mTOR signaling promotes stem cell activation via counterbalancing BMP-mediated suppression during hair regeneration

Hairfollicles(HFs)undergocyclesofdegeneration(catagen),rest(telogen),andregeneration(anagen)phases.Anagenbeginswhenthe hair follicle stemcells (HFSCs) obtain sufficient activation cuesto overcome suppressivesignals, mainly the BMP pathway, fromtheir niche cells. Here, we unveil that mTOR complex 1 (mTORC1) signaling is activated in HFSCs, which coincides with the HFSCactivationatthetelogen-to-anagentransition.ByusingbothaninducibleconditionalgenetargetingstrategyandapharmacologicalinhibitionmethodtoablateorinhibitmTORsignalinginadultskinepitheliumbeforeanageninitiation,wedemonstratethatHFsthatcannotrespondtomTORsignalingdisplaysignificantlydelayedHFSCactivationandextendedtelogen.Unexpectedly,BMPsignalingactivityisdramaticallyprolongedinmTORsignaling-deficientHFs.Throughbothgain-andloss-of-functionstudiesinvitro,weshowthat mTORC1 signaling negativelyaffects BMP signaling, which serves as a main mechanism whereby mTORC1 signaling facilitatesHFSC activation. Indeed, in vivo suppression of BMP by its antagonist Noggin rescues the HFSC activation defect in mTORC1-nullskin.OurfindingsrevealacriticalroleformTORsignalinginregulatingstemcellactivationthroughcounterbalancingBMP-mediatedrepressionduring hair regeneration.