S.E. Mayer J.F. Toner J. Oehninger S. Saffan D.S. Muasher S. Pregnancy following transfer of ooplasm from cryopreserved-thawed donor oocytes into recipient oocytes.Fertil Steril. 1999; 71: 575-577Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar), as in multiple other animal species (4Zeng H.T. Ren Z. Yeung W.S. Shu Y.M. Xu Y.W. Zhuang G.L. et al.Low mitochondrial DNA and ATP contents contribute to the absence of birefringent spindle imaged with Polscope in in vitro matured human oocytes.Hum Reprod. 2007; 22: 1681-1686Crossref PubMed Scopus (111) Google Scholar, 12Chiaratti M.R. Ferreira C.R. Perecin F. Meo S.C. Sangalli J.R. Mesquita L.G. et al.Ooplast-mediated developmental rescue of bovine oocytes exposed to ethidium bromide.Reprod Biomed Online. 2011; 22: 172-183Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 16Yi Y.C. Chen M.J. Ho J.Y. Guu H.F. Ho E.S. Mitochondria transfer can enhance the murine embryo development.J Assist Reprod Genet. 2007; 24: 445-449Crossref PubMed Scopus (36) Google Scholar, 17Pinkert C.A. Irwin M.H. Johnson L.W. Moffatt R.J. Mitochondria transfer into mouse ova by microinjection.Transgenic Res. 1997; 6: 379-383Crossref PubMed Scopus (86) Google Scholar, 18El Shourbagy S.H. Spikings E.C. Freitas M. St John J.C. Mitochondria directly influence fertilisation outcome in the pig.Reproduction. 2006; 131: 233-245Crossref PubMed Scopus (254) Google Scholar), the addition of mitochondria or cytoplasm from donor oocytes to heterologous oocytes has been claimed to improve egg quality and IVF success. Indeed, although not currently in use due to ethical burdens related to heteroplasmy (mixing of mitochondrial DNA from a donor oocyte with mitochondrial DNA from a recipient heterologous oocyte), 25 babies have been delivered by donor cytoplasm injection (13Barritt J.A. Brenner C.A. Malter H.E. Cohen J. Mitochondria in human offspring derived from ooplasmic transplantation.Hum Reprod. 2001; 16: 513-516Crossref PubMed Scopus (265) Google Scholar, 14Cohen J. Scott R. Alikani M. Schimmel T. Munne S. Levron J. et al.Ooplasmic transfer in mature human oocytes.Mol Hum Reprod. 1998; 4: 269-280Crossref PubMed Scopus (280) Google Scholar, 15Lanzendorf S.E. Mayer J.F. Toner J. Oehninger S. Saffan D.S. Muasher S. Pregnancy following transfer of ooplasm from cryopreserved-thawed donor oocytes into recipient oocytes.Fertil Steril. 1999; 71: 575-577Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). In these human studies, the presence of more than one source of mitochondrial DNA in the resulting egg was considered to be experimental and thus required further testing as mandated by the United States Food and Drug Administration (FDA). However, further testing was not pursued by the IVF clinics that published this approach, with the hope that new technologies could provide an autologous source of mitochondria. Furthermore, ethical concerns related to the babies’ health and especially to the transmission of mitochondrial diseases from the donor led to the advice of the FDA to stop using these mitochondrial replacement techniques. Creation of gametes from induced pluripotent cells by means of cell reprogramming could be an alternate source of healthy oocytes (and spermatozoa) and could change this practice. However, the well known epigenetic changes that occur in these cells limits use of this approach owing to safety concerns (19Hayashi 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; 338: 971-975Crossref PubMed Scopus (524) Google Scholar). Pluripotent stem cells can be an interesting source of other cellular regeneration alternatives. Human pluripotent stem cells (20Wanet A. Arnould T. Najimi M. Renard P. Connecting mitochondria, metabolism, and stem cell fate.Stem Cells Dev. 2015; 24: 1957-1971Crossref PubMed Scopus (202) Google Scholar) display undifferentiated, round, and globular immature mitochondria, similar to those found in the human metaphase II (MII) oocyte (21Schatten H. Sun Q.Y. Prather R. The impact of mitochondrial function/dysfunction on IVF and new treatment possibilities for infertility.Reprod Biol Endocrinol. 