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Article ; Online: The Role of Mitochondria in Oocyte Maturation.

Kirillova, Anastasia / Smitz, Johan E J / Sukhikh, Gennady T / Mazunin, Ilya

2021 Volume 10, Issue 9

Abstract: With the nucleus as an exception, mitochondria are the only animal cell organelles containing their own genetic information, called mitochondrial DNA (mtDNA). During oocyte maturation, the mtDNA copy number dramatically increases and the distribution of ... ...

Abstract	With the nucleus as an exception, mitochondria are the only animal cell organelles containing their own genetic information, called mitochondrial DNA (mtDNA). During oocyte maturation, the mtDNA copy number dramatically increases and the distribution of mitochondria changes significantly. As oocyte maturation requires a large amount of ATP for continuous transcription and translation, the availability of the right number of functional mitochondria is crucial. There is a correlation between the quality of oocytes and both the amount of mtDNA and the amount of ATP. Suboptimal conditions of in vitro maturation (IVM) might lead to changes in the mitochondrial morphology as well as alternations in the expression of genes encoding proteins associated with mitochondrial function. Dysfunctional mitochondria have a lower ability to counteract reactive oxygen species (ROS) production which leads to oxidative stress. The mitochondrial function might be improved with the application of antioxidants and significant expectations are laid on the development of new IVM systems supplemented with mitochondria-targeted reagents. Different types of antioxidants have been tested already on animal models and human rescue IVM oocytes, showing promising results. This review focuses on the recent observations on oocytes' intracellular mitochondrial distribution and on mitochondrial genomes during their maturation, both in vivo and in vitro. Recent mitochondrial supplementation studies, aiming to improve oocyte developmental potential, are summarized.
MeSH term(s)	Animals ; Antioxidants/metabolism ; Humans ; Mitochondria/physiology ; Oocytes/cytology ; Oocytes/physiology ; Oogenesis ; Oxidative Stress ; Reactive Oxygen Species/metabolism
Chemical Substances	Antioxidants ; Reactive Oxygen Species
Language	English
Publishing date	2021-09-19
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10092484
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Article ; Online: In vitro

Herta, Anamaria C / Lolicato, Francesca / Smitz, Johan E J

Reproduction (Cambridge, England)

2018 Volume 156, Issue 1, Page(s) F59–F73

Abstract: The currently available assisted reproduction techniques for fertility preservation (i.e. ...

Abstract	The currently available assisted reproduction techniques for fertility preservation (i.e.
MeSH term(s)	Female ; Fertility Preservation/methods ; Fertilization in Vitro/methods ; Humans ; In Vitro Oocyte Maturation Techniques/methods ; Ovarian Follicle/cytology ; Vitrification
Language	English
Publishing date	2018-06-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2034501-X
ISSN	1741-7899 ; 1470-1626 ; 1476-3990
ISSN (online)	1741-7899
ISSN	1470-1626 ; 1476-3990
DOI	10.1530/REP-18-0173
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Article ; Online: Mouse oocytes restore antral stage partial mechanical denudation in vitro.

Herta, Anamaria-Cristina / Akin, Nazli / Segers, Ingrid / Billooye, Katy / Smitz, Johan / Anckaert, Ellen

Reproduction (Cambridge, England)

2023 Volume 166, Issue 6, Page(s) 369–381

Abstract: In brief: Partially denuded mouse cumulus-oocyte complexes restore likely functional transzonal projections in culture, under meiotic inhibition, with no detectable impact on oocyte competence. This proof-of-concept study constitutes positive premises ... ...

