Regulation of Stem Cell Systems by PI3K/Akt Signaling

Abstract

Stem cells can replenish their own population while supplying the cells necessary to maintain tissue homeostasis. Pluripotent stem cells, which have broader developmental potency than tissue stem cells, are derived from the same source in mice and humans. In this review, we summarize the functions of phosphoinositide-3 kinase (PI3K) and its downstream serine/threonine kinase Akt in a variety of stem cell systems. Primordial germ cells (PGCs), which are embryonic germ cell precursors, are unique in that they acquire pluripotency under cultural and pathological conditions. PGCs lacking Pten, which encodes a phosphatase that antagonizes PI3K signaling, give rise to early-onset testicular teratomas in vivo and augment the derivation of pluripotent embryonic germ (EG) cells in vitro. Transient activation of Akt sufficiently recapitulates the effects of Pten deficiency on EG cell derivation. Enhanced EG cell derivation is brought about by the Akt-mediated inhibition of the tumor suppressor p53. In embryonic stem (ES) cells, PI3K/Akt signaling plays a pivotal role in maintaining pluripotency in part via transcriptional activation of the pluripotent transcription factor Nanog. In turn, the expression of Tcl1, a cofactor of Akt, is activated by pluripotent transcription factors, including Oct-3/4. Therefore, PI3K/Akt signaling and the transcription factor network constitute the positive feedback circuitry necessary to maintain pluripotency in ES cells. In tissue stem cells, such as hair follicular, intestinal, and hematopoietic stem cells, PI3K/Akt signaling activates quiescent stem cells, leading to the generation of committed progenitors and cancer stem cells. These findings underscore the idea that PI3K/Akt signaling regulates “stemness” in many stem cell systems.