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 through activation of β-catenin. 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:

• Boiani M, Schöler HR (2005) Regulatory networks in embryo-derived pluripotent stem cells. Nat. Rev. Mol. Cell Biol. 6(11), 872–84.
• Liu N, Lu M, Tian X, Han Z (2007) Molecular mechanisms involved in self-renewal and pluripotency of embryonic stem cells. J. Cell. Physiol. 211(2), 279–86.
• Okita K, Yamanaka S (2006) Intracellular signaling pathways regulating pluripotency of embryonic stem cells. Curr Stem Cell Res Ther 1(1), 103–11.
• 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.