Dynamic Changes in the Copy Number of Pluripotency and Cell Proliferation Genes in Human ESCs and iPSCs during Reprogramming and Time in Culture

Laurent, Louise C.; Ulitsky, Igor; Slavin, Ileana; Tran, Ha Thi Thanh; Schork, Andrew J.; Morey, Robert; Lynch, C.; Harness, Julie V.; Lee, Sunray; Barrero, María J.; Ku, Sherman; Martynova, M. Yu.; Semechkin, Ruslan; Galat, Vasiliy; Gottesfeld, Joel M.; Belmonte, Juan Carlos Izpisúa; Murry, Chuck; Keirstead, Hans S.; Park, Hyun Sook; Schmidt, Uli; Laslett, Andrew L.; Müller, Franz‐Josef; Nievergelt, Caroline M.; Shamir, Ron; Loring, Jeanne F.

doi:10.1016/j.stem.2010.12.003

Cited by 820 publications

(767 citation statements)

References 31 publications

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“…Another study focused on copy number variation (CNV) (approximately 0.6-12,000 kb stretches of genomic DNA) of a large number of pluripotent and somatic samples. iPSC had on average 17 CNV per sample [70]. As a comparison ESC also had 17 and nonpluripotent samples had 12 CNV.…”

Section: Mutational Load Of Ipscmentioning

confidence: 95%

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Concise Review: Induced Pluripotent Stem Cells Versus Embryonic Stem Cells: Close Enough or Yet Too Far Apart?

2011

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Section: Mutational Load Of Ipscmentioning

confidence: 95%

“…Besides epigenetic aberrations it is reported that iPSC also bear genomic mutations [69][70][71][72]. These could arise from the reprogramming itself and from the in vitro expansion of cells afterward.…”

Section: Mutational Load Of Ipscmentioning

confidence: 99%

Concise Review: Induced Pluripotent Stem Cells Versus Embryonic Stem Cells: Close Enough or Yet Too Far Apart?

2011

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“…A series of recent articles suggest that iPSCs display more abnormalities than do ESCs and fibroblasts. Chromosomal abnormalities seem to appear earlier in iPSCs cultures, 70 and higher frequency of mutations and greater number of novel copy number variants are also present in iPSCs. 70,71 Aberrant DNA methylation and retention of epigenetic markers from the cell of origin also suggest significant reprogramming variability in human iPSCs.…”

Section: From Embryonic Stem Cells To Germ Cellsmentioning

confidence: 97%

“…Chromosomal abnormalities seem to appear earlier in iPSCs cultures, 70 and higher frequency of mutations and greater number of novel copy number variants are also present in iPSCs. 70,71 Aberrant DNA methylation and retention of epigenetic markers from the cell of origin also suggest significant reprogramming variability in human iPSCs. 72 As it stands, the lack of genetic stability in iPSCs precludes their use in clinical applications in humans until further research defines the effect of this recent finding.…”

Section: From Embryonic Stem Cells To Germ Cellsmentioning

confidence: 97%

Can we grow sperm? A translational perspective on the current animal and human spermatogenesis models

