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1 LocationofcornealepithelialstemcellsAris
LocationofcornealepithelialstemcellsArisingfrom:Majo,F.,Rochat,A.,Nicolas,M.,Jaoude,G.A.&Barrandon,Y.Nature456,250254(2008).Thelongstandingconceptthatcornealepithelialstemcellsresidemainlyinthelimbusissupportedbytheabsenceofmajorcornealepithelialdifferentiationmarkers,thatis,K3andK12keratins,inlimbalbasalcells(thesemarkersareexpressed,however,incornealbasalcells,thusdistinguishingthemodeofkeratinexpressionincornealepitheliumfromthatofallotherstratifiedepithelia),thecentripetalmigrationofcornealepithelialcells,theexclusivelocationofslow-cyclingcellsinthelimbalbasallayer,thesuperiorinvitroproliferativepotentialoflimbalepithelialcells,andthetransplantedlimbalcellsabilitytoreconstitutecornealepitheliuminvivo(reviewedinrefs14).Moreover,previousdataindicatethatcornealandconjunctivalepitheliarepresenttwoseparatecelllineages(reviewedinrefs14).Majoetal.5suggested,however,thatcornealandconjunctivalepitheliaareequipotent,andthatidenticaloligo-potentstemcellsarepresentthroughoutthecorneal,limbalandconjunctivalepithelia.Wepointoutherethatthesesuggestionsare NATURE|Vol463|25February2010BRIEFCOMMUNICATIONSARISINGE10Macmillan Publishers Limited. All rights reserved©2010 Majoetal.replyReplyingto:T.-T.Sun,S.C.Tseng&R.M.LavkerNature463,doi:10.1038/nature08805(2010)Ourclaimisnotthattherearenostemcellsinthelimbus,butthatthereismoretocornealrenewalthanthelimbusandthatthedouble-dome-shapedstructureofthecorneaandphysicalconstraintshaveacrucialimpactoncelldynamics1.Sunandcolleagues2implythatinourpaper3wemisusedthetermholoclonesthatwedefinedasstemcells4;thecentralcorneaofthepigcontainsnumeroustrueholoclones,meaningthatthecorneaofthepighasextensivegrowthpotentialandtheabilitytobeserialpassagedinvitro.Weagreethattherearespeciesdifferencesamongmammals;nonetheless,allcorneasthatwehaveinvestigated,includingcalfandhuman,containcolony-formingcells.FiftycelldoublingsinpigcorneaisnottrivialandcontradictsthemodelproposedbySunandcolleagues5;wequotetheirabstractwedemonstratetheexistenceofahierarchyofTAcells;thoseofperipheralcorneaundergoatleasttworoundsofDNAsynthesisbeforetheybecomepost-mitotic,whereasthoseofcentralcorneaarecapableofonlyoneroundofdivision.ItalsodoesnotagreewithHuangandTsengsexperiment6showingthat,afterlimbalremoval,rabbitcentralcornealepitheliumcanremainapparentlyintactforalongtimeuntilitiswounded,indicatingthatcentralcorneacellshaveasignificantmaintenancepotential.Ourresultsshowthatcornealcellscanformgobletcellswhentheymigrateontoaconjunctivalenvironment(inmouse)orgeneratetruegobletcellcolonieswhencloned(inpig).Cornealdifferentiationisfoundinhumanconjunctiva7,conjunctivalcellsmaybesuccessfullytransplantedinthehumantoreplacecornea8,andtherearereportsofcornearemainingtransparentforyearsinlimbaldeficiency9.Furthermore,cornealcells10,likeconjunctivalcells(ourunpublishedresults),canformhairyskinwhenexposedtoaninductiveskinmicroenvironment,indicatingagreaterplasticitythananticipatedandthatstemcellfatestronglydependsonstromalsignals.Wearenotawareofanypaperthatclearlydemonstratesstemcellmigrationfromthelimbus.Buck11inhislandmarkpaperhasnotdemonstratedbasalcellmigration;wequotehisabstract:themediandistancemigratedwasabout17mmperday.Thisfigurerepresentsthedistancethroughwhichsuperficialandwingcellshadmigrated;thedistancemigratedbybasalcellswasnotdetermined.NagazakiandZhao12havepresentedevidenceofmovementinthecorneabutnotthatthemigratingcellsactuallyoriginatedfromthelimbus(fromisnotthesameasnear).An
