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Ware CB, Angelique M. Nelson AM, Mecham B, Hesson J, Zhou W, Jonlin EC, Jimenez-Caliani AJ, Deng X, Cavanaugh C, Cook S, Tesar PJ, Okada J, Margaretha L, Sperber H, Choi M, Blau CA, Treuting PM, Hawkins RD, Cirulli V, Ruohola-Baker H. Derivation of naïve human embryonic stem cells. Proc Natl Acad Sci 2014;111:4484-89.

Prepared by: Anna Pang, Fall 2014

Lay Summary

At first glance, the topic of human embryonic stem cells (hESCs) may spark a wide range of controversy. The cryopreserved human embryos used in this paper were donated from fertility clinic patients. Thus, these human embryos would have been destroyed regardless of this experiment. The author of this paper used two new routes to generate “naïve” hESCs, which represent the developmentally earliest state described for human established cells. First, existing hESC lines in a later “primed” state can be reversed to a “naïve” state by pre-exposure to a “naïve” culture. Second, a new line of hESCs was established using a frozen human embryo under “naïve” culture conditions. It is important to note that these two routes involve the acquisition of embryonic cells from in vitro fertilization. These human “naïve” cells then met the mouse criteria for the “naïve” state. There are practical advantages for these human “naïve” cells, which may include an increase in the developmental potential and a more accurate correlation to the mouse embryonic stem cell data.

Scientific Summary

Studies using mouse epiblast stem cells (mEpiSCs) that pluripotency encompasses more than one stage of development (1,2). The earlier “naïve” stage represented the pre-implantation inner cell mass and was characterized by mouse ES cells (mESCs) (3). On the other hand, the “primed” stage represented the post-implantation epiblast and was characterized by mEpiSCs and human ES cells (hESCs) (3). The “naïve” pluripotent state has been shown in mice to be more extensive and significant developmental potential in comparison to “primed” mouse epiblast cells (3). The current method for deriving “naïve” hESCs focused on the use of transgenes, and forced expression of Oct4, KLF4, and KLF2 in order to maintain human cells in a “naïve” state (3). The author of this paper presented two routes to generate nontransgenic “naïve” hESCs. First, they reversed toggling of preexisting “primed” hESC lines by preculture in the histone deacetylase inhibitors butyrate and suberoylanilide hydroxamic acid (B/S), followed by culture in MEK/ERK and GSK3 inhibitors (2i) with FGF2 (3). Secondly, direct derivation from a human embryo in 2i with FGF2 1. It is important to note that these two routes involve the acquisition of embryonic cells from in vitro fertilization. The “naïve” state in humans met the criteria for the “naïve” state in mice; furthermore, “naïve” hESCs showed expanded endoderm developmental capacity (3). These “naïve” human pluripotent cells represent the developmentally earliest state described for human established cells and may lead to practical advantages in the future (3).

References

1. Brons IG, et al. (2007) Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 448(7150):191–195.
2. Tesar PJ, et al. (2007) New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 448(7150):196–199.
3. Ware CB, et al. (2014) Derivation of naïve human embryonic stem cells. Proc Natl Acad Sci USA 111(12);4484-4489.

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