Abstract	In brief: Partially denuded mouse cumulus-oocyte complexes restore likely functional transzonal projections in culture, under meiotic inhibition, with no detectable impact on oocyte competence. This proof-of-concept study constitutes positive premises for improving the developmental competence of human capacitation (CAPA)-in vitro maturation (IVM) oocytes with inadequate somatic cell connections. Abstract: In vitro oocyte culture might be the sole option for fertility preservation in some patients. This relies on constant oocyte-somatic bidirectional communication, and its precocious disruption alters oocyte competence. In non-human chorionic gonadotropin-triggered human in vitro maturation (IVM), retrieval of cumulus-oocyte complexes (COCs) by needle aspiration from the targeted small follicles (2-8 mm) leads to the collection of some partially denuded (PD) COCs with poor developmental competence. Hypothetically, re-establishing connectivity in these COCs could rescue oocyte quality. To test this, we used a well-characterized mouse preantral follicle culture system. On day 8, at antral stage, in part of the follicles, the oocytes were mechanically denuded while in other follicles in vitro grown oocytes were replaced with age matched fully stripped in vivo grown ones. The denuded oocytes were cultured on top of the somatic compartment until day 12, when oocyte-somatic reconnection was assessed. Furthermore, to better mimic the current biphasic IVM setup, fully surrounded (FS) COCs were collected from 19- to 21- day-old unprimed mice. Following partial mechanical denudation, COCs were cultured under meiotic inhibition for 2-4 days, to test oocyte-cumulus cell (CC) reconnection. Meiotic and developmental competence endpoints were compared between reconnected and FS-cultured COCs. We concluded that (i) in vivo- and in vitro- grown antral oocytes reconnect with in vitro-grown somatic companions; (ii) PD-COCs restore the FS morphology in culture, under meiotic inhibition; and (iii) oocyte quality from reconnected and intact cultured COCs is comparable. These observations encourage translational work to rescue partially denuded oocytes in human IVM.
MeSH term(s)	Female ; Humans ; Animals ; Mice ; Ovarian Follicle ; In Vitro Oocyte Maturation Techniques ; Oocytes ; Meiosis ; Cumulus Cells
Language	English
Publishing date	2023-10-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2034501-X
ISSN	1741-7899 ; 1470-1626 ; 1476-3990
ISSN (online)	1741-7899
ISSN	1470-1626 ; 1476-3990
DOI	10.1530/REP-23-0191
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Article ; Online: Protective Effects of Antioxidants on Cyclophosphamide-Induced Ovarian Toxicity.

Barberino, Ricássio S / Silva, Regina Lucia S / Palheta Junior, Raimundo C / Smitz, Johan E J / Matos, Maria Helena T

Biopreservation and biobanking

2022 Volume 21, Issue 2, Page(s) 121–141

Abstract: The most common limitation of anticancer chemotherapy is the injury to normal cells. Cyclophosphamide, which is one of the most widely used alkylating agents, can cause premature ovarian insufficiency and infertility since the ovarian follicles are ... ...

Abstract	The most common limitation of anticancer chemotherapy is the injury to normal cells. Cyclophosphamide, which is one of the most widely used alkylating agents, can cause premature ovarian insufficiency and infertility since the ovarian follicles are extremely sensitive to their effects. Although little information is available about the pathogenic mechanism of cyclophosphamide-induced ovarian damage, its toxicity is attributed to oxidative stress, inflammation, and apoptosis. The use of compounds with antioxidant and cytoprotective properties to protect ovarian function from deleterious effects during chemotherapy would be a significant advantage. Thus, this article reviews the mechanism by which cyclophosphamide exerts its toxic effects on the different cellular components of the ovary, and describes 24 cytoprotective compounds used to ameliorate cyclophosphamide-induced ovarian injury and their possible mechanisms of action. Understanding these mechanisms is essential for the development of efficient and targeted pharmacological complementary therapies that could protect and prolong female fertility.
MeSH term(s)	Female ; Humans ; Antioxidants/pharmacology ; Antioxidants/therapeutic use ; Cyclophosphamide/adverse effects ; Ovarian Follicle ; Primary Ovarian Insufficiency/chemically induced ; Primary Ovarian Insufficiency/prevention & control ; Primary Ovarian Insufficiency/pathology
Chemical Substances	Antioxidants ; Cyclophosphamide (8N3DW7272P)
Language	English
Publishing date	2022-06-13
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2593993-2
ISSN	1947-5543 ; 1947-5535
ISSN (online)	1947-5543
ISSN	1947-5535
DOI	10.1089/bio.2021.0159
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Article ; Online: Are human oocytes from stem cells next?

