ESC Pluripotency and Differentiation

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Pathway Description:

Two distinguishing characteristics of embryonic stem cells (ESCs) are pluripotency and their ability to self renew. These traits, which allow ESCs to grow into any cell type in the body and to divide continuously in the undifferentiated state, are regulated by a number of cell signaling pathways. In human ESCs (hESCs), the predominant signaling pathways involved in pluripotency and self renewal are TGF-β, which signals through Smad2/3/4, and FGFR, which activates the MAPK and Akt pathways. The Wnt pathway also promotes pluripotency, although this may occur through a non-canonical mechanism involving a balance between the transcriptional activator TCF1 and the repressor TCF3. Signaling through these pathways results in the expression and activation of three key transcription factors: Oct-4, Sox2, and Nanog. These transcription factors activate gene expression of ESC-specific genes, regulate their own expression, and also serve as hESCs markers. Other markers used to identify hESCs are the cell surface glycolipid SSEA3/4, and glycoproteins TRA-1-60 and TRA-1-81. Loss of pluripotency results in differentiation into primordial germ cells or one of the three primary germ layers: endoderm, mesoderm, or ectoderm. One of the primary signaling pathways responsible for this process is the BMP pathway, which uses Smad/1/5/8 to promote differentiation by both inhibiting expression of Nanog, as well as activating the expression of differentiation-specific genes. Notch also plays a role in this process through the notch intracellular domain (NICD). As differentiation continues, cells from each primary germ layer further differentiate along lineage-specific pathways.

Selected Reviews:

• Bilic J, Izpisua Belmonte JC (2012) Concise review: Induced pluripotent stem cells versus embryonic stem cells: close enough or yet too far apart? Stem Cells 30(1), 33–41.
• Boiani M, Schöler HR (2005) Regulatory networks in embryo-derived pluripotent stem cells. Nat. Rev. Mol. Cell Biol. 6(11), 872–84.
• Guenther MG (2011) Transcriptional control of embryonic and induced pluripotent stem cells. Epigenomics 3(3), 323–43.
• Heng JC, Orlov YL, Ng HH (2010) Transcription factors for the modulation of pluripotency and reprogramming. Cold Spring Harb. Symp. Quant. Biol. 75, 237–44.
• Pan G, Thomson JA (2007) Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res. 17(1), 42–9.
• Pei D (2009) Regulation of pluripotency and reprogramming by transcription factors. J. Biol. Chem. 284(6), 3365–9.
• Welham MJ, Kingham E, Sanchez-Ripoll Y, Kumpfmueller B, Storm M, Bone H (2011) Controlling embryonic stem cell proliferation and pluripotency: the role of PI3K- and GSK-3-dependent signalling. Biochem. Soc. Trans. 39(2), 674–8.