Molecular basis of embryonic stem cell self-renewal: from signaling pathways to pluripotency network

Abstract

Embryonic stem cells (ESCs) can be maintained in culture indefinitely while retaining the capacity to generate any type of cell in the body, and therefore not only hold great promise for tissue repair and regeneration, but also provide a powerful tool for modeling human disease and understanding biological development. In order to fulfill the full potential of ESCs, it is critical to understand how ESC fate, whether to self-renew or to differentiate into specialized cells, is regulated. On the molecular level, ESC fate is controlled by the intracellular transcriptional regulatory networks that respond to various extrinsic signaling stimuli. In this review, we discuss and compare important signaling pathways in the self-renewal and differentiation of mouse, rat, and human ESCs with an emphasis on how these pathways integrate into ESC-specific transcription circuitries. This will be beneficial for understanding the common and conserved mechanisms that govern self-renewal, and for developing novel culture conditions that support ESC derivation and maintenance.

Pediatric dilated cardiomyopathy hearts display a unique gene expression profile

“…Network analysis of these pathways revealed a high degree of cross-talk, denoted by 112 nodes sharing 372 edges, suggesting a high degree of cooperation between mechanisms of signal transduction ( Figure 1C). Interestingly, the combined activation of Notch, WNT, and FGF signaling is implicated in the induction of pluripotent stem cells (9)(10)(11)(12).…”

“…As shown in Figure 1, combined database analysis of differentially expressed genes suggests enrichment of FGF (signaling by FGFR2 mutants), WNT (negative regulation of T cell factor-dependent [TFC-depen signaling is implicated in the induction of pluripotent stem cells (9)(10)(11)(12). Moreover, when expression of dysregulated genes was filtered to detect genes specifically involved in signal transduction, enrichment of genes involved in cell cycle progression and stem cell pluripotency signaling was observed (Table 2).…”

Modeling heterogeneity in the pluripotent state: A promising strategy for improving the efficiency and fidelity of stem cell differentiation

“…Interestingly, several studies have demonstrated that pluripotency regulators form intricate circuits at the transcriptional level 13, 36, 53, 54, and many of the TFs ( Essrb , Klf4 , Stat3 , Tcf3 ) in these regulatory motifs are downstream effectors of the signaling pathways regulating self‐renewal and differentiation. Although the complete spectrum of signaling pathways regulating pluripotency has not been fully described 55, these results demonstrate the confluence of different environmental signals from the microenvironment for the regulation of pluripotency. It has recently been shown that within the heterogeneous population of Neural Stem Cells, there exist dormant subpopulations of cells that are able to enter a primed‐quiescent state before activation, which is accompanied by down‐regulation of glycolytic metabolism, Notch and BMP signaling, and a concomitant up‐regulation of lineage‐specific transcription factors and protein synthesis 56.…”

Full biological characterization of human pluripotent stem cells will open the door to translational research

“…For detailed reading on mouse compared to human cell cycle regulation, refer to (Singh and Dalton 2009). For detailed reading on pluripotency network and self-renewal in human, please refer to Huang et al (2015) and Rizzino (2013).…”