Smitz, Johan E J / Gilchrist, Robert B

Nature biotechnology

2016 Volume 34, Issue 12, Page(s) 1247–1248

MeSH term(s)	Animals ; Female ; Germ Cells ; Humans ; Mice ; Oocytes ; Stem Cells
Language	English
Publishing date	2016-11-28
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
DOI	10.1038/nbt.3742
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Zs.A 2167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: The Role of Mitochondria in Oocyte Maturation

Anastasia Kirillova / Johan E. J. Smitz / Gennady T. Sukhikh / Ilya Mazunin

Cells, Vol 10, Iss 2484, p

2021 Volume 2484

Abstract	With the nucleus as an exception, mitochondria are the only animal cell organelles containing their own genetic information, called mitochondrial DNA (mtDNA). During oocyte maturation, the mtDNA copy number dramatically increases and the distribution of mitochondria changes significantly. As oocyte maturation requires a large amount of ATP for continuous transcription and translation, the availability of the right number of functional mitochondria is crucial. There is a correlation between the quality of oocytes and both the amount of mtDNA and the amount of ATP. Suboptimal conditions of in vitro maturation (IVM) might lead to changes in the mitochondrial morphology as well as alternations in the expression of genes encoding proteins associated with mitochondrial function. Dysfunctional mitochondria have a lower ability to counteract reactive oxygen species (ROS) production which leads to oxidative stress. The mitochondrial function might be improved with the application of antioxidants and significant expectations are laid on the development of new IVM systems supplemented with mitochondria-targeted reagents. Different types of antioxidants have been tested already on animal models and human rescue IVM oocytes, showing promising results. This review focuses on the recent observations on oocytes’ intracellular mitochondrial distribution and on mitochondrial genomes during their maturation, both in vivo and in vitro. Recent mitochondrial supplementation studies, aiming to improve oocyte developmental potential, are summarized.
Keywords	oocyte maturation ; mtDNA copy number ; mitochondria distribution ; IVM ; mitochondrial supplementation reagents ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Prospects of Rescuing Young Eggs for Oncofertility.

Bertoldo, Michael J / Smitz, Johan / Wu, Lindsay E / Lee, Hoi Chang / Woodruff, Teresa K / Gilchrist, Robert B

Trends in endocrinology and metabolism: TEM

2020 Volume 31, Issue 10, Page(s) 708–711

Abstract: Childhood cancer patients undergoing cancer therapy can be rendered infertile during adulthood. With more girls surviving cancer, fertility preservation in young cancer patients is a major clinical challenge. Advances in egg culture may offer benefits ... ...

Abstract	Childhood cancer patients undergoing cancer therapy can be rendered infertile during adulthood. With more girls surviving cancer, fertility preservation in young cancer patients is a major clinical challenge. Advances in egg culture may offer benefits for the fertility of these patients in the future.
MeSH term(s)	Animals ; Cancer Survivors ; Child ; Cryopreservation ; Female ; Fertility Preservation ; Humans ; Oocytes
Language	English
Publishing date	2020-08-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1042384-9
ISSN	1879-3061 ; 1043-2760
ISSN (online)	1879-3061
ISSN	1043-2760
DOI	10.1016/j.tem.2020.07.004
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Article ; Online: Genome-wide assessment of DNA methylation alterations induced by superovulation, sexual immaturity and in vitro follicle growth in mouse blastocysts.

Saucedo-Cuevas, Laura / Ivanova, Elena / Herta, Anamaria-Cristina / Krueger, Felix / Billooye, Katy / Smitz, Johan / Kelsey, Gavin / Anckaert, Ellen

Clinical epigenetics

2023 Volume 15, Issue 1, Page(s) 9

Abstract: Background: In their attempt to fulfill the wish of having children, women who suffer from fertility issues often undergo assisted reproductive technologies such as ovarian stimulation, which has been associated with adverse health outcomes and ... ...

