肠上皮细胞功能

REVIEWTheintestinalepitheliumtuftcells:specificationandfunctionFranc¸oisGerbe•CatherineLegraverend•PhilippeJayReceived:23February2012/Revised:21March2012/Accepted:26March2012/Publishedonline:19April2012TheAuthor(s)2012.ThisarticleispublishedwithopenaccessatSpringerlink.comAbstractTheintestinalepithelium,composedofatleastsevendifferentiatedcelltypes,representsanextraordinarymodeltounderstandthedetailsofmulti-lineagedifferen-tiation,aquestionthatishighlyrelevantindevelopmentalbiologyaswellasforclinicalapplications.Thisreviewfocusesonintestinalepithelialtuftcellsthathavebeenacknowledgedasaseparateentityformorethan60yearsbutwhosefunctionremainsamystery.Wediscusswhatiscurrentlyknownaboutthemolecularbasisoftuftcellfateanddifferentiationandwhyelucidatingtuftcellfunctionhasbeensodifficult.Finally,wesummarizethecurrenthypothesesontheirpotentialinvolvementindiseasesofthegastro-intestinaltract.KeywordsTuftcellsBrushcellsIntestinalepitheliumAtoh1CelldifferentiationDclk1AbbreviationsAc-tubulinAcetylatedtubulinAtoh1Atonalhomolog1BrdU5-Bromo-20-deoxyuridineCFTRCysticfibrosistransmembraneconductanceregulatorhomologCK-18Cytokeratin18DCLK1Doublecortin-likekinase1DllDelta-likeF-actinFibrillaractinGfi1Growthfactorindependent1Gfi1bGrowthfactorindependent1bGIGastro-intestinalGIPGastricinhibitorypolypeptideGLP-1Glucagon-likepeptide1Hes1Hairyandenhancerofsplit1HpgdsHematopoieticprostaglandinDsynthaseKlf4Kruppel-likefactor4L-FABPFattyacid-bindingprotein1,liverLgr5Leucine-richrepeat-containingGprotein-coupledreceptor5Neurog3Neurogenin3nNOSNitricoxidesynthase1,neuronalPGD2ProstaglandinD2PLCb2PhospholipaseC,Beta2PLCc2PhospholipaseC,Gamma2PtgsProstaglandin-endoperoxidesynthaseSox9SRY-boxcontaininggene9SpdefSAMpointeddomaincontainingRtstranscriptionfactorT1RTastereceptor,type1Trpm5Transientreceptorpotentialcationchannel,subfamilyM,member5UEA-1Ulexeuropaeus-IlectinF.GerbeC.LegraverendP.JayCNRSUMR5203,34094Montpellier,FranceF.GerbeC.LegraverendP.JayINSERMU661,34094Montpellier,FranceF.GerbeC.LegraverendP.JayMontpellierIUniversity,34094Montpellier,FranceF.GerbeC.LegraverendP.JayMontpellierIIUniversity,34094Montpellier,FranceF.GerbeC.LegraverendP.Jay(&)InstituteofFunctionalGenomics,141ruedelaCardonille,34094MontpellierCedex5,Francee-mail:[e-mail].(2012)69:2907–2917DOI10.1007/s00018-012-0984-7CellularandMolecularLifeSciences123ScopeofthisreviewDuringthefivedecadesthatfollowedtheirdiscoveryintherattrachea[1]andinthemouseglandularstomach[2],thecharacterizationoftuftcellshasbeenhamperedbythelackofspecificmolecularmarkers,andnexttonothingwasknownabouttheirfunctions,butthisischanging.Severalmolecularmarkersthatallowtheirunambiguousidentifi-cationarenowavailable,andthesecanbeusedtocreatemouselinesinwhichreportersarespecificallyexpressedintuftcells.Theseadvancesaremakingtuftcellsamenabletothoroughanalysis,andweanticipatethatinsightsintotheirfunctionswillbeobtainedinthenearfuture.Theultra-structuralpropertiesoftuftcellshavealreadybeenthesubjectofexcellentreviews[3,4]andwillnotbedetailedhere.Wewillinsteadsummarizerecentlypublisheddataontheirproteinexpressionprofile,developmentaltiming,andlineagerelationshipstotheothercelltypescomposingtheintestinalepithelium.Wewillalsodiscusstheirpotentialimplicationinintestinaldiseases,and,relyingondatafromotherorgans,speculateonhowtheymaycon-tributetointestinalhomeostasis.CellularcompositionofthesmallintestinalepitheliumTheintestinalepitheliumiscomposedofafoldedcellmonolayerorganizedintocryptsthatinvaginateintotheunderlyingmesenchyme,andvilliprojectingintothelumen.Thecryptsandvillicomprisetheproliferativeanddiffer-entiatedcompartments,respectively.Eachvillusreceivesinputsfromseveralcryptsandisthereforepolyclonal.Thestemcells,onwhichtherapidandpermanentrenewaloftheintestinalepitheliumrelies,arelocatedinthebaseofthecrypts,yettheirprecisenatureisstillamatterofdebate[5].Theprogenyofthestemcellpopulationfeedsintoshorter-livedprogenitorsoftheso-called‘‘transit-amplifying’’zonewhilemovingupwards.Migrationcontinuesbutprolifera-tionceaseswhencellsreachthecrypt–villusboundary,andthevilluscontainsonlypost-mitoticcells.Althoughatleastsevendifferentcelltypeshavenowbeenidentifiedintheintestinalepithelium(Fig.1),onlyfourareusuallyconsid-ered,andseverallineageanalyseshaveshownthatthesefourcelltypesareproducedfromthecryptbasecolumnarstemcells[6–8].Enterocytesareresponsiblefornutrientabsorptionandrepresentthevastmajorityofvillouscellsinthesmallintestine.Gobletcellsarescatteredthroughouttheepitheliumandproduceaprotectivemucuslayer.Hormone-producingenteroendocrinecellsrepresentapproximately1%ofallepithelialcells,andregulatevariousfunctionsoftheintestinalepithelium,andbeyond.Panethcells,clusteredinthebottomofthecrypts,produceantimicrobialpeptidesthatregulatethegutmicrobiota,aswellasgrowthfactorsinvolvedinthemaintenanceoftheneighboringstemcells,andinthehealthymouse,theirpresenceislimitedtothesmallintestine.Whereastheentireepitheliumisrenewedwithin4–7days,Panethcellshavealifespanofabout2months.Exceptfo