Akt modes of stem cell regulation: more than meets the eye?

Akt signaling regulates many cellular functions that are essential for the proper balance between selfrenewal and differentiation of tissue-specific and embryonic stem cells (SCs). However, the roles of Akt and its downstream signaling in SC regulation are rather complex, as Akt activation can either promote SC self-renewal or depletion in a contextdependent manner. In this review we have evidenced three “modes” of Akt-dependent SC regulation, which can be exemplified by three different SC types. In particular, we will discuss: 1) the integration of Akt signaling within the “core” SC signaling circuitry in the maintenance of SC selfrenewal and pluripotency (embryonic SCs); 2) quantitative changes in Akt signaling in SC metabolic activity and exit from quiescence (hematopoietic SCs); 3) qualitative changes of Akt signaling in SC regulation: signaling compartmenttalization and isoform-specific functions of Akt proteins in SC self-renewal and differentiation (limbal-corneal keratinocyte SCs). These diverse modes of action are not to be intended as mutually exclusive. Rather, it is likely that Akt proteins participate with multiple parallel mechanisms to regulation of the same SC type. We propose that under specific circumstances dictated by distinct developmental stages, differentiation programs or tissue culture conditions, one mode of Akt action prevails over the others in determining SC fates.