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SkinregenerationandrepaircédricBlanpainDifferenttypesofstemcellmaintaintheskin’sepidermisandcontributetoitshealingafterdamage.Theidentityofastem-celltypethatgivesrisetodifferentepidermal-celllineageshasjustbeenrevealed.Skinactsasanessentialbarrier,protectingorganismsfromtheirenvironment.Itiscomposedoftwoparts:theepidermis,thecellsofwhichformthebarrier;andthedermis,whichprovidessupportandnutritiontotheepidermis.Theepidermisalsoproducesappendages,includingsweatglands,andhairfolliclesandtheirassociat(yī)edsebaceousglands.Thedifferentepidermalcompartmentsundergoconstantcellularturnovertoreplacethedeadordamagedcells.Thishomeostaticprocessisthoughttoinvolveseveraltypesofstemcell,eachlocatedinaspecificepidermalregionandcontributingtothemaintenanceofadiscretecompartmentoftheskin1(Fig.1a).InapaperpublishedinScience,Snippertetal.identifythe“Lgr6”proteinasthemarkerofprogenitorsthatcandifferentiateintodifferentcelllineagesThefirstevidencethatskinstemcellscandifferentiateintointerfollicularepidermis,sebaceousglandandhairfolliclelineagescamefromtransplantationofbulgestemcells(3,4)—acellpopulationlocatedatthebaseofhairfollicles.Furtherexperimentsrevealedthat,duringbothembryonicdevelopmentandnormaladultskinhomeostasis,bulgestemcellsandtheirprogenycontributetohair-follicleregenerationbutnottothemaintenanceoftheinterfollicularepidermis(4–6).Inconditionssuchaswounding,however,bulgestemcellsrapidlymigratetowardstheinterfollicularepidermistohelpwiththerapidregenerationofthewoundedskin(5,7,8).Laterfindingsalsoshowedthatsebaceousglandcellsaremaintainedbyprogenitorslocatedabovethebulge,whichexpresstheBlimp1proteinduringmorphogenesis(9).Maintenanceoftheinterfollicularepidermis,meanwhile,involvesmanysmallunitsofproliferat(yī)ionscatteredthroughoutthisskinlayer,calledepidermalproliferat(yī)iveunits(10,11).Theinfundibulum—theupperpartofthehairfollicle,whichinterfaceswiththeinterfollicularepidermis—isthoughttobemaintainedbyprogenitorslocatedinahair-follicleregionknownastheisthmus;thesecells,whichexpressthemarkerproteinsMTS24andLrig1(refs12–14),candifferentiateintoallepidermalcelllineagesaftertransplantation(13,14).Snippertetal.2setouttoidentifythe‘mother’oftheseepidermalstemcells.Theyfindthat,duringskinformationinmice,thetransmembranereceptorLgr6isexpressedinboththehairfollicleandtheinterfollicularepidermis.Inadultanimals,however,Lgr6expressionbecomesrestrictedtotheisthmus,whereaboutone-thirdofLgr6-markedcellsalsoexpressMTS24andafewco-expressBlimp1.TomorepreciselydefinethedifferentiationpotentialofLgr6-expressingcells,theauthorsusedgeneticwizardrytopermanentlylabelLgr6-expressingcellsandtheirprogeny.Asexpectedfromthefirstsetofresults2,aswellaspreviousdata6,8,Lgr6-expressingcellsgaverisetocellsofboththehairfollicleandthesebaceousglandduringembryonicdevelopment.Moreover,somecellsoftheinterfollicularepidermiswerederivedfromLgr6-expressingcells(Fig.1b).Theauthors’lineagetracingofadultskinshowsthat(yī)Lgr6labellingwasinitiallyrestrictedmainlytothecellsoftheisthmusregion,withsomelabellingofcellsintheinterfollicularepidermisandotherpartsofthehairfollicles,albeitatlowerfrequency.Twomonthslater,Lgr6progenywerefoundmainlyintheisthmusandsebaceousgland,withsomeintheinterfollicularepidermis,andmorerarelyelsewhereinthehairfollicle.ThesefindingssuggestthatLgr6-expressingcellscontributemostlytothehomeostasisoftheisthmusregionandthesebaceousgland,whereasafewmayhavethepotentialtodifferentiateintootherepidermallineages.ItremainsunclearwhetherasinglesubpopulationwithintheLgr6-markedcellsregeneratesboththeisthmusandsebaceousglandorwhetherLgr6isexpressedinboththepreviouslyidentified12–14isthmusprogenitorsexpressingLrig1andMTS24,andtheBlimp1-expressingsebaceous-glandprogenitors(9).Snippertetal.alsofindthat,likeisthmusstemcells13,14,Lgr6-expressingcellstransplantedintoimmunodeficientmicegiverisetoallepidermalcelllineages.Moreover,likebulgestemcells,Lgr6-expressingstemcellsareactivat(yī)edbywoundingandmigratetowardstheepidermistoaidwoundrepair(Fig.1b).Theseintriguingobservationssuggestthat(yī)atleasttwodifferenthair-folliclestem-cellpopulationscanactivelycontributetotherepairofthedamagedepidermis.ThepresenceofLgr6-derivedcellsintheinterfollicularepidermisduringtissuehomeostasisismorepuzzling.Accordingtopreviouscell-lineagetracingofembryonicskin6,8,allcellsofthemat(yī)urehairfollicle,includingthoseoftheisthmusregion,arederivedfromcellsexpressingtwootherprogenitormarkers,ShhandSox9.Bycontrast,theinterfollicularepidermisisnotlabelledwiththesemarkersunlesswounded,suggestinglittleornocontributionofhair-folliclecellstothemaintenanceoftheinterfollicularepidermis6,8.ThreescenarioscouldexplainSnippertandcolleagues’observationthatLgr6-derivedcellsarepresentintheinterfollicularepidermis.First,somerareLgr6-expressingisthmuscellsmightoriginatefromapoolofhair-follicleprogenitorsdifferentfromthoseexpressingShhandSox9,andthesewouldthenmigratetotheinterfollicularepidermistocontributetoitsmaintenance.Second,Lgr6mightbemorebroadlyexpressedthanShhorSox9,thusmarkingapopulationofprogenitorsthatresidesintheinterfollicularepidermis,andcontributinglocallytothedevelopmentandhomeostasisofcellsthere.Finally,micro-woundingorstresstotheepidermismightcausemigrat(yī)ionofcellsfromthefollicleintotheinterfollicularepidermis.Thisstudy2addsyetanotherpiecetothecomplexpuzzleofskinhomeostasis,clearlydemonstratingthatLgr6-expressingprogenitorsactivelycycletoensuretherenewaloftheisthmusregionandthesebaceousglandunderphysiologicalconditions.Duringwounding,bothbulgestemcells5,7,8andLgr6-expressingstemcells2areactivelyrecruitedtorepairtheinterfollicularepidermis.Formostskinstemcells,thenaturalturnoverofcellsservesseveralpurposes:toreplacethedeadcellsthatareshedfromtheskinsurface(interfollicularepidermalstemcells),tofuelhairgrowth(bulgestemcells)ortomakeoilcells(sebaceous-glandstemcells).ButLgr6-expressingcellsarec
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