2014; 12: 111Crossref PubMed Scopus (106) Google Scholar), perinuclearly localized and containing few cristae, characteristic of energy production by glycolysis instead of by oxidative phosphorylation. Unlike induced pluripotent cells, ovarian or oogonial stem cells (OSCs) are unipotent and can differentiate only into the oocyte lineage, but they also contain the improved cell machinery and energetics of germline cells, so they could be an ideal source to repair aged cell content from old oocytes. Although there is controversy related to the existence of these cells (22Zhang H. Panula S. Petropoulos S. Edsgard D. Busayavalasa K. Liu L. et al.Adult human and mouse ovaries lack DDX4-expressing functional oogonial stem cells.. 2015; 21: 1116-1118Google Scholar), several groups propose that OSCs can be collected, cultured, and developed into oocytes under certain conditions (23Johnson J. Canning J. Kaneko T. Pru J.K. Tilly J.L. Germline stem cells and follicular renewal in the postnatal mammalian ovary.Nature. 2004; 428: 145-150Crossref PubMed Scopus (983) Google Scholar, 24White Y.A. Woods D.C. Takai Y. Ishihara O. Seki H. Tilly J.L. Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women.Nat Med. 2012; 18: 413-421Crossref PubMed Scopus (524) Google Scholar). Therefore, OSCs could be a perfect source for mitochondrial supplementation, because they represent an autologous source of mitochondria that can be obtained from the patient herself. This approach seems to solve challenges raised by the use of heterologous mitochondrial donor oocytes and the ethical burdens associated with heteroplasmy because there is only one source of mitochondrial DNA (OSCs and recipient oocytes from same patient). In this review, we aim to provide an overview of state of the art techniques for mitochondrial supplementation when applied as a tool to increase oocyte developmental potential and oocyte rejuvenation. With this purpose, advantages and limitations of each mitochondrial source and procedure are highlighted in the quest for a suitable and successful source of young, healthy, autologous mitochondria to improve oocyte and embryo quality. All the methods described are used once the first meiotic division has occurred; the mitochondrial supplementation at this stage can not repair any aneuploidy that originated before. Oocyte rejuvenation by mitochondrial supplementation has been achieved at varying success rates following approaches that include heterologous or autologous mitochondrial replacement. In this section, we review such approaches and discuss their goals and biases. A scheme of these techniques is shown in Figure 1. Partial cytoplasm transfer (or cytotransfer) implies transference of several components included as a portion of donor oocyte cytoplasm or cytoplasm to restore recipient oocyte competence and improve embryo quality. Unlike transfer of isolated mitochondria, this technique also involves transfer of other cytoplasmic organelles, metabolic intermediates, energy factors, proteins, and a diverse pool of RNAs present in the human oocyte (25Sathananthan A.H. Ultrastructural changes during meiotic maturation in mammalian oocytes: unique aspects of the human oocyte.Microsc Res Tech. 1994; 27: 145-164Crossref PubMed Scopus (49) Google Scholar, 26Sathananthan A.H. 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Two approaches were initially investigated with this purpose: fusion of donor oocyte cytoplast (membrane-enclosed cytoplasm fraction) with patient oocyte, or direct injection of a small amount of donor cytoplasm into a patient oocyte. Normal fertilization rates are significantly higher after direct cytoplasm injection (63%, five cases) compared with fusion (23%, three cases) (14Cohen J. Scott R. Alikani M. Schimmel T. Munne S. Levron J. et al.Ooplasmic transfer in mature human oocytes.Mol Hum Reprod. 1998; 4: 269-280Crossref PubMed Scopus (280) Google Scholar). Therefore, the fusion approach was abandoned and replaced by a more efficient and simple technique consisting of a modified intracytoplasmic sperm injection (ICSI) procedure, where both the sperm and ∼5%–10% of donor cytoplasm are simultaneously injected into a recipient oocyte. This methodology was used for the majority of reported cytoplasm transfers (14Cohen J. Scott R. Alikani M. Schimmel T. Munne S. Levron J. et al.Ooplasmic transfer in mature human oocytes.Mol Hum Reprod. 1998; 4: 269-280Crossref PubMed Scopus (280) Google Scholar, 30Cohen J. Scott R. Schimmel T. Levron J. Willadsen S. Birth of infant after transfer of anucleate donor oocyte cytoplasm into recipient eggs.Lancet. 