Impact of meiotic and mitotic non-disjunction on generation of human embryonic stem cell lines

Verlinsky, Yury; Strelchenko, Nick; Kukharenko, V. I.; Zech, Nicolas H.; Shkumatov, Artem; Zlatopolsky, Zev; Kuliev, Anver

doi:10.1016/s1472-6483(10)60433-6

Cited by 10 publications

(5 citation statements)

References 30 publications

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“…In a recent publication, Conlin et al [25] used a similar approach to uncover the origin of the aneuploidy in patients with chromosomal mosaicism, uniparental disomy, and chimerism. Another study aiming to derive aneuploid hESCs reported very low incidence of aneuploidies, and based on earlier biopsies of the embryos concluded that all cell lines have originated from meiotic errors [26, 27]. On the other hand, CSES16 and CSES23 carrying trisomy of chromosome 13 or X respectively, were found to originate from mitotic errors during the cleavage of the zygote.…”

Section: Discussionmentioning

confidence: 99%

Human Embryonic Stem Cells as Models for Aneuploid Chromosomal Syndromes

et al. 2010

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Syndromes caused by chromosomal aneuploidies are widely recognized genetic disorders in humans and often lead to spontaneous miscarriage. Preimplantation genetic screening is used to detect chromosomal aneuploidies in early embryos. Our aim was to derive aneuploid human embryonic stem cell (hESC) lines that may serve as models for human syndromes caused by aneuploidies. We have established 25 hESC lines from blastocysts diagnosed as aneuploid on day 3 of their in vitro development. The hESC lines exhibited morphology and expressed markers typical of hESCs. They demonstrated long-term proliferation capacity and pluripotent differentiation. Karyotype analysis revealed that two-third of the cell lines carry a normal euploid karyotype, while one-third remained aneuploid throughout the derivation, resulting in eight hESC lines carrying either trisomy 13 (Patau syndrome), 16, 17, 21 (Down syndrome), X (Triple X syndrome), or monosomy X (Turner syndrome). On the basis of the level of single nucleotide polymorphism heterozygosity in the aneuploid chromosomes, we determined whether the aneuploidy originated from meiotic or mitotic chromosomal nondisjunction. Gene expression profiles of the trisomic cell lines suggested that all three chromosomes are actively transcribed. Our analysis allowed us to determine which tissues are most affected by the presence of a third copy of either chromosome 13, 16, 17 or 21 and highlighted the effects of trisomies on embryonic development. The results presented here suggest that aneuploid embryos can serve as an alternative source for either normal euploid or aneuploid hESC lines, which represent an invaluable tool to study developmental aspects of chromosomal abnormalities in humans. STEM CELLS 2010;28:1530-1540 Disclosure of potential conflicts of interest is found at the end of this article.

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Section: Discussionmentioning

confidence: 99%

Human Embryonic Stem Cells as Models for Aneuploid Chromosomal Syndromes

et al. 2010

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“…However, human embryos are replaced whole to the uterus and do not grow in monolayer, plus they do not go through so many passages before differentiating into tissues. In addition, according to Verlinsky et al [53] abnormal embryos that self correct in monolayer had often started as normal zygotes that became abnormal postmeiotically (normal polar bodies, abnormal day 3 biopsy), and thus were already mosaics, than those that started as abnormal zygotes (abnormal polar bodies, abnormal day 3 biopsy).…”

Section: Introductionmentioning

confidence: 99%

Preimplantation Genetic Diagnosis for Aneuploidy and Translocations Using Array Comparative Genomic Hybridization

Munné¹

2012

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At least 50% of human embryos are abnormal, and that increases to 80% in women 40 years or older. These abnormalities result in low implantation rates in embryos transferred during in vitro fertilization procedures, from 30% in women <35 years to 6% in women 40 years or older. Thus selecting normal embryos for transfer should improve pregnancy results. The genetic analysis of embryos is called Preimplantation Genetic Diagnosis (PGD) and for chromosome analysis it was first performed using FISH with up to 12 probes analyzed simultaneously on single cells. However, suboptimal utilization of the technique and the complexity of fixing single cells produced conflicting results. PGD has been invigorated by the introduction of microarray testing which allows for the analysis of all 24 chromosome types in one test, without the need of cell fixation, and with staggering redundancy, making the test much more robust and reliable. Recent data published and presented at scientific meetings has been suggestive of increased implantation rates and pregnancy rates following microarray testing, improvements in outcome that have been predicted for quite some time. By using markers that cover most of the genome, not only aneuploidy can be detected in single cells but also translocations. Our validation results indicate that array CGH has a 6Mb resolution in single cells, and thus the majority of translocations can be analyzed since this is also the limit of karyotyping. Even for translocations with smaller exchanged fragments, provided that three out of the four fragments are above 6Mb, the translocation can be detected.

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“…Frydman et al [11] reported a low derivation rate (4.5 %) from PGDblastocysts with chromosomal abnormalities whereas Peura et al [22] and Taei et al [31] presented derivation rates of 26.8 % and 18.2 % respectively. Verlinsky et al [40,41] found a correlation between chromosomal aneuploidies and the efficiency of establishing hESC lines; they observed that embryos with aneuploidies originated from meiotic non-disjunction have a lower derivation rate than those resulting from mitotic non-disjunction. Ilic et al, [13] referred no hESC lines established from 12 karyotypically abnormal embryos versus 2 lines from 4 normal embryos.…”

Section: Discussionmentioning

confidence: 99%

Vitrified blastocysts from Preimplantation Genetic Diagnosis (PGD) as a source for human Embryonic Stem Cell (hESC) derivation

Arán

Solé

Rodríguez-Pizà

et al. 2012

J Assist Reprod Genet

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Embryos diagnosed as abnormal in Preimplantation Genetic Diagnosis (PGD) cycles are useful for the establishment of human Embryonic Stem Cells (hESC) lines with genetic disorders. These lines can be helpful for drug screening and for the development of new treatments. Vitrification has proved to be an efficient method to preserve human blastocysts. One hundred and three abnormal or undiagnosed vitrified blastocysts from the PGD programme at Institut Universitari Dexeus were donated for human embryonic stem cell derivation. The overall survival rate after warming was 70.6 %. Our results showed better survival rates when blastocysts have not started the hatching process (initial/expanded 87.8 %, hatching 68.3 % and hatched 27.3 %). Thirty-five blastocysts and 12 partially surviving embryos were seeded. One hESC line with the multiple exostoses type 2 paternal mutation was obtained.

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Impact of meiotic and mitotic non-disjunction on generation of human embryonic stem cell lines

Cited by 10 publications

References 30 publications

Human Embryonic Stem Cells as Models for Aneuploid Chromosomal Syndromes

Human Embryonic Stem Cells as Models for Aneuploid Chromosomal Syndromes

Preimplantation Genetic Diagnosis for Aneuploidy and Translocations Using Array Comparative Genomic Hybridization

Vitrified blastocysts from Preimplantation Genetic Diagnosis (PGD) as a source for human Embryonic Stem Cell (hESC) derivation

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