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    • The nuclear factor kappa B

    2018-11-09

    The nuclear factor kappa B (NF-κB) is known for its key role in the regulation of many cellular processes. The classical NF-κB is a heterodimer of p50 and p65/RelA proteins, in which the p65/RelA subunit has transactivation activity. The IκB kinase (IKK) complex mediates the degradation of IκBs to activate NF-κB (Krum et al., 2010). Recent studies have suggested that NF-κB may also play a role in stem cell self-renewal and differentiation (Armstrong et al., 2006; Dreesen and Brivanlou, 2007). The NF-κB subunits, including p65, p50, IκBα, and IκBβ, were found to be present throughout differentiation of hESCs (Yang et al., 2010). Although NF-κB signaling activity is low in hESCs, its inhibition leads to significant cell differentiation (Armstrong et al., 2006), suggesting that basal level of NF-κB activity is required for hESC identity. On the other hand, p65 overexpression caused loss of pluripotency and hESC differentiation (Luningschror et al., 2012). Moreover, it has been shown that Nanog maintains the pluripotency of mouse ESCs by binding to and suppressing the functions of NF-κB transcriptional activity (Torres and Watt, 2008). Given these seemingly contradictory reports, the precise regulatory functions of NF-κB in hESC differentiation require further investigation.
    Results
    Discussion Recent studies have suggested that NF-κB signaling is involved in both maintenance and differentiation of ESCs (Dreesen and Brivanlou, 2007). While a low but detectable level of NF-κB activity was found in both mouse ESCs (mESCs) and hESCs (Torres and Watt, 2008; Yang et al., 2010), the functional role of NF-κB signaling was found to be contradictory. In mESCs, endogenous NF-κB activity and target gene nampt inhibitor was observed to have increased during the differentiation process. In addition, forced expression of the NF-κB subunit p65 caused mESC differentiation and loss of pluripotency (Luningschror et al., 2012). Conversely, NF-κB inhibition in mice increases expression of pluripotency markers (Dutta et al., 2011). miR-290, an ESC-specific microRNA cluster that targets p65, maintains pluripotency in mESCs by repressing NF-κB signaling (Luningschror et al., 2012). Similarly, Nanog’s binding to NF-κB inhibits the transcriptional activity of NF-κB and collaborates with Stat3 to promote self-renewal and impair differentiation (Torres and Watt, 2008). In contrast, it is reported that NF-κB inhibition in hESCs leads to hESC differentiation and loss of pluripotency (Armstrong et al., 2006). Using two different approaches for inhibiting NF-κB, our findings confirmed the notion that NF-κB inhibition promoted hESC differentiation. Importantly, we found that inhibition obtained significantly higher yields of MSCs. It was reported that nampt inhibitor there was a significant increase in expression of the NF-κB pathway components, p50 and phosphorylated form of p65, during embryonic body-mediated differentiation of hESCs grown in mouse embryonic feeder (MEF) layers (Yang et al., 2010). Similarly, here we demonstrated an increase in phosphorylated p65, indicative of heightened IKK/NF-κB activity, as hESCs differentiated in the monolayer culturing system and lost their pluripotency. It is noteworthy that such heightened activity was present only during the initial 4 days of differentiation and quickly returned to the basal level. When this transient upregulation of IKK/NF-κB signaling was inhibited, hESC differentiation was enhanced, suggesting that IKK/NF-κB activity may act as a compensatory mechanism to suppress its differentiation into progenitor cells during the early stages. Indeed, such a compensatory mechanism was also seen in previous studies. NF-κB activity is high during the development of bone but decreases in adult bone (Krum et al., 2010). Previously, we have found that the inhibition of NF-κB signaling promotes osteogenic differentiation of MSCs in vivo and in vitro (Chang et al., 2009, 2013). Altogether, our results suggest that NF-κB is a negative regulator of MSC differentiation from ESCs and bone formation.