Lo¹,

Domes²

2011

Asian J Androl

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There have been tremendous advances in both the diagnosis and treatment of male factor infertility; however, the mechanisms responsible to recreate spermatogenesis outside of the testicular environment continue to elude andrologists. Having the ability to 'grow' human sperm would be a tremendous advance in reproductive biology with multiple possible clinical applications, such as a treatment option for men with testicular failure and azoospermia of multiple etiologies. To understand the complexities of human spermatogenesis in a research environment, model systems have been designed with the intent to replicate the testicular microenvironment. Currently, there are both in vivo and in vitro model systems. In vivo model systems involve the transplantation of either spermatogonial stem cells or testicular xenographs. In vitro model systems involve the use of pluripotent stem cells and complex coculturing and/or three-dimensional culturing techniques. This review discusses the basic methodologies, possible clinical applications, benefits and limitations of each model system. Although these model systems have greatly improved our understanding of human spermatogenesis, we unfortunately have not been successful in demonstrating complete human spermatogenesis outside of the testicle. Asian Journal of Andrology (2011) 13, 677-682; doi:10.1038/aja.2011.88; published online 18 July 2011 Keywords: fertility preservation; spermatogenesis models; spermatogonial stem cells INTRODUCTIONRecreating human spermatogenesis outside of its original environment remains the 'Holy Grail' for generations of andrologists. To grow sperm is not only a matter of scientific curiosity, but also a quest for the treatment of male infertility. A well-characterized model for spermatogenesis in humans will have a huge impact on our understanding on the physiological and genetic pathways of male reproduction. Its clinical applications also extend to the study of human reproductive toxicology and preservation of fertility in treated cancer patients.While significant progress has been made in the laboratory, multiple obstacles remain. Current knowledge on the control of gonadogenesis, spermatogenesis and steroidogenesis are based on the examination of histology, immunohistochemistry, hormonal assays, and phenotypes of single gene or small groups of gene alterations in animal models. Human studies in male reproduction are hindered by the lack of human testicular specimens, which are not as readily available as our animal counterparts, for ethical and practical reasons. In this review, we will examine the existing literature on the experimental models and their limitations in growing sperm to provide a foundation for future investigation and clinical application ( Table 1).

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“…[52][53][54] The same is true for the facts, that the epigenetic memory of the original differentiated state is not perfectly erased during reprogramming 55,56 and that iPS cells have been reported to accumulate karyotypic abnormalities and gene mutations during propagation in culture. [57][58][59][60] AFS very likely do not harbour accumulated somatic mutations, because they are primary cells of a very early stage of human development. Furthermore, monoclonal human AFS cell lines have been reported to maintain genome stability during expansion and do not induce tumour formation in severe combined immunodeficient mice.…”

Section: Amniotic Fluid Stem (Afs) Cells Could Be a Useful Tool To Stmentioning

confidence: 99%

Amniotic fluid stem cell-based models to study the effects of gene mutations and toxicants on male germ cell formation

Gundacker¹,

Dolznig²,

Mikula³

et al. 2012

Asian J Androl

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Male infertility is a major public health issue predominantly caused by defects in germ cell development. In the past, studies on the genetic regulation of spermatogenesis as well as on negative environmental impacts have been hampered by the fact that human germ cell development is intractable to direct analysis in vivo. Compared with model organisms including mice, there are fundamental differences in the molecular processes of human germ cell development. Therefore, an in vitro model mimicking human sperm formation would be an extremely valuable research tool. In the recent past, both human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells have been reported to harbour the potential to differentiate into primordial germ cells and gametes. We here discuss the possibility to use human amniotic fluid stem (AFS) cells as a biological model. Since their discovery in 2003, AFS cells have been characterized to differentiate into cells of all three germ layers, to be genomically stable, to have a high proliferative potential and to be non-tumourigenic. In addition, AFS cells are not subject of ethical concerns. In contrast to iPS cells, AFSs cells do not need ectopic induction of pluripotency, which is often associated with only imperfectly cleared epigenetic memory of the source cells. Since AFS cells can be derived from amniocentesis with disease-causing mutations and can be transfected with high efficiency, they could be used in probing gene functions for spermatogenesis and in screening for male reproductive toxicity.

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Dynamic Changes in the Copy Number of Pluripotency and Cell Proliferation Genes in Human ESCs and iPSCs during Reprogramming and Time in Culture

Cited by 820 publications

References 31 publications

Concise Review: Induced Pluripotent Stem Cells Versus Embryonic Stem Cells: Close Enough or Yet Too Far Apart?

Concise Review: Induced Pluripotent Stem Cells Versus Embryonic Stem Cells: Close Enough or Yet Too Far Apart?

Can we grow sperm? A translational perspective on the current animal and human spermatogenesis models

Amniotic fluid stem cell-based models to study the effects of gene mutations and toxicants on male germ cell formation

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