Inhibition of Apoptosis Overcomes Stage-Related Compatibility Barriers to Chimera Formation in Mouse Embryos

Hara, Masaki; Kato-Itoh, Megumi; Takahashi, Yusuke; Umino, Ayumi; Sato, Hideyuki; Ito, Keiichi; Yanagida, Akira; Nishimura, Toshinobu; Yamaguchi, Tomoyuki; Hirabayashi, Masumi; Era, Takumi; Loh, Kyle M.; Wu, Sean M.; Weissman, Irving L.; Nakauchi, Hiromitsu

doi:10.1016/j.stem.2016.10.013

Cited by 98 publications

(103 citation statements)

References 29 publications

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“…Indeed, forced expression of the apoptosis regulator BCL2 in mouse and rat EpiSCs allowed these cells to form chimeras when introduced into pre-implantation mouse blastocysts. Furthermore, not only EpiSCs, but also apoptosis-resistant endoderm progenitor cells, could form region-specific chimeras after transplantation into pre-implantation blastocysts (Masaki et al, 2016). If this system can also be applied to human cells, then it might prove possible to assess the developmental potency of cells by interspecies chimera assay.…”

Section: Chimera Generation By Apoptosis-resistant Cellsmentioning

confidence: 99%

“…The data from the Masaki et al (2016) study are intriguing for a number of reasons. First, they seem to hint at the existence of a mechanism that eliminates cells that are unmatched in terms of developmental stage by apoptosis.…”

Section: Chimera Generation By Apoptosis-resistant Cellsmentioning

confidence: 99%

“…Judging from the results published so far for human-animal interspecies chimeras (Masaki et al, 2015;Wu et al, 2017), it is unlikely that chimerism in the central nervous system or in gametes is high enough to cause concern and, in the case of the latter, current restrictions prohibit the breeding of interspecies chimeras. Nonetheless, if the contribution to these organs reaches a problematic level, then it might be necessary to adopt ʻtargeted organ generation' approaches, for example by using genetic methods to restrict developmental potency or by transplantation of apoptosis-resistant progenitor cells with a more restricted and defined cell fate (Masaki et al, 2016).…”

Section: Ethical Concerns and Future Perspectivesmentioning

confidence: 99%

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Interspecies chimeras for human stem cell research

Hara

Nakauchi

2017

Development

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Interspecies chimeric assays are a valuable tool for investigating the potential of human stem and progenitor cells, as well as their differentiated progeny. This Spotlight article discusses the different factors that affect interspecies chimera generation, such as evolutionary distance, developmental timing, and apoptosis of the transplanted cells, and suggests some possible strategies to address them. A refined approach to generating interspecies chimeras could contribute not only to a better understanding of cellular potential, but also to understanding the nature of xenogeneic barriers and mechanisms of heterochronicity, to modeling human development, and to the creation of human transplantable organs.

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Section: Chimera Generation By Apoptosis-resistant Cellsmentioning

confidence: 99%

Section: Chimera Generation By Apoptosis-resistant Cellsmentioning

confidence: 99%

Section: Ethical Concerns and Future Perspectivesmentioning

confidence: 99%

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Interspecies chimeras for human stem cell research

Hara

Nakauchi

2017

Development

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“…Recently, Mashaki et al . revealed that E-CADHERIN (CDH1 ) and BCL2 play important roles in chimeric contribution by PSCs25. In this context, naïve-like CMK6 enhanced the expression of E-CADHERIN , but failed to express BCL2 (Fig.…”

Section: Resultsmentioning

confidence: 89%

Discrimination of Stem Cell Status after Subjecting Cynomolgus Monkey Pluripotent Stem Cells to Naïve Conversion

Honda

Kawano

Izu

et al. 2017

Sci Rep

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Experimental animal models have played an indispensable role in the development of human induced pluripotent stem cell (iPSC) research. The derivation of high-quality (so-called “true naïve state”) iPSCs of non-human primates enhances their application and safety for human regenerative medicine. Although several attempts have been made to convert human and non-human primate PSCs into a truly naïve state, it is unclear which evaluation methods can discriminate them as being truly naïve. Here we attempted to derive naïve cynomolgus monkey (Cm) (Macaca fascicularis) embryonic stem cells (ESCs) and iPSCs. Several characteristics of naïve Cm ESCs including colony morphology, appearance of naïve-related mRNAs and proteins, leukaemia inhibitory factor dependency, and mitochondrial respiration were confirmed. Next, we generated Cm iPSCs and converted them to a naïve state. Transcriptomic comparison of PSCs with early Cm embryos elucidated the partial achievement (termed naïve-like) of their conversion. When these were subjected to in vitro neural differentiation, enhanced differentiating capacities were observed after naïve-like conversion, but some lines exhibited heterogeneity. The difficulty of achieving contribution to chimeric mouse embryos was also demonstrated. These results suggest that Cm PSCs could ameliorate their in vitro neural differentiation potential even though they could not display true naïve characteristics.

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“…This migration causes the embryo to elongate, generating an asymmetrical elongated anterior to posterior epiblast (APE) (Degrelle et al, 2005; Lawson et al, 1991; Maddox-Hyttel et al, 2003). The epiblast in ERSE and APE stages remain pluripotent as suggested by clonal studies performed in the mouse (Lawson et al, 1991) and by chimera studies using mouse epiblast stem cells (mEpiSCs) (Huang et al, 2012; Masaki et al, 2016). Despite many conserved morphological features, the establishment of PSC cultures in vitro has proved challenging in species other than mouse and primates.…”

Section: Introductionmentioning

confidence: 99%

Mammalian embryo comparison identifies novel pluripotency genes associated with the naïve or primed state

et al. 2018

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During early mammalian development, transient pools of pluripotent cells emerge that can be immortalised upon stem cell derivation. The pluripotent state, ‘naïve’ or ‘primed’, depends on the embryonic stage and derivation conditions used. Here we analyse the temporal gene expression patterns of mouse, cattle and porcine embryos at stages that harbour different types of pluripotent cells. We document conserved and divergent traits in gene expression, and identify predictor genes shared across the species that are associated with pluripotent states in vivo and in vitro. Amongst these are the pluripotency-linked genes Klf4 and Lin28b. The novel genes discovered include naïve- (Spic, Scpep1 and Gjb5) and primed-associated (Sema6a and Jakmip2) genes as well as naïve to primed transition genes (Dusp6 and Trip6). Both Gjb5 and Dusp6 play a role in pluripotency since their knockdown results in differentiation and downregulation of key pluripotency genes. Our interspecies comparison revealed new insights of pluripotency, pluripotent stem cell identity and a new molecular criterion for distinguishing between pluripotent states in various species, including human.

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Inhibition of Apoptosis Overcomes Stage-Related Compatibility Barriers to Chimera Formation in Mouse Embryos

Cited by 98 publications

References 29 publications

Interspecies chimeras for human stem cell research

Interspecies chimeras for human stem cell research

Discrimination of Stem Cell Status after Subjecting Cynomolgus Monkey Pluripotent Stem Cells to Naïve Conversion

Mammalian embryo comparison identifies novel pluripotency genes associated with the naïve or primed state

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