LIF/Stat3 signaling is critical for maintaining the self-renewal and differentiation potential of mouse embryonic stem cells (mES cells). However, the upstream effectors of this pathway have not been clearly defined. Here, we show that periodic tryptophan protein 1 (Pwp1), a WD-40 repeat-containing protein associated with histone H4 modification, is required for the exit of mES cells from the pluripotent state into all lineages. Knockdown of Pwp1 does not affect mES cell proliferation, self-renewal or apoptosis. However, knockdown of Pwp1 impairs the differentiation potential of mES cells both in vitro and in vivo. PWP1 ChIP-seq results revealed that the PWP1-occupied regions were marked with significant levels of H4K20me3. Moreover, Pwp1 binds to sites in the upstream region of Stat3. Knockdown of Pwp1 decreases the level of H4K20me3 in the upstream region of Stat3 gene and upregulates the expression of Stat3. Furthermore, Pwp1 knockdown (KD) mES cells recover their differentiation potential through suppressing the expression of Stat3 or inhibiting the tyrosine phosphorylation of STAT3. Together, our results suggest that Pwp1 plays important roles in the differentiation potential of mES cells. Stem Cells 2014.
The low efficiency of reprogramming and genomic integration of virus vectors obscure the potential application of induced pluripotent stem (iPS) cells; therefore, identification of chemicals and cooperative factors that may improve the generation of iPS cells will be of great value. Moreover, the cellular mechanisms that limit the reprogramming efficiency need to be investigated. Through screening a chemical library, we found that two chemicals reported to upregulate E-cadherin considerably increase the reprogramming efficiency. Further study of the process indicated that E-cadherin is upregulated during reprogramming and the established iPS cells possess E-cadherin-mediated cell-cell contact, morphologically indistinguishable from embryonic stem (ES) cells. Our experiments also demonstrate that overexpression of E-cadherin significantly enhances reprogramming efficiency, whereas knockdown of endogenous E-cadherin reduces the efficiency. Consistently, abrogation of cell-cell contact by the inhibitory peptide or the neutralizing antibody against the extracellular domain of E-cadherin compromises iPS cell generation. Further mechanistic study reveals that adhesive binding activity of E-cadherin is required. Our results highlight the critical role of E-cadherin-mediated cell-cell contact in reprogramming and suggest new routes for more efficient iPS cell generation.
Cytokines have been implicated in a variety of physiological processes involving lymphoid tissue development, lymphocyte activation, and control of regenerative processes such as wound healing. The first characterization of a cytokine implicated in abolishing or killing tumor cells - the tumor necrosis factor (TNF) - fostered and boosted a completely new field of research that in addition to cancer research started to generate an overwhelming amount of knowledge in immunology, various pathological processes, and other fields of research. Due to the complex networks and versatile functions of cytokines, it soon became clear that cytokines can possess diametric functions in various biological processes. As for tumor research it was shown that some cytokines - depending on the type of organ, the time of action, gender, and the cellular environment - can have either pro- or anticarcinogenic action. For those cytokines reported to be procarcinogenic, this could be accomplished by directly acting as oncogenes or generating an inflammatory environment that is procarcinogenic. Here we review a novel role for TNF family members - in particular lymphotoxin (LT) ? and ? - in physiology and in driving tumorigenesis, with special focus on the liver. We believe that recent findings on this particular cytokine might have strong implications for the therapy of liver cancer or other inflammation-induced cancer types.
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