mTORC1 controls the adaptive transition of quiescent stem cells from G^sub 0^ to G^sub Alert

A unique property of many adult stem cells is their ability to exist in a non-cycling, quiescent state. Although quiescence serves an essential role in preserving stem cell function until the stem cell is needed in tissue homeostasis or repair, defects in quiescence can lead to an impairment in tissue function. The extent to which stem cells can regulate quiescence is unknown. Here we show that the stem cell quiescent state is composed of two distinct functional phases, G^sub 0^ and an 'alert' phase we term G^sub Alert^. Stem cells actively and reversibly transition between these phases in response to injury-induced systemic signals. Using genetic mouse models specific to muscle stem cells (or satellite cells), we show that mTORC1 activity is necessary and sufficient for the transition of satellite cells from G^sub 0^ into G^sub Alert^ and that signalling through the HGF receptor cMet is also necessary. We also identify G^sub 0^-to-G^sub Alert^ transitions in several populations of quiescent stem cells. Quiescent stem cells that transition into G^sub Alert^ possess enhanced tissue regenerative function. We propose that the transition of quiescent stem cells into G^sub Alert ^ functions as an 'alerting'mechanism, an adaptive response that positions stem cells to respond rapidly under conditions of injury and stress, priming them for cell cycle entry.