1. ¹Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan
2. ²Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
3. ³Genome Information Research Center, Osaka University, Suita, Osaka, Japan

Correspondence: Dr T Kimura or Professor T Nakano, Department of Pathology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail: tkimura@patho.med.osaka-u.ac.jp or E-mail: tnakano@patho.med.osaka-u.ac.jp

Received 26 July 2005; Revised 2 November 2005; Accepted 4 November 2005; Published online 9 January 2006.

Abstract

Embryonic stem (ES) cells can self-renew indefinitely without losing their differentiation ability to any cell types. Phosphoinositide-3 kinase (PI3K)/Akt signaling plays a pivotal role in various stem cell systems, including the formation of embryonic germ (EG) cells from primordial germ cells and self-renewal of neural stem cells. Here, we show that myristoylated, active form of Akt (myr-Akt) maintained the undifferentiated phenotypes in mouse ES cells without the addition of leukemia inhibitory factor (LIF). The effects of myr-Akt were reversible, because LIF dependence and pluripotent differentiation activity were restored by the deletion of myr-Akt. In addition, myr-Akt-Mer fusion protein, whose enzymatic activity is controlled by 4-hydroxy-tamoxifen, also maintained the pluripotency of not only mouse but also cynomolgus monkey ES cells. These results clearly demonstrate that Akt signaling sufficiently maintains pluripotency in mouse and primate ES cells, and support the notion that PI3K/Akt signaling axis regulates 'stemness' in a broad spectrum of stem cell systems.