Abstract	Background: In their attempt to fulfill the wish of having children, women who suffer from fertility issues often undergo assisted reproductive technologies such as ovarian stimulation, which has been associated with adverse health outcomes and imprinting disorders in children. However, given the crucial role of exogenous hormone stimulation in improving human infertility treatments, a more comprehensive analysis of the potential impacts on DNA methylation in embryos following ovarian stimulation is needed. Here, we provide genome-wide DNA methylation profiles of blastocysts generated after superovulation of prepubertal or adult mice, compared with blastocysts derived from non-stimulated adult mice. Additionally, we assessed the impact of the in vitro growth and maturation of oocytes on methylation in blastocysts. Results: Neither hormone stimulation nor sexual maturity had an impact on the low global methylation levels characteristic of the blastocyst stage or was associated with extensive DNA methylation alterations. However, we found hormone- and age-associated changes at specific positions but dispersed throughout the genome. In particular, we detected anomalous methylation at a limited number of CpG islands. Additionally, superovulation in adult mice was associated with alterations at the Sgce and Zfp777 imprinted genes. On the other hand, in vitro culture of follicles from the early pre-antral stage was associated with globally reduced methylation and increased variability at imprinted loci in blastocysts. Conclusions: Our results indicate a minimal effect of ovarian stimulation of adult and prepubertal mice on the DNA methylation landscape attained at the blastocyst stage, but potentially greater impacts of in vitro growth and maturation of oocytes. These findings have potential significance for the improvement of assisted reproductive techniques, in particular for those related to treatments in prepubertal females, which could be crucial for improving human fertility preservation strategies.
MeSH term(s)	Animals ; Female ; Mice ; Blastocyst/metabolism ; DNA Methylation ; Hormones/metabolism ; Oocytes/metabolism ; Superovulation
Chemical Substances	Hormones
Language	English
Publishing date	2023-01-16
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553921-8
ISSN	1868-7083 ; 1868-7075
ISSN (online)	1868-7083
ISSN	1868-7075
DOI	10.1186/s13148-023-01421-z
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Article ; Online: Immunolocalization of melatonin receptor type 1 in the sheep ovary and involvement of the PI3K/Akt/FOXO3a signaling pathway in the effects of melatonin on survival and in vitro activation of primordial follicles.

Barberino, Ricássio S / Macedo, Taís J S / Lins, Thae Lanne B G / Menezes, Vanúzia G / Silva, Regina L S / Monte, Alane P O / Palheta, Raimundo C / Smitz, Johan E J / Matos, Maria Helena T

Molecular reproduction and development

2022 Volume 89, Issue 10, Page(s) 485–497

Abstract: This study characterized the expression of melatonin receptor type 1 (MT ... 1 ... ) protein in sheep ovaries, evaluated melatonin effects on primordial follicle survival and development after in vitro culture of ovarian tissue and verified the ... ...