1997; 350: 186-187Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar). Several sources of donor cytoplasm have been tested for transference, including fresh and cryopreserved MII oocytes and tripronuclear zygotes. Depending on the developmental cell-cycle stage between donor and recipient cells, procedures were also described as synchronous transfer (when both cells were at the same stage, MII to MII) or asynchronic (interphase zygote cytoplasm into MII [13Barritt J.A. Brenner C.A. Malter H.E. Cohen J. Mitochondria in human offspring derived from ooplasmic transplantation.Hum Reprod. 2001; 16: 513-516Crossref PubMed Scopus (265) Google Scholar, 31Darbandi S. Darbandi M. Khorram Khorshid H.R. Sadeghi M.R. Agarwal A. Sengupta P. et al.Ooplasmic transfer in human oocytes: efficacy and concerns in assisted reproduction.Reprod Biol Endocrinol. 2017; 15: 77Crossref PubMed Scopus (21) Google Scholar]), challenging the rationale behind the original idea (32Krauchunas A.R. Wolfner M.F. Molecular changes during egg activation.Curr Top Dev Biol. 2013; 102: 267-292Crossref PubMed Scopus (44) Google Scholar, 33Zhang L. Jiang X.H. [Ultrastructure of unfertilized human oocytes and undivided human zygoytes].Sichuan Da Xue Xue Bao Yi Xue Ban. 2010; 41: 810-813PubMed Google Scholar). Using synchronous cytotransfer, a total of 21 babies out of 78 IVF procedures have been born (13Barritt J.A. Brenner C.A. Malter H.E. Cohen J. Mitochondria in human offspring derived from ooplasmic transplantation.Hum Reprod. 2001; 16: 513-516Crossref PubMed Scopus (265) Google Scholar, 15Lanzendorf S.E. Mayer J.F. Toner J. Oehninger S. Saffan D.S. Muasher S. Pregnancy following transfer of ooplasm from cryopreserved-thawed donor oocytes into recipient oocytes.Fertil Steril. 1999; 71: 575-577Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 34Opsahl M.S. Thorsell L.P. Geltinger M.E. Iwaszko M.A. Blauer K.L. Sherins R.J. Donor oocyte cytoplasmic transfer did not enhance implantation of embryos of women with poor ovarian reserve.J Assist Reprod Genet. 2002; 19: 113-117Crossref PubMed Scopus (8) Google Scholar, 35Dale B. Wilding M. Botta G. Rasile M. Marino M. Di Matteo L. et al.Pregnancy after cytoplasmic transfer in a couple suffering from idiopathic infertility: case report.Hum Reprod. 2001; 16: 1469-1472Crossref PubMed Google Scholar). Regarding asynchronous transfers, five offspring out of nine IVF procedures were achieved in patients who had repeated implantation failure (36Huang C.C. Cheng T.C. Chang H.H. Chang C.C. Chen C.I. Liu J. et al.Birth after the injection of sperm and the cytoplasm of tripronucleate zygotes into metaphase II oocytes in patients with repeated implantation failure after assisted fertilization procedures.Fertil Steril. 1999; 72: 702-706Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). Fresh donor oocytes have been the most used cytoplasm source. However, this strategy demands exquisite synchrony between donor and recipient oocyte retrievals. Thus, cryopreserved oocytes seem to be a good option to facilitate the entire process, as suggested by pregnancies (15Lanzendorf S.E. Mayer J.F. Toner J. Oehninger S. Saffan D.S. Muasher S. Pregnancy following transfer of ooplasm from cryopreserved-thawed donor oocytes into recipient oocytes.Fertil Steril. 1999; 71: 575-577Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 34Opsahl M.S. Thorsell L.P. Geltinger M.E. Iwaszko M.A. Blauer K.L. Sherins R.J. Donor oocyte cytoplasmic transfer did not enhance implantation of embryos of women with poor ovarian reserve.J Assist Reprod Genet. 2002; 19: 113-117Crossref PubMed Scopus (8) Google Scholar) and live births of healthy male and female babies in young patients with poor embryo quality (15Lanzendorf S.E. Mayer J.F. Toner J. Oehninger S. Saffan D.S. Muasher S. Pregnancy following transfer of ooplasm from cryopreserved-thawed donor oocytes into recipient oocytes.Fertil Steril. 1999; 71: 575-577Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). However, the competence of such cryopreserved cytoplasm still needs to be quantified, because it did not improve clinical outcomes in patients with advanced maternal age (34Opsahl M.S. Thorsell L.P. Geltinger M.E. Iwaszko M.A. Blauer K.L. Sherins R.J. Donor oocyte cytoplasmic transfer did not enhance implantation of embryos of women with poor ovarian reserve.J Assist Reprod Genet. 