ReviewTheMetabolicMicroenvironmentSteersBoneTissueRegenerationJuliaLoeffler,1,2GeorgN.Duda,1,2,3F.AndreaSass,1,2,3andAnkeDienelt1,2,3,*Overthepastyears,basicfindingsincancerresearchhaverevealedmetabolicsymbiosisbetweendifferentcelltypestocopewithhighenergydemandsunderlimitednutrientavailability.Althoughthisalsoappliestoregeneratingtissueswithdisruptedphysiologicalnutrientandoxygensupply,theimpactofthismetaboliccooperationandmetabolicreprogrammingoncellulardevelop-ment,fate,andfunctionduringtissueregenerationhaswidelybeenneglectedsofar.Withthisreview,weaimtoprovideaschematicoverviewonmetaboliclinksthathaveahighpotentialtodrivetissueregeneration.Asboneis,asidefromliver,theonlytissuethatcanregeneratewithoutexcessivescartissueformation,wewillusebonehealingasanexemplarilymodelsystem.DoesMetabolicImprintingImpactTissueRegeneration?Asidefromtheliver,boneistheonlyothertissueinthehumanbodythatcanregeneratewithoutexcessivescarformationevenintheadult.Thus,thesequentialappearanceofdiversecelltypesconnectedtothesecretionofdifferentcytokinesandgrowthfactorsduringfracturerepaircouldberegardedasablueprintforregeneration.Thereisgrowingevidencethatnumerouscells,suchasmacrophagesandTcells,aresensitivetometabolicreprogrammingandthatacell’smetabolicconfigurationaffectsadditionalcellularfunctionsbeyondtherequestforenergyprovision.Consideringintensecompetitionfornutrientsatthefracturesiteduetotheirlimitedavailability,deprivationofmetabolicresourcesbysomecellsmayforceothercellstoengagedifferentmetabolicpathwaysthatareconnectedtoanalteredcellfunctionality.Thishighlightsthepossibilitythatenergymetabolismdrivenbytheaccessiblenutrientsandthemetabolicmicroenvironmenttriggerstissueregenerationnotonlybyfuelingpresentcells,butalsobyaffectingtheirphenotype,molecularsignature,andfunctiononalocallevel.Althoughknowl-edgeexistsonhowtheoverallbodymetabolismchangesduringtissuerepairprocesses,itiswidelyunknownhowlocalenergeticchangesandrelatedmetabolicreprogrammingofcellularsignalingpathwaysandfunctio...
