An Elaborate Regulation of Mammalian Target of Rapamycin Activity Is Required for Somatic Cell Reprogramming Induced by Defined Transcription Factors

The mammalian target of the rapamycin (mTOR) signaling pathway functions in many cellular processes, including cell growth, proliferation, differentiation, and survival. Recent advances have demonstrated that differentiated somatic cells can be directly reprogrammed into the pluripotent state by overexpression of several pluripotency transcription factors. However, whether the mTOR signaling pathway is involved in this somatic cell-reprogramming process remains unknown. Here, we provide evidence that an elaborate regulation of the mTOR activity is required for the successful reprogramming of somatic cells to pluripotency. The reprogramming of somatic cells collected from the Tsc2(-/-) embryo, in which the mTOR activity is hyperactivated, is entirely inhibited. By taking advantage of the secondary inducible pluripotent stem (iPS) system, we demonstrate that either elevating the mTOR activity by Tsc2 shRNA knockdown or using high concentrations of rapamycin to completely block the mTOR activity in cells derived from iPS mice greatly impairs somatic cell reprogramming. Secondary iPS induction efficiency can only be elevated by elaborately regulating the mTOR activity. Taken together, our data demonstrate that the precise regulation of the mTOR activity plays a critical role in the successful reprogramming of somatic cells to form iPS cells.