Unequal segregation of parental chromosomes in embryonic stem cell hybrids

Matveeva, N. M.; Pristyazhnyuk, Inna E.; Temirova, S. A.; Мензоров, А. Г.; Vasilkova, Anna A.; Shilov, A. A.; Smith, Austin; Serov, O. L.

doi:10.1002/mrd.20266

Cited by 36 publications

(25 citation statements)

References 27 publications

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“…Unequal segregation of chromosomes and even a degree of chromosome selectivity in this process favoring the embryonic chromosomes (ie, loss of somatic chromosomes) has been reported. 51 It is therefore possible that the complete somatic genome contingent of somatic/ESC hybrid cells may not be represented in the teratoma cells, and this might lead to false impressions of genome reprogramming.…”

Section: Discussionmentioning

confidence: 99%

Checkpoint-apoptosis uncoupling in human and mouse embryonic stem cells: a source of karyotpic instability

Mantel

Guo

Lee

et al. 2007

Blood

132

116

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Karyotypic abnormalities in cultured embryonic stem cells (ESCs), especially near-diploid aneuploidy, are potential obstacles to ESC use in regenerative medicine. Events causing chromosomal abnormalities in ESCs may be related to events in tumor cells causing chromosomal instability (CIN) in human disease. However, the underlying mechanisms are unknown. Using multiparametric permeabilized-cell flow cytometric analysis, we found that the mitotic-spindle checkpoint, which helps maintain chromosomal integrity during all cell divisions, functions in human and mouse ESCs, but does not initiate apoptosis as it does in somatic cells. This allows an unusual tolerance to polyploidy resulting from failed mitosis, which is common in rapidly proliferating cell populations and which is reduced to near-diploid aneuploidy, which is also common in human neoplastic disease. Checkpoint activation in ESC-derived early-differentiated cells results in robust apoptosis without polyploidy/aneuploidy similar to that in IntroductionAn important task facing living organisms from birth to death is maintenance of the genome and its transfer to offspring. Elaborate mechanisms have developed to detect, repair, and prevent transfer of genome damage. 1,2 Mechanisms such as DNA repair or apoptotic culling of damaged cells have been evolutionarily conserved from the simplest multicellular organisms. Genome maintenance is especially important in cells of developing mammalian embryos deriving from a single zygotic cell and in adult stem cells, such as hematopoietic stem cells. A particularly vulnerable time in the life of eutherian mammals is the time from fertilization through cleavage and blastocyst formation, prior to uterine implantation, where developing embryos must survive almost independent from maternal nurturing. A highly specialized program of cellular regulation operates during this time, especially in pluripotent embryonic stem cells (ESCs) derived from the blastocyst that give rise to all adult somatic tissues. [3][4][5][6][7][8][9][10][11] ESCs from several mammalian species, including humans, isolated and cultured in vitro as immortalized cell lines, 12,13 provide the potential for therapeutic use in humans. Understanding these specialized embryonic strategies of genome maintenance is necessary to ensure their safe and effective use and may also reveal clues for studies of potentially similar behavior in adult stem cells.Immortalized mouse (m) and human (h) ESCs are subject to genetic and epigenetic instability, primarily chromosomal aberrations such as loss of heterozygosity, uniparental disomy, and aneuploidy. [14][15][16][17][18][19][20][21] This increases the risk of tumorigenic potential and other complications if hESCs are to be used therapeutically. Such behavior is likely related to their specialized strategies for genome maintenance, such as truncated cell cycles with very short or absent gap phases and differences in certain cell-cycle checkpoints compared with somatic cells. 2-5 A problem with analyzing protein biochemi...

