Letterhttps://doi.org/10.1038/s41586-018-0554-8DiscoveryofaperiostealstemcellmediatingintramembranousboneformationShawonDebnath1,Alishar.Yallowitz1,JasonMcCormick2,SarfarazLalani1,tuoZhang3,renXu1,NaLi1,YifangLiu4,YeonSukYang5,Markeiseman1,Jae-HyuckShim5,MeeraHameed6,JohnH.Healey7,MathiasP.Bostrom8,9,DanAviLandau10,11&MatthewB.Greenblatt1*Boneconsistsofseparateinnerendostealandouterperiostealcompartments,eachwithdistinctcontributionstobonephysiologyandeachmaintainingseparatepoolsofcellsowingtophysicalseparationbythebonecortex.Theskeletalstemcellthatgivesrisetoendostealosteoblastshasbeenextensivelystudied;however,theidentityofperiostealstemcellsremainsunclear1–5.Hereweidentifyaperiostealstemcell(PSC)thatispresentinthelongbonesandcalvariumofmice,displaysclonalmultipotencyandself-renewal,andsitsattheapexofadifferentiationhierarchy.Single-cellandbulktranscriptionalprofilingshowthatPSCsdisplaytranscriptionalsignaturesthataredistinctfromthoseofotherskeletalstemcellsandmaturemesenchymalcells.Whereasotherskeletalstemcellsformboneviaaninitialcartilagetemplateusingtheendochondralpathway4,PSCsformboneviaadirectintramembranousroute,providingacellularbasisforthedivergencebetweenintramembranousversusendochondraldevelopmentalpathways.However,thereisplasticityinthisdivision,asPSCsacquireendochondralboneformationcapacityinresponsetoinjury.GeneticblockadeoftheabilityofPSCstogiverisetobone-formingosteoblastsresultsinselectiveimpairmentsincorticalbonearchitectureanddefectsinfracturehealing.AcellanalogoustomousePSCsispresentinthehumanperiosteum,raisingthepossibilitythatPSCsareattractivetargetsfordrugandcellulartherapyforskeletaldisorders.TheidentificationofPSCsprovidesevidencethatbonecontainsmultiplepoolsofstemcells,eachwithdistinctphysiologicfunctions.Amajorlimitationtoidentifyingperiostealstemcellshasbeenthelackofgeneticmarkersthatdiscriminatebetweenperiostealandendostealmesenchyme.Whilestudyingthespecificityofskeletaltar-getingcrestrains,weobservedthatcathepsinK-Cre(Ctskcre)label...