2002; 19: 113-117Crossref PubMed Scopus (8) Google Scholar). Concerns with mitochondrial heteroplasmy prompted a search for the presence of donor mitochondrial DNA in the recipients. This active search demonstrated that donor mitochondrial DNA lasts throughout development, with positive results in arrested embryos, amniocytes, placentas, fetal cord, and blood saliva smears of children (13Barritt J.A. Brenner C.A. Malter H.E. Cohen J. Mitochondria in human offspring derived from ooplasmic transplantation.Hum Reprod. 2001; 16: 513-516Crossref PubMed Scopus (265) Google Scholar, 37Brenner C.A. Barritt J.A. Willadsen S. Cohen J. Mitochondrial DNA heteroplasmy after human ooplasmic transplantation.Fertil Steril. 2000; 74: 573-578Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 38Chen S.H. Pascale C. Jackson M. Szvetecz M.A. Cohen J. A limited survey-based uncontrolled follow-up study of children born after ooplasmic transplantation in a single centre.Reprod Biomed Online. 2016; 33: 737-744Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). As recently demonstrated by Chen et al. (38Chen S.H. Pascale C. Jackson M. Szvetecz M.A. Cohen J. A limited survey-based uncontrolled follow-up study of children born after ooplasmic transplantation in a single centre.Reprod Biomed Online. 2016; 33: 737-744Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar), such tissue heteroplasmy did not negatively affect cytotransfer in children aged 13–18 years (38Chen S.H. Pascale C. Jackson M. Szvetecz M.A. Cohen J. A limited survey-based uncontrolled follow-up study of children born after ooplasmic transplantation in a single centre.Reprod Biomed Online. 2016; 33: 737-744Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). However, because available data are rather limited and the research did not continue, the benefit of cytotransfer remains unknown. Total cytoplasm transfer refers to thorough replacement of a pathologic cytoplasm with a competent one with the use of nuclear transfer technology. This strategy, originally proposed to overcome maternal mitochondrial disease transmission by transferring the maternal spindle into a healthy recipient donor cytoplasm (the “three-parent baby” technique), may also provide a potential therapeutic option for women who suffer from age-related infertility by transferring the germinal vesicle (GV) nucleus or metaphase spindle from an older woman's oocyte into a donated cytoplasm from a young woman. Whereas both GV and spindle transfer techniques have been extensively explored in nonhuman domestic mammals (39Zhang J. Liu H. Luo S. Lu Z. Chavez-Badiola A. Liu Z. et al.Live birth derived from oocyte spindle transfer to prevent mitochondrial disease.Reprod Biomed Online. 2017; 34: 361-368Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar, 40Fulka Jr., J. First N.L. Moor R.M. Nuclear and cytoplasmic determinants involved in the regulation of mammalian oocyte maturation.Mol Hum Reprod. 1998; 4: 41-49Crossref PubMed Scopus (133) Google Scholar, 41Fulka Jr., J. Loi P. Ledda S. Moor R.M. Fulka J. Nucleus transfer in mammals: how the oocyte cytoplasm modifies the transferred nucleus.Theriogenology. 2001; 55: 1373-1380Crossref PubMed Scopus (23) Google Scholar, 42Liu H. Chang H.C. Zhang J. Grifo J. Krey L.C. Metaphase II nuclei generated by germinal vesicle transfer in mouse oocytes support embryonic development to term.Hum Reprod. 2003; 18: 1903-1907Crossref PubMed Scopus (38) Google Scholar, 43Liu H. Wang C.W. Grifo J.A. Krey L.C. Zhang J. Reconstruction of mouse oocytes by germinal vesicle transfer: maturity of host oocyte cytoplasm determines meiosis.Hum Reprod. 1999; 14: 2357-2361Crossref PubMed Scopus (71) Google Scholar, 44Liu H. Zhang J. Krey L.C. Grifo J.A. In-vitro development of mouse zygotes following reconstruction by sequential transfer of germinal vesicles and haploid pronuclei.Hum Reprod. 2000; 15: 1997-2002Crossref PubMed Scopus (42) Google Scholar, 45Zhang J. Wang C.W. Krey L. Liu H. Meng L. Blaszczyk A. et al.In vitro maturation of human preovulatory oocytes reconstructed by germinal vesicle transfer.Fertil Steril. 1999; 71: 726-731Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar), the unique “three-parent baby” technique to avoid mitochondrial disease transmission (39Zhang J. Liu H. Luo S. Lu Z. Chavez-Badiola A. Liu Z. et al.Live birth derived from oocyte spindle transfer to prevent mitochondrial disease.Reprod Biomed Online. 