Derivation of hypermethylated pluripotent embryonic stem cells with high potency.
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Bao, S., Tang, W., Wu, B., Kim, S., Li, J., Li, L., Kobayashi, T., et al. (2018). Derivation of hypermethylated pluripotent embryonic stem cells with high potency.. Cell research, 28 (1), 22-34. https://doi.org/10.1038/cr.2017.134
Naïve hypomethylated embryonic pluripotent stem cells (ESCs) are apparently closest developmentally to the preimplantation epiblast of blastocysts, with the potential to contribute to all embryonic tissues and the germline, excepting the extra-embryonic tissues in chimeric embryos. By contrast, epiblast stem cells (EpiSCs) resembling postimplantation epiblast are relatively more methylated and show a limited potential for chimerism. Here we reveal a novel developmentally advanced pluripotent stem cells (ASCs) that are developmentally beyond the pluripotent cells in the inner cell mass (ICM) but unlike EpiSCs with a higher potency and DNA methylation. Accordingly, a single ASC contributes very efficiently to the fetus, germline, yolk sac and the placental labyrinth in chimeras. Since they are developmentally more advanced, ASCs do not contribute to the trophoblast. ASCs were derived from blastocysts in two steps in a chemically defined medium with Activin A (ActA) and basic fibroblast growth factor (bFGF), followed by ActA, BMP4, CHIR99021 and Leukaemia inhibitory factor (LIF) (ABCL medium). Notably, ASCs exhibit a distinct transcriptome with the expression of both naïve pluripotency genes, as well as mesodermal somatic genes; Eomes, Eras, Tdgf1, Evx1, hand1, Wnt5a, and distinct repetitive elements. Conversion of established ESCs to ASCs is also possible. Importantly, ASCs exhibit a stable hypermethylated epigenome and mostly intact imprints, compared to the hypomethylated epiblast of blastocysts and naïve ESCs. Properties of ASCs suggest that they represent a cellular state in between the naïve and primed states of pluripotency.
Germ Layers, Animals, Mice, Inbred C57BL, Chimera, Mice, Epidermal Growth Factor, Oncogene Protein p21(ras), Homeodomain Proteins, T-Box Domain Proteins, Membrane Glycoproteins, Neoplasm Proteins, Sequence Analysis, RNA, DNA Methylation, Basic Helix-Loop-Helix Transcription Factors, Mouse Embryonic Stem Cells, Wnt-5a Protein
This work was supported by grants from the Ministry of Science and Technology project of Inner Mongolia (N0. 20130216), the National Natural Science Foundation of China (No.31560335) and by Wellcome Trust Investigator Award to MAS, and by a core grant from the Wellcome Trust and CRUK to the Gurdon Institute.
Wellcome Trust (096738/Z/11/Z)
External DOI: https://doi.org/10.1038/cr.2017.134
This record's URL: https://www.repository.cam.ac.uk/handle/1810/273600
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/
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