May8,2018Circulation.2018;137:2068–2073.DOI:10.1161/CIRCULATIONAHA.117.0321902068MiltonPacker,MDABSTRACT:Theinjectionofmesenchymalstemcellsintotheinjuredmyocardiumtoinducecardiacregenerationhasyieldeddisappointingresults,conceivablybecausecellswithcardioreparativepotentialmustbesuppliedforlongperiodsoftimetoproduceasalutaryeffect.Accordingly,investigatorshavedevisedwaysofdirectingsuchcellstotheheartonanongoingbasis:byenhancingtheactionofendogenouspeptidesthatfunctionascardiachomingsignals(eg,stromalcell–derivedfactor—1).Stromalcell–derivedfactor—1isreleasedduringacutecardiacinjuryandheartfailure,butithasashorthalf-lifebecauseofdegradationbydipeptidylpeptidase–4.Inhibitionofdipeptidylpeptidase–4potentiatestheactionsofstromalcell–derivedfactor—1and,theoretically,couldenhancecardiacrecovery.However,inlarge-scaletrialsinpatientswithtype2diabetesmellitus,dipeptidylpeptidase–4inhibitorshavenotreducedtheriskofatheroscleroticischemicevents,andtheyhaveunexpectedlyincreasedtheriskofheartfailure,mostprobablyheartfailurewithapreservedejectionfraction.Suchanoutcomemightbeexplainedifthechannelingofmesenchymalstemcellstotheheartbytheactionsofstromalcell–derivedfactor—1(especiallyfromnearbyadiposetissue)werefollowedbythetransformationofthesecellsintofibroblastsratherthancardiomyocytes.Thisconcernhasbeensupportedbyexperimentalstudies;theresultingfibrosiswouldbeexpectedtoexacerbatethepathophysiologicalderangementsthatleadtoheartfailurewithapreservedejectionfraction.Giventhewidespreaduseofdipeptidylpeptidase–4inhibitors,thepossibilitythatthesedrugspotentiatethecardiachomingofmesenchymalstemcellsthatcausemyocardialfibrosis(ratherthanrepair)warrantsfurtherstudy.©2018AmericanHeartAssociation,Inc.PRIMERTheAlchemist’sNightmareMightMesenchymalStemCellsThatAreRecruitedtoRepairtheInjuredHeartBeTransformedIntoFibroblastsRatherThanCardiomyocytes?http://circ.ahajournals.orgCirculationKeyWords:cardiacregeneration◼dipeptidylpeptidase-4inhibitors◼mesenchymalstemcells◼stromalcel...
