The molecular circuitry underlying pluripotency in embryonic stem cells

Abstract

Cells in the pluripotent state have the ability to self-renew indefinitely and to differentiate to all the cells of the embryo. These cells provide an in vitro window into development, including human development, as well as holding extraordinary promise for cell-based therapies in regenerative medicine. The recent demonstration that somatic cells can be reprogrammed to the pluripotent state has raised the possibility of patient and disease-specific induced pluripotent cells. In this article, we review the molecular underpinning of pluripotency. We focus on the transcriptional and signaling networks that underlie the state of pluripotency and control differentiation. In general, the action of each of the molecular components and pathways is dose and context dependent highlighting the need for a systems approach to understanding pluripotency.

Figure 1. Early Mammalian Embryonic Development

After morula stages, the first cell fate decisions are made, in which cells sort to outer and inner populations. Outer cells give rise to the extraembryonic trophectoderm (TE), while inner cells form the inner cell mass (ICM). The ICM is located asymmetrically at one side of the blastocoel cavity within the TE. Subsequently, the ICM further differentiates to the extraembryonic endoderm (ExEn) and the epiblast, which gives rise to the embryonic ectoderm, mesoderm and endoderm. Mouse and human embryonic stem cells are derived in vitro by explanting the ICM.

Figure 2. Relationships between signaling pathways, pluripotency, and differentiation

Schematic depicting the relationship between signaling pathways and the indicated cell states. The dashed line indicates a connection only present in human but not mouse ES cells while the red-circled state indicates a state only accessible to mouse but not human cells.

Figure 3. Network of signaling pathways governing pluripotency and differentiation

(A) Schematic depicting the relationships between signaling pathways and genes control cell fate. Red lines denote interactions promoting pluripotency and green lines denote interactions promoting differentiation. Dashed lines indicate interactions only operative at low to intermediate activity of the signaling pathway. (B) Pluripotency is one of a spectrum of possible fates that result from modulating the Activin/Nodal pathway. Lower or higher levels of pathway activity lead to neural or mesendodermal differentiation, respectively.