Pluripotency genes of mammals: a network at work

Abstract

Pluripotency, i.e., the ability to differentiate into cells of all three germ layers, is a transient state of early embryonic cells. In mammals, during progression from pre-implantation to post-implantation stage, pluripotent cells undergo different state transitions characterized by changes in gene expression and development potential. These developmental states include: (i) a naive pluripotency (pre-implantation embryonic stem cells, or ESCs), (ii) an intermediate condition (formative state), and (iii) a primed pluripotency (late post-implantation ESCs derived from epiblasts also named EpiSCs). The transitions are regulated by an interconnected network of pluripotency-related genes. Transcription of genes such as Oct4, Sox2, and Nanog is crucial for obtaining and maintaining pluripotency. These three factors form an autoregulatory loop by binding to each other's promoters to activate their transcription. Other factors play a significant ancillary role in the transcription factor network preserving cell pluripotency. In the review, we will also mention some of the more relevant cytokines, molecules, signaling pathways, and epigenetic modifications that induce and control pluripotency gene expression. The main goal of this review is to bridge the gap between the fields of genetics and stem cell biology and to set the ground for the application of this knowledge to the development of strategies and drugs to be used in a clinical environment.

Keywords: Nanog; Oct4; Sox2; pluripotency genes; pluripotent cells; stem cells.

FIGURE 1

Comparative schematic of mouse (top) and human (bottom) pre-implantation development (from morula to blastocyst, showing the timing of the different morphological stages. The center table (red letters) shows the embryonic day (E) of the associated event.

FIGURE 2

Development potential of mouse pluripotent stem cells expanded in culture. Panel (A) Developmental potential at the three pluripotency stages observed in vitro. Panel (B) Developmental potential of epiblasts during mouse early embryogenesis up to gastrulation. To facilitate the comparison of the pluripotency expressed by the cells in vitro and in vivo, the same color is adopted in the two panels to identify the different tissues. [Modified from (Pera and Rossant, 2021)].

FIGURE 3

Development potential of human pluripotent stem cells expanded in culture. Panel (A) Developmental potential at the three pluripotency stages observed in vitro. At variance with the corresponding mouse cells, human naïve pluripotent stem cells can give origin to primitive endoderm and trophoectoderm, and when they reach the formative stage, they can give origin to amniotic cells. Panel (B) Developmental potential of epiblasts during human early embryogenesis up to gastrulation. To facilitate the comparison of the pluripotency expressed by the cells in vitro and in vivo, the same color is adopted in the two panels to identify the different tissues. [Modified from (Pera and Rossant, 2021)].

FIGURE 4

Modulation of pluripotency genes in response to extrinsic stimuli during the naïve to primed pluripotency transition. Extrinsic signals are important in promoting and retaining pluripotency of stem cells in both mouse and human. The same cytokines (FGF, Wnt, BMP, Nodal) that are involved in the designation of the embryo dorso-ventral and antero-posterior axes and in the positioning of the three germ layers at the time of gastrulation are also playing a major role in ESC self-renewal and progression through the different pluripotency stages. The transition from the primed ESCs and EpiSCs to progenitors specific to the different tissue lineages derived from each germ layer is also under the control of different additional cytokines and factors specific for each lineage (not shown). Colored continuous lines with rows refer to cytokine activation, whereas the same lines with small horizontal bars refer to inhibitory activity.