mTORC1 controls the adaptive transition of quiescent stem cells from G0 to GAlert

A mouse study reveals that the stem cell quiescent state is composed of two distinct phases, G0 and GAlert; stem cells reversibly transition between these two phases in response to systemic environmental stimuli acting through the mTORC1 pathway. This paper demonstrates that the in vivo stem-cell quiescent state is composed of distinct phases, much like the phases of the cell cycle. Thomas Rando and colleagues studied stem-cell quiescence in muscle stem cells in vivo and identified a quiescent phase that they call GAlert, which is distinct from the familiar G0 state and is stable, reversible and regulated by environmental stimuli through mTORC1. The authors propose that the transition of quiescent stem cells into GAlert functions as an 'alerting' mechanism by which stem cells can rapidly respond to injury and stress without requiring cell cycle entry or a cell fate commitment. A unique property of many adult stem cells is their ability to exist in a non-cycling, quiescent state1. 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 function2. 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, G0 and an ‘alert’ phase we term GAlert. 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 G0 into GAlert and that signalling through the HGF receptor cMet is also necessary. We also identify G0-to-GAlert transitions in several populations of quiescent stem cells. Quiescent stem cells that transition into GAlert possess enhanced tissue regenerative function. We propose that the transition of quiescent stem cells into GAlert 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.