Evidence has previously been demonstrated for the role of NK cells in specific elimination of healthy stem cells (e.g. hMSC, hDPSC, hESC, hiPSC) as well as cancer stem cells, but not their differentiated counterparts. There is also a stage-wise susceptibility to NK cell-mediated cyto-toxicity in tumors, in which case the poorly-differentiated tumors are lysed much more than moderately-differentiated tumors. Well-differentiated tumors were lysed the least compared to either moderately- or poorly-differentiated tumors. It has also been reported that inhibition of differentiation or reversion of cells to a less-differentiated stage by blocking NF-κB or by gene deletion of COX2 significantly augmented NK cell cytotoxicity against both transformed and healthy cells. Additionally, the cytotoxic function of NK cells was severely inhibited against stem cells when they were cultured in the presence of monocytes. Therefore, it is proposed that CD16(+)CD56(dim)CD69(-) NK cells were important for the selection of stem cells, whereas the CD16(dim/-)CD56(dim/+)CD69(+) anergized NK cells were important for differentiation and eventual regeneration of the tissues and the resolution of inflammation, thus potentially serving as regulatory NK (NK(reg)) cells. The concept of 'split anergy' in NK cells and the generation of NK(reg) cells with regard to contributions to cell differentiation, tissue repair and regeneration and in tumor resistance are discussed in this review.
Keywords: Apoptosis; NFκB; NK; cancer stem cells; differentiation; regulation.