Abstract	This study characterized the expression of melatonin receptor type 1 (MT<sub>1</sub> ) protein in sheep ovaries, evaluated melatonin effects on primordial follicle survival and development after in vitro culture of ovarian tissue and verified the possible involvement of the phosphatidylinositol-3-kinase/protein kinase B/forkhead box O3a (PI3K/Akt/FOXO3a) pathway in the melatonin actions. Ovine ovarian fragments were cultured in α-modified minimum essential medium alone (α-MEM<sup>+</sup> ) or supplemented with 100, 500, or 1000 pg/ml melatonin for 7 days. PI3K inhibition was performed through pretreatment of ovarian fragments with LY294002. Thereafter, immunohistochemistry was performed to evaluate the expression of cleaved caspase-3, Akt, phosphorylated-Akt, and phosphorylated-FOXO3a (p-FOXO3a). The immunohistochemical localization of the MT<sub>1</sub> receptor protein was documented in sheep preantral and antral follicles. After in vitro culture, 100 pg/ml melatonin showed higher follicular survival and activation than α-MEM<sup>+</sup> and other melatonin concentrations. After PI3K inhibition, there was an increase in cleaved caspase-3-positive follicles, and a decrease in the primordial follicle activation, Akt phosphorylation, and nuclear exclusion of p-FOXO3a. In conclusion, MT<sub>1</sub> receptor protein is present in the sheep ovary. Furthermore, 100 pg/ml melatonin maintains survival and stimulates activation of primordial follicles through the PI3K/Akt/FOXO3a signaling pathway after in vitro culture of sheep ovarian tissue.
MeSH term(s)	Female ; Sheep ; Animals ; Proto-Oncogene Proteins c-akt/metabolism ; Ovary/metabolism ; Melatonin/pharmacology ; Melatonin/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Receptors, Melatonin/metabolism ; Caspase 3/metabolism ; Signal Transduction ; Phosphatidylinositols/metabolism ; Phosphatidylinositols/pharmacology
Chemical Substances	Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Melatonin (JL5DK93RCL) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Receptors, Melatonin ; Caspase 3 (EC 3.4.22.-) ; alpha minimal essential medium ; Phosphatidylinositols
Language	English
Publishing date	2022-08-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	20321-x
ISSN	1098-2795 ; 1040-452X
ISSN (online)	1098-2795
ISSN	1040-452X
DOI	10.1002/mrd.23639
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Zs.A 2759: Show issues

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Article ; Online: Non-invasive cumulus cell analysis can be applied for oocyte ranking and is useful for countries with legal restrictions on embryo generation or freezing.

Adriaenssens, Tom / Van Vaerenbergh, Inge / Van Landuyt, Lisbet / Verheyen, Greta / De Brucker, Michaël / Camus, Michel / Platteau, Peter / De Vos, Michel / Reis, Maria / Van Hecke, Elien / Rosenthal, André / Smitz, Johan

PloS one

2024 Volume 19, Issue 1, Page(s) e0297040

Abstract: Research question: Can a strategy for scoring oocyte quality, based on cumulus cell (CC) gene expression, prioritize oocytes with the highest implantation potential, while limiting the number of embryos to be processed in culture and the number of ... ...

Abstract	Research question: Can a strategy for scoring oocyte quality, based on cumulus cell (CC) gene expression, prioritize oocytes with the highest implantation potential, while limiting the number of embryos to be processed in culture and the number of supernumerary embryos to be vitrified? Design: An interventional, blinded, prospective cohort study was retrospectively analyzed. In the original study, patients underwent a fresh Day3 single embryo transfer with embryos ranked based on morphology and CC gene expression (Aurora Test). The additional ranking of the embryos with the Aurora Test resulted in significant higher clinical pregnancy and live birth rates. Now it is investigated if the Aurora Test ranking could be applied to select oocytes. The effect of an Aurora Test based restriction to 2 and 3 2PN or MII oocytes on clinical pregnancy and other outcomes, was analyzed in two subsets of patients with all 2PN (n = 83) or all MII oocytes (n = 45) ranked. Results: Considering only the top three ranked 2PN oocytes, 95% of the patients would have received a fresh SET on Day3 resulting in 65% clinical pregnancies. This was not different from the pregnancy rate obtained in a strategy using all oocytes but significantly reduced the need for vitrification of supernumerary embryos by 3-fold. Considering only top-ranked MII oocytes gave similar results. Conclusions: In countries with legal restrictions on freezing of embryos, gene expression of CC can be used for the selective processing of oocytes and would thus decrease the twin pregnancy rate and workload, especially for embryo morphology scoring and transfers as the handling and processing of lower competence oocytes is prevented, while improving the ART outcome.
MeSH term(s)	Pregnancy ; Female ; Humans ; Freezing ; Retrospective Studies ; Prospective Studies ; Embryo Transfer ; Cumulus Cells/metabolism ; Oocytes/metabolism ; Pregnancy Rate ; Vitrification ; Cryopreservation/methods
Language	English
Publishing date	2024-01-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0297040
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