2017; 34: 361-368Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar) requires a thorough safety assessment and alternate genetic sources before clinical implementation in humans. Technically, GV transfer is efficient in all studied species (mice, humans, and rabbit). Moreover, it has been reported that the invasive nuclear handling does not compromise fertilization or subsequent embryo development to the blastocyst stage. In this scenario, efficiency might be due to recipient cytoplast competence. Thus, using the human model or xeno-oocytes (human nuclear origin and immature GV cytoplasm from rabbit or mice [46Zhang J. Liu H. Cytoplasm replacement following germinal vesicle transfer restores meiotic maturation and spindle assembly in meiotically arrested oocytes.Reprod Biomed Online. 2015; 31: 71-78Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar]), transferred GV can progress to the MII stage but follows cytoplasmic dominance for species-specific maturation dynamics and rates. In mice, the procedure is reported to be ∼12%–18% to term (42Liu H. Chang H.C. Zhang J. Grifo J. Krey L.C. Metaphase II nuclei generated by germinal vesicle transfer in mouse oocytes support embryonic development to term.Hum Reprod. 2003; 18: 1903-1907Crossref PubMed Scopus (38) Google Scholar). In humans, studies report that four out of seven human oocytes reconstructed from GV of old oocytes (women aged >38 y) with cytoplasm of young oocytes (women aged <31 y) display normal second meiotic chromosome complement (45Zhang J. Wang C.W. Krey L. Liu H. Meng L. Blaszczyk A. et al.In vitro maturation of human preovulatory oocytes reconstructed by germinal vesicle transfer.Fertil Steril. 1999; 71: 726-731Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). Furthermore, in the limited number of observations of an aged GV transferred into a younger ooplasm, an appropriate chromosomal segregation was recorded, demonstrating that this kind of human GV-reconstituted oocyte is able to undergo maturation, fertilization, and embryo cleavage, maintaining normal ploidy (47Takeuchi T. Gong J. Veeck L.L. Rosenwaks Z. Palermo G.D. Preliminary findings in germinal vesicle transplantation of immature human oocytes.Hum Reprod. 2001; 16: 730-736Crossref PubMed Scopus (51) Google Scholar). Ultrastructure studies of human GV oocytes show that some mitochondria adjacent to the GV are likely carried over into reconstructed oocytes during GV transfer (26Sathananthan A.H. Ultrastructure of the human egg.Hum Cell. 1997; 10: 21-38PubMed Google Scholar), thus creating mitochondrial DNA heteroplasmy. Therefore, besides the maturation process itself, which requires improvement, a challenge in most GV transfer techniques is to completely remove mitochondrial DNA from the patient when performing GV transfer. Similarly, spindle transfer is technically reliable in several nonhuman mammalian species. However, in mice, nearly 5.5% heteroplasmy is detected in pups from F1 and F2 after GV transfer (48Wang T. Sha H. Ji D. Zhang H.L. Chen D. Cao Y. et al.Polar body genome transfer for preventing the transmission of inherited mitochondrial diseases.Cell. 2014; 157: 1591-1604Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar). Similar to mitochondrial “contamination” due to GV transfer, pronuclear (PN) transfer also induces a high level of heteroplasmy in mice (48Wang T. Sha H. Ji D. Zhang H.L. Chen D. Cao Y. et al.Polar body genome transfer for preventing the transmission of inherited mitochondrial diseases.Cell. 2014; 157: 1591-1604Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar). In humans, several ethical concerns rule out this strategy, because embryo generation and destruction are required for subsequent parental reconstruction on a healthy cytoplasm. Alternatively, Wakayama and Yanagimachi (49Wakayama T. Yanagimachi R. The first polar body can be used for the production of normal offspring in mice.Biol Reprod. 1998; 59: 100-104Crossref PubMed Scopus (72) Google Scholar) proposed and demonstrated the potential reproductive use of all four subproducts of meiosis in mice. The two polar bodies (PBs) have been used for reproductive endings and live-born pups (48Wang T. Sha H. Ji D. Zhang H.L. Chen D. Cao Y. et al.Polar body genome transfer for preventing the transmission of inherited mitochondrial diseases.Cell. 2014; 157: 1591-1604Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar, 49Wakayama T. Yanagimachi R. The first polar body c
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