2 overcrowdingofthecornealepithelium,asour
overcrowdingofthecornealepithelium,asourceoftensionandslidingaspreviouslyemphasizedbySunandcolleagues13,orsequentialactivationoftheb-actinpromotercaneasilyexplaintheseobservations.Similarly,thespiralstripeorganiza-tionmixingclockwiseandcounterclockwiseclones14ishighlyremini-scentofcentrifugalgrowthoriginatingfromasmallnumberofstemcellsoriginallylocatedincentralcornea.Thisbiologicalmodeloccurswidelyinnature,forinstanceinthegrowthofadaisy,astheeasiestandmostefficientwaytofillspace,anotionsupportedbymathematicalmodels15andaclothoidgrowthmodel(Eulerspiral).Franc¸oisMajo1,ArianeRochat2,3,MichaelNicolas1,GeorgesAbouJaoude´4&YannBarrandon2,31HopitalOphtalmiqueJulesGonin,AvenuedeFrance15,1004LausanneCH,Switzerland.2DepartmentofExperimentalSurgeryLausanneUniversityHospital(CHUV),1011LausanneCH,Switzerland.3LaboratoryofStemCellDynamics,EcolePolytechniqueFe´de´raledeLausanne(EPFL),1015LausanneCH,Switzerland.e-mail:yann.barrandon@epfl.ch4LaboratoryofInformaticsandVisualization,EcolePolytechniqueFe´de´raledeLausanne(EPFL),1015LausanneCH,Switzerland.1.Dupps,W.J.Jr&Wilson,S.E.Biomechanicsandwoundhealinginthecornea.Exp.EyeRes.83,709720(2006).2.Sun,T.-T.,Tseng,S.C.&Lavker,R.M.Locationofcornealepithelialstemcells.Nature463,doi:10.1038/nature08805(2010).3.Majo,F.,Rochat,A.,Nicolas,M.,Jaoude,G.A.&Barrandon,Y.Oligopotentstemcellsaredistributedthroughoutthemammalianocularsurface.Nature456,250254(2008).4.Barrandon,Y.&Green,H.Threeclonaltypesofkeratinocytewithdifferentcapacitiesformultiplication.Proc.NatlAcad.Sci.USA84,23022306(1987).5.Lehrer,M.S.,Sun,T.T.&Lavker,R.M.Strategiesofepithelialrepair:modulationofstemcellandtransitamplifyingcellproliferation.J.CellSci.111,28672875(1998).6.Huang,A.J.&Tseng,S.C.Cornealepithelialwoundhealingintheabsenceoflimbalepithelium.Invest.Ophthalmol.Vis.Sci.32,96105(1991).7.Kawasaki,S.etal.Clustersofcornealepithelialcellsresideectopicallyinhumanconjunctivalepithelium.Invest.Ophthalmol.Vis.Sci.47,13591367(2006).8.DiGirolamo,N.etal.Acontactlens-basedtechniqueforexpansionandtransplantationofautologousepithelialprogenitorsforocularsurfacereconstruction.Transplantation87,15711578(2009).9.Dua,H.S.,Miri,A.,Alomar,T.,Yeung,A.M.&Said,D.G.Theroleoflimbalstemcellsincornealepithelialmaintenance:testingthedogma.Ophthalmology116,856863(2009).10.Ferraris,C.,Chevalier,G.,Favier,B.,Jahoda,C.A.&Dhouailly,D.Adultcornealepitheliumbasalcellspossessthecapacitytoactivateepidermal,pilosebaceousandsweatglandgeneticprogramsinresponsetoembryonicdermalstimuli.Development127,54875495(2000).11.Buck,R.C.Measurementofcentripetalmigrationofnormalcornealepithelialcellsinthemouse.Invest.Ophthalmol.Vis.Sci.26,12961299(1985).12.Nagasaki,T.&Zhao,J.Centripetalmovementofcornealepithelialcellsinthenormaladultmouse.Invest.Ophthalmol.Vis.Sci.44,558566(2003).13.Lavker,R.M.etal.Relativeproliferativeratesoflimbalandcornealepithelia.Implicationsofcornealepithelialmigration,circadianrhythm,andsuprabasallylocatedDNA-synthesizingkeratinocytes.Invest.Ophthalmol.Vis.Sci.32,18641875(1991).14.Collinson,J.M.etal.Clonalanalysisofpatternsofgrowth,stemcellactivity,andcellmovementduringthedevelopmentandmaintenanceofthemurinecornealepithelium.Dev.Dyn.224,432440(2002).15.Stewart,I.Mathematicalrecreations:Daisy,Daisy,givemeyouranswer,do.Sci.Am.272,9699(1995).Competingfinancialinterests:declarednone.doi:10.1038/nature08806 NATURE|Vol463|25February2010BRIEFCOMMUNICATIONSARISINGE11Macmillan Publishers Limited. All rights reserved©201