Autophagymaintainsthemetabolismandfunctionofyoungandold(hematopoietic)stemcellsTheodoreT.Ho1,MatthewR.Warr1,EmmaleeR.Adelman2,OliviaM.Lansinger1,JohannaFlach1,EvgeniaV.Verovskaya1,MariaE.Figueroa2,andEmmanuellePassegué1,*1DepartmentofMedicine,Hem/OncDivision,TheEliandEdytheBroadCenterforRegenerativeMedicineandStemCellResearch,UniversityofCaliforniaSanFrancisco,SanFrancisco,CA94143,USA2DepartmentofPathology,UniversityofMichiganSchoolofMedicine,AnnArbor,MI48109,USAAbstractWithage,hematopoieticstemcells(HSCs)losetheirabilitytoregeneratethebloodsystem,andpromotediseasedevelopment.Autophagyisassociatedwithhealthandlongevity,andiscriticalforprotectingHSCsfrommetabolicstress.Here,weshowthatlossofautophagyinHSCscausesaccumulationofmitochondriaandanactivatedmetabolicstate,whichdrivesacceleratedmyeloiddifferentiationmainlythroughepigeneticderegulations,andimpairsHSCself-renewalactivityandregenerativepotential.Strikingly,themajorityofHSCsinagedmicesharethesealteredmetabolicandfunctionalfeatures.However,~1/3ofagedHSCsexhibithighautophagylevelsandmaintainalowmetabolicstatewithrobustlong-termregenerationpotentialsimilartohealthyyoungHSCs.OurresultsdemonstratethatautophagyactivelysuppressesHSCmetabolismbyclearingactive,healthymitochondriatomaintainquiescenceandstemness,andbecomesincreasinglynecessarywithagetopreservetheregenerativecapacityofoldHSCs.Agingisthegreatestriskfactorformanypathologicalconditionsincludingcancers,neurodegenerativedisorders,cardiovasculardiseases,anddiabetes1.Physiologicalagingisacomplexandmultifactorialprocessthatisregulatedbybothgeneticandenvironmentalfactors2.Althoughtissuesacrossthebodyareseeminglyaffectedindifferentways,oneemerginghallmarkofagingisthatreductionintissuefunctionusuallycorrelateswithareductioninstemcellactivity3.Thebloodsystemiscriticalformanyaspectsoforganismalhealth,andpropermaintenanceofbloodproductionreliesontheabilityofHSCstoself-renewanddifferentiateintoalllineagesofmaturebloodcells4.Inadults,HSCsarerareandUsersmayview,print,cop...
