Epigenetic regulation occurs in multiple waves during early embryonic development. After fertilization, both maternal and paternal copies of the genome undergo global epigenetic changes. This converts the epigenome of the differentiated gametes into that of the zygote, triggering zygote-specific gene expression. During blastocyst formation, a second global change occurs: the ablation of DNA methylation patterns, distinct changes in histone modifications, and the reactivation of both X chromosomes in female cells. In the post-implantation epiblast, a third change occurs: chromatin becomes progressively inaccessible, repressive epigenetic marks increase, and an X chromosome is inactivated in female cells.
In general, studies suggest cultured embryonic stem (ES) cells are able to recapitulate the epigenetic landscape observed in the developing embryo. This is important since the epigenetic plasticity of stem cells, with more accessible chromatin domains and less heterochromatin foci, enables them to react to distinctive stimuli and undergo differentiation into a wide range of tissues. For the generation of induced pluripotent stem (iPS) cell cultures, the restricted somatic chromatin is extensively reorganized into the more accessible epigenetic landscape indicative of ES cells. There is a substantial latency in this reprogramming process, with epigenetic aberrations present in early passage numbers reflecting transient epigenetic memory from the cell types that the iPS cells are derived from. Using only iPS cells that have fully reprogrammed is therefore important, and can be assessed using functional assays such as trilineage differentiation potential. In studies comparing the epigenomes of iPS cells and ES cells, both DNA methylation patterns and histone modifications are highly similar.
- Atlasi and Stunnenberg review epigenetic modification of chromatin, a dynamic process that shapes early development and differentiation.
Atlasi Y & Stunnenberg HG (2017) The interplay of epigenetic marks during stem cell differentiation and development. Nat Rev Genet 18(11): 643-58.
- Bilic et al. review the epigenetic landscape of pluripotent stem cells, in particular, epigenetic comparison between induced pluripotent stem cells and embryonic stem cells.
Bilic J & Izpisua Belmonte JC (2012) Concise review: Induced pluripotent stem cells versus embryonic stem cells: close enough or yet too far apart? Stem Cells 30(1): 33-41.
- Liang and Zhang review epigenetic landscapes of embryonic stem cells and induced pluripotent stem cells.
Liang G & Zhang Y (2013) Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective. Cell Res 23(1): 49-69.
- Takashima et al. report resetting of the human pluripotent state through short-term expression of NANOG and KLF2. They observed similar transcriptome and metabolism between these reset cells and mouse ground-state embryonic stem cells, and the inhibition of ERK and protein kinase C sustained a transgene-independent rewired state in human pluripotent stem cells. These findings demonstrate feasibility of induction and expansion of ground-state pluripotency in human cells.
Takashima Y et al (2014) Resetting transcription factor control circuitry toward ground-state pluripotency in human. Cell 158(6): 1254-69.
- Pastor et al. report on the methylation landscape of naïve human pluripotent stem cells. Reversion or derivation of human embryonic stem (hES) cells in 5iLAF naïve condition resulted in SSEA4 negative cells, which showed gene expression that is consistent with naïve pluripotency. Naïve hES cells showed loss of DNA methylation imprinting and loss of “memory” of the methylation state of the human oocyte.
Pastor WA et al (2016) Naive human pluripotent cells feature a methylation landscape devoid of blastocyst or germline memory. Cell Stem Cell 18(3): 323-9.
Induce and Expand Naïve Reset Human Pluripotent Stem Cells
NaïveCult™ Induction Kit
NaïveCult™ Induction Kit contains defined cell culture media for the chemical induction of transgene-free reset naïve human embryonic stem (ES) and induced pluripotent stem (iPS) cells from the primed state. The kit was developed under license from the Cambridge Stem Cell Institute at the University of Cambridge, UK based on Guo et al. (2017).
NaïveCult™ Expansion Medium
NaïveCult™ Expansion Medium is a defined medium for the robust expansion of reset naïve human embryonic stem (ES) and induced pluripotent stem (iPS) cells. This medium was developed under license from the Cambridge Stem Cell Institute at the University of Cambridge, UK based on the t2iL + Gö formulation developed by Austin Smith.