Mesenchymalstemcell-macrophagecrosstalkandbonehealingJukkaPajarinen,TzuhuaLin,EmmanuelGibon,YusukeKohno,MasahiroMaruyama,KarthikNathan,LauraLu,ZhenyuYao,andStuartB.Goodman*OrthopaedicResearchLaboratories,DepartmentofOrthopaedicSurgery,StanfordUniversitySchoolofMedicine,Stanford,CA,USAAbstractRecentresearchhasbroughtaboutaclearunderstandingthatsuccessfulfracturehealingisbasedoncarefullycoordinatedcross-talkbetweeninflammatoryandboneformingcells.Inparticular,thekeyrolethatmacrophagesplayintherecruitmentandregulationofthedifferentiationofmesenchymalstemcells(MSCs)duringboneregenerationhasbeenbroughttofocus.Indeed,animalstudieshavecomprehensivelydemonstratedthatfracturesdonothealwithoutthedirectinvolvementofmacrophages.Yettheexactmechanismsbywhichmacrophagescontributetoboneregenerationremaintobeelucidated.Macrophage–derivedparacrinesignalingmoleculessuchasOncostatinM,ProstaglandinE2(PGE2),andBoneMorphogeneticProtein-2(BMP2)havebeenshowntoplaycriticalroles;howevertherelativeimportanceofinflammatory(M1)andtissueregenerative(M2)macrophagesinguidingMSCdifferentiationalongtheosteogenicpathwayremainspoorlyunderstood.Inthisreview,wesummarizethecurrentunderstandingoftheinteractionofmacrophagesandMSCsduringboneregeneration,withtheemphasisontheroleofmacrophagesinregulatingboneformation.Thepotentialimplicationsofagingtothiscellularcross-talkarereviewed.EmergingtreatmentoptionstoimprovefacturehealingbyutilizingortargetingMSC-macrophagecrosstalkarealsodiscussed.KeywordsFracturehealing;Mesenchymalstemcell;Macrophage;OncostatinM;ProstaglandinE2;BoneMorphogeneticProtein-21.IntroductionBonefracturesareoneofthemostcommoninjuriesseeninemergencydepartments,withnearly4millionfracturesseenintheUnitedStatesin2013[1].Despitethebesttreatmentefforts,upto10%ofbonefracturecasesstillreportundesirableoutcomes;intheUSAalone,100,000fracturesperyearresultinpainfulnon-union[2].Treatmentofthesenon-unitedfracturesandbonedefectsconstitutesamajorhealthproblemwithsignificantclinical,social,andeconomicimp...
