Stepwise pluripotency transitions in mouse stem cells

Abstract

Pluripotent cells in mouse embryos, which first emerge in the inner cell mass of the blastocyst, undergo gradual transition marked by changes in gene expression, developmental potential, polarity, and morphology as they develop from the pre-implantation until post-implantation gastrula stage. Recent studies of cultured mouse pluripotent stem cells (PSCs) have clarified the presence of intermediate pluripotent stages between the naïve pluripotent state represented by embryonic stem cells (ESCs-equivalent to the pre-implantation epiblast) and the primed pluripotent state represented by epiblast stem cells (EpiSCs-equivalent to the late post-implantation gastrula epiblast). In this review, we discuss these recent findings in light of our knowledge on peri-implantation mouse development and consider the implications of these new PSCs to understand their temporal sequence and the feasibility of using them as model system for pluripotency.

Keywords: epiblast; formative; naïve; pluripotency; primed.

Figure 1. Developmental continuum of pre‐ and early post‐implantation mouse embryos

Key cell types of mouse embryos from E4.5 to E6.75 are shown. Bottom panel shows changes in marker gene expression and signaling pathway activities in developing epiblast cells.

Figure 2. Correlation heatmap and Principal Component Analysis (PCA) of state‐specific marker gene expression in mouse PSC lines and E5.5–E6.5 epiblasts

RNA‐seq data were obtained from NCBI GEO (GSE105762, GSE131553, and GSE154290), and the expressions of state‐specific marker genes in mouse PSC lines and E5.5–E6.5 epiblasts were analyzed using iDEP (Ge et al, 2018).

Figure 3. Model of pluripotency transition

Developmental continuum in vivo and the recent derivation of intermediate PSC lines underscore a stepwise sequence of pluripotency transition from ground naïve to primed through rosette and formative states. In the model, circled cells represent pluripotent cells, while others represent lineage‐committed cells. Solid black arrows indicate one step differentiation, while dashed black arrows indicate multi‐step differentiation. Blue arrows indicate reversible differentiation.

Figure 4. Schematic representation of the time course of epiblast development from the blastocyst stage recapitulated by respective in vitro models

Black solid arrows indicate the transition approximately recapitulating the developmental time course in the embryo. Black dashed arrows indicate the transition that requires long‐term adaptation to the culture condition.