Stem Cell Signaling

Self-renewal and differentiation potential, two key defining stem cell properties, are underscored by a network of transcription factors, epigenetic modifiers and modulating kinase signaling pathways. The Yamanaka factors, which include octamer-binding transcription factor-4 (Oct4), sex-determining region Y-box 2 (Sox2), Kruppel-like factor-4 (Klf4), and c-myelocytomatosis (c-Myc), were shown by Takahashi and Yamanaka to play a key role in the maintenance of pluripotency. Their work described for the first time the generation of induced pluripotent stem cells (iPSCs) by exogenous expression of a transcriptional pluripotency program in adult differentiated cells. Oct4, Sox2 and Nanog are now commonly considered core pluripotency factors.

Kinase Modulating Pathways

Several kinase signal transduction pathways modulate the core pluripotency transcription factors in response to both intrinsic and extrinsic stimuli, preserving stem cell self-renewal and differentiation potential. Synergy between these pathways ensures the maintenance of pluripotency.

WNT signaling- Involved in the regulation of cellular proliferation, adhesion, and migration. Canonical WNT signaling leads to the stabilization of the transcriptional co-activator beta-catenin. Formation of a nuclear complex between b-catenin and T-cell factor/lymphoid enhancer factor (TCF/LEF) supports the expression of Oct4 and Nanog in pluripotent stem cells (mESC and hESC).

TGF-β signaling- Involved in the regulation of a wide range of cellular processes such as differentiation, proliferation, and programmed cell death. Important for the maintenance of self-renewal and differentiation potential of mESCs and hESCs. For example, canonical TGF-β signaling initiated by BMP4 leads to Smad1/5/8 activation and induction of Inhibitor of DNA-binding/differentiation (Id) proteins for maintenance of mESCs. In contrast, TGF-β signaling initiated by TGF-β and Activin activate Smad2 for maintenance of primed-mESCs and hESCs.

LIF signaling- The simultaneous activation of the JAK/STAT3 and PI 3-K/AKT pathways plays an important role in the maintenance of mESC pluripotency. Activation of JAK/STAT3 leads to the induction of Klf4 and expression of SOX2, while activation of the P I3-K/AKT pathway increases the expression of Nanog by induction of Tbx3.

FGF signaling- Regulates various cellular processes including cell proliferation, migration, differentiation, and survival. Activation of ERK/MAPK signaling downstream of tyrosine kinase receptor/FGF2 stimulation is involved in the maintenance of hESC pluripotency. FGF/ERK signaling is not required for mESC maintenance, rather ERK activation leads to the differentiation of mESCs.