Epiblast-derived stem cells

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After the blastocyst stage, once an embryo implanted in endometrium (in case of rodent), the inner cell mass (ICM) of a fertilized embryo segregates into two layers: hypoblast and epiblast. The epiblast cells are the functional progenetors of soma and germ cells which later differentiate into 3 layers, definitive endoderm, mesoderm and ectoderm. Stem cells derived from epiblast are pluripotent. These cells are called epiblast-derived stem cells (EpiSC) and have several different cellular and molecular characteristics with Embryonic Stem Cells (ESC) (De-Miguel et al., 2009). Pluripotency in EpiSC is essentially different from that of embryonic stem cells. The pluripotency of EpiSC is primed pluripotency: primed to differentiate into specific cell linages. Naïve pluripotent stem cells (e.g. ESC) and primed pluripotent stem cells (e.g. EpiSC) not only sustain the ability to self-renew but also maintain the capacity to differentiate (Nichols and Smith, 2009). Since the cell status is primed to differentiate in EpiSC, however, one copy of the X chromosome in XX cells (female cells) in EpiSC is silenced (XaXi). EpiSC is unable to colonize and is not available to be used to produce chimeras. Conversely, XX cells in ESC are both active and can produce chimera when inserted into a blastocyst. Both ESC and EpiSC induce teratoma when injected in the test animals (skid mice) which proves pluripotency. EpiSC display several distinctive characteristics distinct from ESC (table 1). The celluar status of human ESC (hESC) is similar to primed state mouse stem cells rather than Naïve state (Hanna et al., 2010).

Table 1. Comparison of Naïve and Primed pluripotent states (Nichols and Smith, 2009)

Property Naive State Primed State
Embryonic tissue Early epiblast Egg cylinder or embryonic disc
Culture stem cell Rodent ESCs Rodent EpiSCs; primate "ESCs"
Blatocyst chimaeras Yes No
Teratomas Yes Yes
Pluripotency factors Oct4, Nanog, Sox2, Klf2, Klf4 Oct4, Sox2, Nanog
Naive markers Rex1, Nr0b1, Fgf4 Absent
Specification markers Absent Fgf5, T
Response to Lif/Stat3 Self-renewal None
Response to Fgf/Erk Differentiation Self-renewal
Clonogenicity High Low
XX status Both active One X inactive

EpiSC-ESC conversion

Differentiating naïve pluripotent stem cells into primed pluripotent stem cells (e.g. adding activin and Fgf in the culture medium) can be accomplished rather easily but reprogramming of primed cells into naïve cells is more difficult. Several approaches to reprogramming EpiSC to achieve Naïve pluripotency have been applied. One of those methods is transfecting the primed pluripotent stem cell with a reprogramming factor, Klf4 (Guo et al., 2009). [1] [2] [3] [4]

The reversion back to the naive-state has also been achieved by suppressing the activity of the histone methyltransferase MLL1, also known as KMT2A. The inhibition of MLL1 via the small-molecule inhibitor MM-401 in EpiSC showed marked increase in alkaline phosphatase staining as well as upregulation of "naive" markers such as Rex1 and downregulation of "primed" markers such as Fgf5. Moreover, beyond the potency-state comparison, MLL1 inhibition was also shown to reactivate the silenced X-chromosome which is typically deactivated in post-implantation epiblast stem cells, suggesting a epigenetic reversion back to a more ground-level, naive state. What's more, some EpiSCs affected by the MLL1 inhibition-induced reversion were able to contribute to germline-competent chimeras, which had been considered as one of the most major differences between ESCs and EpiSCs. [5]


Scientists have been able to demonstrate the induction of EpiSC-like cells in vitro from mouse ESCs, which are referred to as Epiblast-like cells (EpiLC). [6] Many studies have used EpiLC as suitable analogues for actual post-implantation derived epiblast stem cells, especially in attempts at reversion back to the "naive" state. Recently, overexpression of PR-domain Zinc Finger Protein 14 (PRDM14) in EpiLC was shown to cause a reversion back to a ESC-like state (with levels of Alkaline Phosphatase staining recovered to that observed in ESCs as well as more ESC-like cell morphology), with Klf2 being required for the mechanism to occur. [7] It has been proposed that PRDM14 induces this state by activating Klf2 via active demethylation recruitment of Oct-4; such technique has yet to be demonstrated in actual epiblast-derived EpiSCs.


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  5. PMID 26996599 (PubMed)
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  6. PMID 24506884 (PubMed)
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  7. PMID 27866876 (PubMed)
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