Capturing pluripotency

Abstract

In this Essay, we argue that pluripotent epiblast founder cells in the embryo and embryonic stem (ES) cells in culture represent the ground state for a mammalian cell, signified by freedom from developmental specification or epigenetic restriction and capacity for autonomous self-replication. We speculate that cell-to-cell variation may be integral to the ES cell condition, safe-guarding self-renewal while continually presenting opportunities for lineage specification.

Figure 1

Maintaining Pluripotency Autoinductive FGF4/Erk signaling poises embryonic stem (ES) cells for lineage entry and must be resisted to allow self-renewal. (A) Oct4 and Sox2 direct expression of fgf4 and poise ES cells for lineage commitment. Elevated Erk activity provides a signal that renders pluripotent cells susceptible to lineage inductive cues. (B) Self-renewal of the pluripotent ES cell state requires overcoming the FGF4/Erk signal. The actions of FGF can be (1) blocked by selective pharmacological inhibitors of the FGF receptor (FGFR) and of Mek; (2) reversed by constitutive expression of Nanog; (3) counteracted by blockade of commitment effectors by the cytokine leukemia inhibitory factor (LIF) and the morphogen BMP4.

Figure 2

A Metastable Coalition The transcription factor Nanog secures self-renewal of ES cells, and cell-to-cell variation creates the possibility for differentiation. (A) Embryonic stem (ES) cells are heterogeneous. Immunostaining shows highly variable levels of Nanog protein in Oct4-positive undifferentiated ES cells. (B) In our model, lineage-associated transcriptional circuits (A, B, and C) are maintained below threshold levels due to mutual antagonism and suppression by the three transcription factors Oct4, Sox2, and Nanog. A destabilized transitional state arises when downregulation of Nanog coincides with increased activation of Erk. Phosphorylated Erk (pErk) may activate inductive signaling pathways or directly promote lineage-affiliated transcriptional networks. The fluctuations in network activities generated by pErk confer an opportunity to establish a new stable cell state. However, if Nanog levels rise before commitment is effected, the actions of pErk are neutralized, the metastable ground state is restored, and the gate is closed. Photo courtesy of J. Silva and A. Smith.