Pluripotency and Differentiation

Two distinguishing characteristics of embryonic stem cells (ESCs) are pluripotency and the ability to self-renew. These traits, which allow ESCs to grow into any cell type in.the adult body and 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 supports the pluripotent state, which relies predominantly upon three key transcription factors: Oct-4, Sox2, and Nanog. These transcription factors activate gene expression of ESC-specific genes, regulate their own expression, suppress genes involved in differentiation, 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. In vitro, hESCs can be coaxed into derivatives of the three primary germ layers, endoderm, mesoderm, or ectoderm, as well as primordial germ cell-like cells. One of the primary signaling pathways responsible for this process is the BMP pathway, which uses Smad1/5/9 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 differentiation 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.
• Dalton S (2013) Signaling networks in human pluripotent stem cells. Curr. Opin. Cell Biol. 25(2), 241–6.
• Guenther MG (2011) Transcriptional control of embryonic and induced pluripotent stem cells. Epigenomics 3(3), 323–43.
• Jaenisch R, Young R (2008) Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell 132(4), 567–82.
• Ng HH, Surani MA (2011) The transcriptional and signalling networks of pluripotency. Nat. Cell Biol. 13(5), 490–6.
• Pan G, Thomson JA (2007) Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res. 17(1), 42–9.
• 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.
• Young RA (2011) Control of the embryonic stem cell state. Cell 144(6), 940–54.

We would like to thank Justin Brumbaugh and Prof. Konrad Hochedlinger, HHMI and MGH Cancer Center, Center for Regenerative Medicine, Harvard University, Cambridge, MA, for reviewing this diagram.

created May 2009

revised September 2016