New cell lines from mouse epiblast share defining features with human embryonic stem cells

Abstract

The application of human embryonic stem (ES) cells in medicine and biology has an inherent reliance on understanding the starting cell population. Human ES cells differ from mouse ES cells and the specific embryonic origin of both cell types is unclear. Previous work suggested that mouse ES cells could only be obtained from the embryo before implantation in the uterus. Here we show that cell lines can be derived from the epiblast, a tissue of the post-implantation embryo that generates the embryo proper. These cells, which we refer to as EpiSCs (post-implantation epiblast-derived stem cells), express transcription factors known to regulate pluripotency, maintain their genomic integrity, and robustly differentiate into the major somatic cell types as well as primordial germ cells. The EpiSC lines are distinct from mouse ES cells in their epigenetic state and the signals controlling their differentiation. Furthermore, EpiSC and human ES cells share patterns of gene expression and signalling responses that normally function in the epiblast. These results show that epiblast cells can be maintained as stable cell lines and interrogated to understand how pluripotent cells generate distinct fates during early development.

Distinct Developmental Ground States of Epiblast Stem Cell Lines Determine Different Pluripotency Features

“…S1B). Lines E3, T9, and C1a1 have previously been characterized using this assay [2][3][4]. Taken together, these data demonstrate that these six cell lines were pluripotent EpiSC lines.…”

“…For example, mESCs undergo self-renewal in the presence of leukemia inhibitory factor (LIF) and inhibitors of fibroblast growth factor (FGF) signaling [1]. In contrast, EpiSCs require FGF and Activin signaling to sustain self-renewal [2][3][4]. Intriguingly, human embryonic stem cells (hESCs), although derived from preimplantation embryos, appear to share more characteristics with EpiSCs than with mESCs.…”

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

“…Indeed, ESCs cultured in LIF/FCS have been proposed to contain a mixture of pluripotent cells that have progressed to different extents toward a primed state (Hackett & Surani, 2014). Such a primed state can also be captured in vitro as EpiSC, by explantation and culture of post‐implantation epiblast cells (Brons et al , 2007; Tesar et al , 2007). In contrast, ESCs cultured in LIF supplemented with inhibitors of both MEK and GSK3b (two inhibitors or 2i; Ying et al , 2008) may represent the opposite end of the range of pluripotent states that can be maintained in vitro (Hackett & Surani, 2014).…”

Concise Review: Induced Pluripotent Stem Cells Versus Embryonic Stem Cells: Close Enough or Yet Too Far Apart?

“…Epiblast stem cells present the next stage in development and therefore have a more limited developmental potential. They show poor success in generating chimeras and can manifest expression of early lineage commitment markers [20,21]. Thus, the similarity of mouse EpiESC to human ESC/iPSC, together with the limited pluripotency tests available in human lines, raise questions on whether those cells are capable of producing whole embryos and about their general level of pluripotency.…”