The immune system and cardiac repair.docx
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The immune system and cardiac repair.docx
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Theimmunesystemandcardiacrepair
Theimmunesystemandcardiacrepair
PharmacologicalresearchtheofficialjournaloftheItalianPharmacologicalSociety(2008)
Volume:
58,Issue:
2,Publisher:
Elsevier,Pages:
88-111
Myocardialinfarctionisthemostcommoncauseofcardiacinjuryandresultsinacutelossofalargenumberofmyocardialcells.Becausethehearthasnegligibleregenerativecapacity,cardiomyocytedeathtriggersareparativeresponsethatultimatelyresultsinformationofascarandisassociatedwithdilativeremodelingoftheventricle.Cardiacinjuryactivatesinnateimmunemechanismsinitiatinganinflammatoryreaction.Toll-likereceptor-mediatedpathways,thecomplementcascadeandreactiveoxygengenerationinducenuclearfactor(NF)-kappaBactivationandupregulatechemokineandcytokinesynthesisintheinfarctedheart.Chemokinesstimulatethechemotacticrecruitmentofinflammatoryleukocytesintotheinfarct,whilecytokinespromoteadhesiveinteractionsbetweenleukocytesandendothelialcells,resultingintransmigrationofinflammatorycellsintothesiteofinjury.Monocytesubsetsplaydistinctrolesinphagocytosisofdeadcardiomyocytesandingranulationtissueformationthroughthereleaseofgrowthfactors.Clearanceofdeadcellsandmatrixdebrismaybeessentialforresolutionofinflammationandtransitionintothereparativephase.Transforminggrowthfactor(TGF)-betaplaysacrucialroleincardiacrepairbysuppressinginflammationwhilepromotingmyofibroblastphenotypicmodulationandextracellularmatrixdeposition.Myofibroblastproliferationandangiogenesisresultinformationofhighlyvascularizedgranulationtissue.Asthehealinginfarctmatures,fibroblastsbecomeapoptoticandacollagen-basedmatrixisformed,whilemanyinfarctneovesselsacquireamuscularcoatanduncoatedvesselsregress.Timelyresolutionoftheinflammatoryinfiltrateandspatialcontainmentoftheinflammatoryandreparativeresponseintotheinfarctedareaareessentialforoptimalinfarcthealing.Targetinginflammatorypathwaysfollowinginfarctionmayreducecardiomyocyteinjuryandattenuateadverseremodeling.Inaddition,understandingtheroleoftheimmunesystemincardiacrepairisnecessaryinordertodesignoptimalstrategiesforcardiacregeneration.
Immunosuppressionbymesenchymalstemcells:
mechanismsandclinicalapplications
SoufianeGhannam1,2,CarineBouffi1,2,FaridaDjouad1,2,ChristianJorgensen1,2,3andDanièleNoël1,2*
StemCellResTher.2010;1
(1):
2.
Abstract
Mesenchymalstemcells(MSCs)aremultipotentialnonhematopoieticprogenitorcellsthatareisolatedfrommanyadulttissues,inparticularfromthebonemarrowandadiposetissue.Alongwiththeircapacityfordifferentiatingintocellsofmesodermallineage,suchasadipocytes,osteoblastsandchondrocytes,thesecellshavealsogeneratedgreatinterestfortheirabilitytodisplayimmunomodulatorycapacities.Indeed,amajorbreakthroughcamewiththefindingthattheyareabletoinduceperipheraltolerance,suggestingtheymaybeusedastherapeutictoolsinimmune-mediateddisorders.ThepresentreviewaimsatdiscussingthecurrentknowledgeonthetargetsandmechanismsofMSC-mediatedimmunosuppressionaswellasthepotentialuseofMSCsasmodulatorsofimmuneresponsesinavarietyofdiseasesrelatedtoalloreactiveimmunityorautoimmunity
Introduction
Mesenchymalstemcells(MSCs),alsonamedmultipotentmesenchymalstromalcells,arelargelystudiedasnewtherapeutictoolsforanumberofclinicalapplications.Indeed,thesecellshavebeenshowntohavedifferentiationcapacitiesaswellasparacrineeffectsviathesecretionofgrowthfactors,cytokines,antifibroticorangiogenicmediators[1].AlargebodyofstudiesalsoindicatesthatMSCspossessanimmunosuppressivefunctionbothinvitroandinvivo.WereviewthepresentknowledgeonthemechanismsunderlyingtheimmunomodulatorycharacteristicsofMSCsandtheirapplicationsinanimalmodelsofimmunesuppressionorinclinics.
Definitionofmesenchymalstemcells
MSCswereinitiallyisolatedfrombonemarrowbutarenowshowntoresideinalmosteverytypeofconnectivetissue[2].MSCsarecharacterizedasaheterogeneouspopulationofcellsthatproliferateinvitroasplastic-adherentcellsabletodevelopasfibroblastcolonyforming-units[3].MSCsaredistinguishedfromhematopoieticcellsbybeingnegativeforthecellsurfacemarkersCD11b,CD14,CD34,CD45andhumanleukocyteantigen(HLA)-DRbutexpressingCD73,CD90andCD105.Importantly,thecapacitytodifferentiateintomultiplemesenchymallineagesincludingbone,fatandcartilageisusedasafunctionalcriteriontodefineMSCs[4].