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Section: Discussionmentioning

confidence: 99%

Checkpoint-apoptosis uncoupling in human and mouse embryonic stem cells: a source of karyotpic instability

Mantel

Guo

Lee

et al. 2007

Blood

132

116

View full text Add to dashboard Cite

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“…Analysis of the chromosomal makeup of both interspecies (Matveeva et al 1998(Matveeva et al , 2005Vasilkova et al 2007) and intraspecies (Matveeva et al 2005;Vasilkova et al 2007) of ES-somatic hybrids demonstrated that most ES cell markers were present for most chromosomes, while somatic markers were present only for a few chromosome pairs suggesting that the somatic chromosomes were preferentially lost. This unequal segregation of parental chromosomes and preferential loss of somatic chromosomes observed in some interand intraspecies mouse ES-somatic cell hybrids suggest that pluripotential is maintained by the ES chromosomes in a cisacting and not in a trans-acting manner (Vasilkova et al 2007).…”

Section: Introductionmentioning

confidence: 98%

Chromosomal and telomeric reprogramming following ES-somatic cell fusion

et al. 2009

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Chromosomal and telomeric reprogramming was assessed in intraspecies hybrids obtained by fusion of embryonic stem (ES) cells and mouse embryonic fibroblasts. Evaluation of the ploidy of ES-somatic hybrids revealed that 21 of 59 clones had a tetraploid DNA profile while the remaining clones showed deviations from the expected profile of fusion between two diploid cells. Microsatellite polymerase chain reaction analysis of four of these clones demonstrated no random loss of somatic chromosome pairs in the ES-somatic cell hybrids. Pluripotential of ES-somatic hybrids was assessed by gene expression analysis, antibody staining for Oct4 and SSEA-1 and teratoma formation containing derivatives of the three germ layers. Reprogramming of telomeric maintenance was observed with ES-somatic hybrids showing high telomerase activity and increased telomere lengths. However, we detected no significant increase in the expression of the three critical telomerase subunits: telomerase reverse transcriptase (TERT), telomerase RNA component (TERC), and dyskerin. This indicates that activation of telomerase and telomere maintenance is not reliant on changes in gene expression of TERT, TERC, and dyskerin following ES-somatic cell fusion or sister chromatid recombination and may arise through elimination of negative regulation of telomerase activity. This is the first demonstration of telomere lengthening following cell fusion and offers a new model for studying and identifying new regulators of telomere maintenance.

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“…In contrast, the DNA content of triploid V79 Chinese hamster lung cells that were established from diploid cells was stable during long-term culturing (FujikawaYamamoto et al 2002). Matveeva et al (2005) reported that the chromosome number was stable in (ES cell)-(ES cell) hybrids, but not in (ES cell)-(somatic cell) hybrids. We were interested in whether or not the DNA content decays in tetraploid ES cells in differentiate circumstances.…”

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confidence: 99%

Cell Proliferation of Diploid and Tetraploid H1 (ES) Cells in L15F10 Medium without Leukemia Inhibitory Factor

et al. 2008

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SummaryMouse diploid and tetraploid H-1 (ES) cells cultured in L15F10 medium (2nH1 and 4nH1 cells, respectively) without leukemia inhibitory factor (LIF) (2nH1 (Ϫ) and 4nH1 (Ϫ) cells, respectively) were examined for their growth and cellular characteristics. Though the doubling times of 2nH1 (Ϫ) and 4nH1 (Ϫ) cells were longer than those of 2nH1 and 4nH1 cells, the phase fractions of 2nH1 (Ϫ) and 4nH1 (Ϫ) cells were the same as those of 2nH1 and 4nH1 cells, suggesting that occasional cell deaths occurred. DNA loss in long-term culturing was observed in 4nH1 (Ϫ) cells, but not in 2nH1 (Ϫ) cells, suggesting that DNA decay was independent of LIF. The cell volume, cellular morphology, and the pluripotent potential of 2nH1 (Ϫ) and 4nH1 (Ϫ) cells were retained during long-term culturing, suggesting that 2nH1 (Ϫ) and 4nH1 (Ϫ) cells survived in the medium without LIF had similar characteristics to those of 2nH1 and 4nH1 cells, respectively.

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Unequal segregation of parental chromosomes in embryonic stem cell hybrids

Cited by 36 publications

References 27 publications

Checkpoint-apoptosis uncoupling in human and mouse embryonic stem cells: a source of karyotpic instability

Checkpoint-apoptosis uncoupling in human and mouse embryonic stem cells: a source of karyotpic instability

Chromosomal and telomeric reprogramming following ES-somatic cell fusion

Cell Proliferation of Diploid and Tetraploid H1 (ES) Cells in L15F10 Medium without Leukemia Inhibitory Factor

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