First pilot study of maternal spindle transfer for the treatment of repeated in vitro fertilization failures in couples with idiopathic infertility

Costa-Borges, Nuno; Nikitos, Eros; Spath, K; Miguel-Escalada, Irene; Ma, Hong; Rink, Klaus; Coudereau, Clément; Darby, Hayley; Koski, Amy; Dyken, Crystal Van; Mestres, Enric; Papakyriakou, Evmorfia; Ziegler, Dominique de; Kontopoulos, George; Mantzavinos, Themis; Vasilopoulos, Ioannis; Grigorakis, Stylianos; Prokopakis, Thomas; Mystakidis, Stylianos; Polyzos, Panagiotis; Vlachos, Nikolaos; Kostaras, Konstantinos; Mitalipov, Shoukhrat; Calderón, Gloria; Psathas, Panagiotis; Wells, Dagan

doi:10.1016/j.fertnstert.2023.02.008

Cited by 34 publications

(19 citation statements)

References 23 publications

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“…Moreover, we showed that MII cytoplasts could induce de novo formation of functional spindles from transplanted DNA of polar body 1 (PB1) ( 14 ). In humans, use of donor MII cytoplasts as a machinery for accurate chromosome segregation has been clinically applied to replace mutant mitochondrial DNA or deficient cytoplasm in patient oocytes, resulting in the birth of healthy children ( 15 ).…”

Section: Resultsmentioning

confidence: 99%

Induction of somatic cell haploidy by premature cell division

Mikhalchenko,

Gutierrez,

Frana

et al. 2024

Sci. Adv.

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Canonical mitotic and meiotic cell divisions commence with replicated chromosomes consisting of two sister chromatids. Here, we developed and explored a model of premature cell division, where nonreplicated, G 0 /G 1 -stage somatic cell nuclei are transplanted to the metaphase cytoplasm of mouse oocytes. Subsequent cell division generates daughter cells with reduced ploidy. Unexpectedly, genome sequencing analysis revealed proper segregation of homologous chromosomes, resulting in complete haploid genomes. We observed a high occurrence of somatic genome haploidization in nuclei from inbred genetic backgrounds but not in hybrids, emphasizing the importance of sequence homology between homologs. These findings suggest that premature cell division relies on mechanisms similar to meiosis I, where genome haploidization is facilitated by homologous chromosome interactions, recognition, and pairing. Unlike meiosis, no evidence of recombination between somatic cell homologs was detected. Our study offers an alternative in vitro gametogenesis approach by directly reprogramming diploid somatic cells into haploid oocytes.

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Section: Resultsmentioning

confidence: 99%

Induction of somatic cell haploidy by premature cell division

Mikhalchenko,

Gutierrez,

Frana

et al. 2024

Sci. Adv.

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“…ST refers to the transfer of spindle apparatus from MII oocyte to denucleated MII donor oocyte ( 191 ). A pilot study conducted in Europe reported the feasibility of ST technology, targeting 25 couples with recurrent IVF failures and giving birth to 6 newborns over 28 ST and ICSI cycles ( 192 ). However, it is worth noting that one child with the same low mtDNA carryover (0.8%) in the blastocyst stage showed an increase in maternal mtDNA haplotype, accounting for 30% to 60% of the total number at birth ( 192 ).…”

Section: Methods To Slow Down Ovarian Aging and Prolong Reproductive ...mentioning

confidence: 99%

Mechanisms of mitochondrial dysfunction in ovarian aging and potential interventions

Ju,

Zhao,

et al. 2024

Front. Endocrinol.

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Mitochondria plays an essential role in regulating cellular metabolic homeostasis, proliferation/differentiation, and cell death. Mitochondrial dysfunction is implicated in many age-related pathologies. Evidence supports that the dysfunction of mitochondria and the decline of mitochondrial DNA copy number negatively affect ovarian aging. However, the mechanism of ovarian aging is still unclear. Treatment methods, including antioxidant applications, mitochondrial transplantation, emerging biomaterials, and advanced technologies, are being used to improve mitochondrial function and restore oocyte quality. This article reviews key evidence and research updates on mitochondrial damage in the pathogenesis of ovarian aging, emphasizing that mitochondrial damage may accelerate and lead to cellular senescence and ovarian aging, as well as exploring potential methods for using mitochondrial mechanisms to slow down aging and improve oocyte quality.

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“…In the other case, the treatment was performed in couples with idiopathic infertility, without any previous detection of mitochondrial disease, by a mixed Spanish-Greek team in Greece, resulting in the birth of six healthy children [30]. The study involved twenty-five infertile couples with multiple previous unsuccessful IVF attempts (3)(4)(5)(6)(7)(8)(9)(10)(11), no previous pregnancy, no confirmed history of mitochondrial disease, and a female age of <40 years.…”

Section: Mitochondrial Replacement Therapiesmentioning

confidence: 99%

“…Their previous IVF attempts were characterized by a pattern of low fertilization rates and/or impaired embryo development. Couples with severe male factor infertility were excluded [30].…”

Section: Mitochondrial Replacement Therapiesmentioning

confidence: 99%

Mitochondria in Human Fertility and Infertility

Mendoza-Tesarik¹

2023

IJMS

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In human spermatozoa and oocytes (and their surrounding granulosa cells), mitochondria carry out important functions relating to human fertility and infertility. Sperm mitochondria are not transmitted to the future embryo, but are closely related to the generation of energy needed for sperm movement, capacitation, and acrosome reactions, as well as for sperm–oocyte fusion. On the other hand, oocyte mitochondria produce energy required for oocyte meiotic division and their abnormalities can thus cause oocyte and embryo aneuploidy. In addition, they play a role in oocyte calcium metabolism and in essential epigenetic events during the oocyte-to-embryo transition. They are transmitted to the future embryos and may thus cause hereditary diseases in the offspring. Due to the long life span of the female germ cells, the accumulation of mitochondrial DNA abnormalities often causes ovarian aging. Mitochondrial substitution therapy is the only way of dealing with these issues nowadays. New therapies based on mitochondrial DNA editing are under investigation.

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First pilot study of maternal spindle transfer for the treatment of repeated in vitro fertilization failures in couples with idiopathic infertility

Cited by 34 publications

References 23 publications

Induction of somatic cell haploidy by premature cell division

Induction of somatic cell haploidy by premature cell division

Mechanisms of mitochondrial dysfunction in ovarian aging and potential interventions

Mitochondria in Human Fertility and Infertility

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