**Acknowledgements**

persistent self-renewal even in the absence of Lif. They are able to undergo the initial steps of differentiation, but their ability for lineage commitment is severely compromised. They fail to downregulate undifferentiated cell markers as well as upregulate differentiation markers [293]. Stat3 has many downstream effectors like the proto-oncogene c-Jun that is part of the AP-1 complex [194]. The transactivation domain of un-phosphorylated c-Jun recruits Mbd3/ NuRD to AP-1 target genes to mediate gene repression. This repression is relieved by c-Jun Nterminal phosphorylation or Mbd3 depletion. Upon JNK activation, NuRD dissociates from c-Jun, which results in de-repression of target gene transcription. Termination of the JNK signal induces Mbd3/NuRD re-binding to un-phosphorylated c-Jun and cessation of target gene

16 Pluripotent Stem Cell Biology - Advances in Mechanisms, Methods and Models

In this review, we have discussed a potentially novel link between inflammatory pathways and efficient cell reprogramming. In this context, our group reported that bone marrow stromal-primed human myeloid cell progenitors are significantly more receptive to reprog‐ ramming stimuli than other cell types [20]. Myeloid cells harbor a unique epigenetic plasticity that allows them to quickly respond to a plethora of pathogens. They are innately equipped to transcriptionally and epigenetically activate key inflammatory pathways via an intercon‐ nected NFκB and STAT3 signaling machinery [294]. Both pathways act as epigenetic modifiers during normal inflammation stimulation, and both are also known to promote ESC pluripo‐ tency by inducing an open chromatin state that allows other transcription factors to regulate cell fates [236]. This epigenetic remodeling may prove crucial for efficient reprogramming, as well as the generation of high quality iPSC that resemble ESC without excessive epigenetic

Moreover, Stat3 is a master reprogramming factor that is able to dominantly instruct pluripo‐ tency, yet is also inherently interconnected with inflammatory signaling cascades (Figure 2). It binds to bivalent histone modifications, and allows rapid transitions between pluripotency and differentiation [193]. The NFκB pathway acts in synergy with downstream STAT3 signaling, whereby non-canonical NFκB signaling maintains pluripotency through epigenetic silencing of differentiation genes and canonical NFκB signaling promotes cell differentiation [296]. Finally, recent evidence suggests that strong chromatin repression by the NuRD complex is a key rate-limiting factor during reprogramming to pluripotency. This important complex may normally function to ensure that differentiated cells do not reactivate pluripotency genes, which might enable tumorigenesis [268]. We propose the hypothesis that NuRD complex silencing might be more easily achieved through the activation of inflammatory pathways in

It remains to be elucidated how all these processes are inter-regulated. It will be especially important to link reprogramming efficiency with the resulting quality of the pluripotent state achieved in hiPSC. We hypothesize that epigenetic plasticity in inflammatory cells that normally allows chromatin accessibility to the transcriptional machinery, could be manipu‐

expression (Figure 2) [199].

memory of their cell of origin [295].

receptive cells such as those from the myeloid lineage.

**10. Conclusions**

JRA was supported by a fellowship from the German Research Foundation (DFG, DJ 71/1-1). ETZ was supported by grants from the NIH/NHLBI U01HL099775 and the Maryland Stem Cell Research Fund (2011-MSCRF-II-0008-00; 2007-MSCRF-II-0379-00). We would like to thank Dr. Alan Friedman for assistance in reading and editing the manuscript.
