title: mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert).
abstract: 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, G0 and an 'alert' phase we term G(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 G0 into G(Alert) and that signalling through the HGF receptor cMet is also necessary. We also identify G0-to-G(Alert) transitions in several populations of quiescent stem cells. Quiescent stem cells that transition into G(Alert) possess enhanced tissue regenerative function. We propose that the transition of quiescent stem cells into G(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.
authors.affiliation: 1] Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, California 94305, USA [2] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Rodgers
authors.affiliation: Department of Pediatrics and Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Katherine Y
authors.initials: KY
authors.lastname: King
authors.affiliation: 1] Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, California 94305, USA [2] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Jamie O
authors.initials: JO
authors.lastname: Brett
authors.affiliation: 1] Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, California 94305, USA [2] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Melinda J
authors.initials: MJ
authors.lastname: Cromie
authors.affiliation: 1] Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, California 94305, USA [2] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Charville
authors.affiliation: 1] Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, California 94305, USA [2] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Katie K
authors.initials: KK
authors.lastname: Maguire
authors.affiliation: 1] Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, California 94305, USA [2] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Brunson
authors.affiliation: 1] Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, California 94305, USA [2] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Namrata
authors.initials: N
authors.lastname: Mastey
authors.affiliation: 1] Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, California 94305, USA [2] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Pediatrics and Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Chang-Ru
authors.initials: CR
authors.lastname: Tsai
authors.affiliation: Department of Pediatrics and Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Goodell
authors.affiliation: 1] Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, California 94305, USA [2] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA [3] Neurology Service and Rehabilitation Research and Development Center of Excellence, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rando
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology* / Q000293:injuries / Q000378:metabolism; D012038:Regeneration / Q000502:physiology; D016192:Resting Phase, Cell Cycle / Q000235:genetics / Q000502:physiology*; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases