Epithelial-MesenchymalMicro-NichesGovernStemCellLineageChoicesHanseulYang1,ReneCAdam1,YejingGe1,ZhongLHua1,andElaineFuchs1,2,*1RobinNeusteinLaboratoryofMammalianDevelopmentandCellBiology,TheRockefellerUniversity,NewYork,NY10065,USA2HowardHughesMedicalInstitute,TheRockefellerUniversity,NewYork,NY10065,USASummaryAdulttissuestemcells(SCs)resideinniches,whichthroughintercellularcontactsandsignaling,influenceSCbehavior.Onceactivated,SCstypicallygiverisetoshort-livedtransit-amplifyingcells(TACs),whichthenprogresstodifferentiateintotheirlineages.Here,usingsinglecellRNA-sequencing,weunearthunexpectedheterogeneityamongSCsandTACsofhairfollicles.Wetracetherootsofthisheterogeneitytomicro-nichesalongepithelial-mesenchymalinterfaces,whereprogenitorsdisplaymolecularsignaturesreflectiveofspatiallydistinctlocalsignalsandintercellularinteractions.Usinglineage-tracing,temporalsinglecellanalysesandchromatinlandscaping,weshowthatSCplasticitybecomesrestrictedinasequentiallyandspatiallychoreographedprogram,culminatinginsevenspatiallyarrangeduni-lineageprogenitorswithinTACsofmaturefollicles.BycompartmentalizingSCsintomicro-niches,tissuesgainprecisecontrolovermorphogenesisandregeneration:Someprogenitorsspecifylineagesimmediately;othersretainpotency,preservingself-renewingfeaturesestablishedearlywhileprogressivelyrestrictinglineagesastheyexperiencedynamicchangesinmicroenvironment.KeywordsStemCells;Epithelial-MesenchymalInteractions;LineageDetermination;TissueRegeneration;SingleCellAnalysesINTRODUCTIONAdultstemcells(SCs)maintaintissuehomeostasisandrepairwounds.TheyresideinspecializednicheswhereneighboringcellsprovidetheinputsthatkeepthesecellsinanCorrespondencew/CellEditors:fuchs@rockefeller.edu.*Leadcontact:fuchslb@rockefeller.eduAuthorContributionsH.Y.,R.C.A.andE.F.designedtheexperimentsandwrotethemanuscript.L.H.andR.C.A.performedlineagetracingexperiments.R.C.Acontributedtoimmunofluorescenceanalyses.Y.G.performedtheATAC-seqexperiment.H.Y.performedtheotherexperimentsandanalyses.Allauthors...