Immunosuppressivemechanismsofmesenchymalstemcells
Immunosuppressivefunctionofmesenchymalstemcellsrequirespreliminaryactivation
MSC-mediatedimmunosuppressionrequirespreliminaryactivationoftheMSCsbyimmunecellsthroughthesecretionoftheproinflammatorycytokineIFNγ,aloneortogetherwithTNFα,IL-1αorIL-1β[5,6].Thisactivationstephasalsobeenshowninvivoinamodelofgraftversushostdisease(GVHD)sincerecipientsofIFNγ-/-TcellsdidnotrespondtoMSCtreatmentandsuccumbedtoGVHD[7].Indeed,MSCsfrommicedeficientfortheIFNγreceptor1donothaveimmunosuppressiveactivity,highlightingtheimportantroleofIFNγinthisprocess[6].
Mesenchymalstemcellimmunosuppressionismediatedbysolublefactors
Althoughtargetcell-MSCinteractionsmayplayarole,theMSC-mediatedimmunosuppressionmainlyactsthroughthesecretionofsolublemoleculesthatareinducedorupregulatedfollowingcross-talkwithtargetcells.Amongthesefactors,indoleamine2,3-dioxygenase(IDO)hasconsistentlybeenreported[8,9].OnstimulationwithIFNγ,thisenzymemetabolizestryptophantokynurenin,causingdepletionoflocaltryptophanandaccumulationoftoxicbreakdownproducts.IDO,however,exertsitseffectsmainlythroughthelocalaccumulationoftryptophanmetabolitesratherthanthroughtryptophandepletion[10].WhereasthemajorityofstudiesindicateapotentiallyimportantfunctionforIDO,humanMSCslackingbothIFNγreceptor1andIDOstillexertedimportantimmunomodulatoryactivity[11].ThisobservationmaybeexplainedatleastinpartbyarecentstudyreportingthatToll-likereceptorsexpressedonMSCsaugmenttheirimmunosuppressiveactivityintheabsenceofIFNγthroughanautocrineIFNβsignalingloop,whichwasdependentonproteinkinaseRandabletoinduceIDO[12].ContrarytohumanMSCs,lackofIDOactivitywasconstantlyreportedformurineMSCs[13,14].
Inductionofinduciblenitric-oxidesynthase(iNOS)bymurineMSCsandproductionofnitricoxidewassuggestedtoplayamajorroleinT-cellproliferationinhibition[15].NitricoxideisagaseousbioactivecompoundaffectingmacrophageandT-cellfunctions.iNOSisinducedinmouseMSCsafteractivationbyIFNγandTNFα,IL-1αorIL-1β,andMSCsfromiNOS-/-micehadareducedabilitytosuppressT-cellproliferation[6](BouffiC,BonyC,CourtiesG,JorgensenC,NoëlD,submitted).TheexpressionlevelofiNOSmRNAinhumanMSCswasminimal[14],however,andsecretionofnitricoxidebyhumanMSCswasundetectable(BouffiC,BonyC,CourtiesG,JorgensenC,NoëlD,unpublishedresults).Indeed,differentmechanismsofimmunosuppressionexistindifferentspeciessincehumanMSCsemployIDOasamajoreffectormoleculewhereasnitricoxideplaysacriticalroleinmouseMSCs[14].
ProstaglandinE2(PGE2)hasalsobeeninvolvedintheimmunosuppressiveactivityofMSCs.PGE2isaproductofarachidonicacidmetabolismthatactsasapowerfulimmunesuppressant,inhibitingT-cellmitogenesisandIL-2production,andisacofactorfortheinductionofT-helper(Th)type2lymphocyteactivity.ProductionofPGE2byMSCsisenhancedfollowingTNFαorIFNγstimulation,anditsinhibitionusingspecificinhibitorsresultedinrestorationofT-lymphocyteproliferation[16].MSC-derivedPGE2wasshowntoactonmacrophagesbystimulatingtheproductionofIL-10andonmonocytesbyblockingtheirdifferentiationtowarddendriticcells(DCs)[17,18].
AnotherMSC-secretedfactor,IL-6,hasbeenreportedtobeinvolvedintheinhibitionofmonocytedifferentiationtowardDCs,decreasingtheirstimulationabilityonTcells[13,19].Inparallel,thesecretionofIL-6byMSCshasalsobeenreportedtodelayapoptosisoflymphocytesandneutrophils[20,21].
Othermediators-suchastransforminggrowthfactorbeta1,hepatocytegrowthfactor,hemeoxygenase1andleukemiainhibitoryfactor-wereshowntobeproducedbyMSCsuponactivation[16,22-24].TheproductionofHLA-G5byMSCshasmorerecentlybeenshowntosuppressT-cellproliferation,aswellasnaturalkillercellcytotoxicityandT-cellcytotoxicity,andtopromotethegenerationofregulatoryT(TREG)cells[25,26].CellcontactbetweenMSCsandactivatedTcellsinducedIL-10production,whichwasessentialtostimulatethereleaseofsolubleHLA-G5.
AnyofthesemoleculesalonedoesnotleadtoacompleteabrogationofT-cellproliferation,indicatingtheirnonexclusiverole.Instead,MSC-mediatedimmunoregulationistheresultofthecumulativeactiondisplayedbyseveralmolecules.
Suppressiveeffectsonimmunecells
BothCD4+andCD8+T-lymphocyteproliferationstimulatedwithmitogensorspecificantigensissuppressedbyMSCs.SuppressionoccurredwithMSCsfromautologousorallogeneicsources,indicatingthatitwasnotrestrictedbymajorhistocompatibilitycomplex(MHC)[27,28].InhibitionofproliferationdependsonthearrestofTcellsintheG0/G1phaseofthecellcycle,independentlyofapoptosis,butinsteadMSCspromotethesurvivalofstimulatedTcells[29,30].MSCsalterotherT-cel
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