manipulation of pluripotent stem cell metabolism for clinical application shugo tohyama资料.pdf

该【manipulation of pluripotent stem cell metabolism for clinical application shugo tohyama资料 】是由【四婆子】上传分享，文档一共【7】页，该文档可以免费在线阅读，需要了解更多关于【manipulation of pluripotent stem cell metabolism for clinical application shugo tohyama资料 】的内容，可以使用淘豆网的站内搜索功能，选择自己适合的文档，以下文字是截取该文章内的部分文字，如需要获得完整电子版，请下载此文档到您的设备，方便您编辑和打印。CurrStemCellRep(2017)3:28–-017-0073-9METABOLISMANDSTEMCELLS(DNAKADA,SECTIONEDITOR)ManipulationofPluripotentStemCellMetabolismforClinicalApplicationShugoTohyama1,2&ShoTanosaki1&ShotaSomeya1&JunFujita1&KeiichiFukuda1Publishedonline:13February2017#TheAuthor(s)(PSCs)havethecapac-itytodifferentiateintovarioustypesofcells,andarepromisingPluripotentstemcells(PSCs),includingembryonicstemcellscellsourcesforregenerativetherapyanddrugscreening.(ESCs)[1]andinducedpluripotentstemcells(iPSCs),canHowever,torealizetheclinicalapplicationofPSCs,alargenum-theoreticallyself-renewinfinitely[2,3]anddifferentiateintoberofhighlyqualifiedtargetcellsmustbestablypreparedwithvarioustypesofcells,includingcardiomyocytes,neurons,,,theclinicalreprogramming,differentiation,,,forrealizationoftheirclinicalapplication,-ThemetabolicprofilesofPSCsareindispensableforthetainthetargetcells,includingreprogramming,differentiation,maintenanceofpluripotency,self-renewal,differentiationca-andeliminationofresidualPSCsfromPSC-,,,andlowercostthanconventionalmethodsfordif-thereprogrammingprocess,useofatemperature-,manipu-mutatedSendaiviruswithYamanakafactors(OCT4,SOX2,lationofPSCmetabolismwillleadtonewtechnologiestoKLF4,andc-MYC)[4].Inaddition,co-expressionofmaternal-specificfactorsinoocytessuchasGLIS1[5],TH2A/TH2B[6],andH1foo[7],humanPSCs(hPSCs)havebeenRegenerativetherapyshowntobecapableofswitchingtothena?vestatebyuseofacombinationofsmallmolecules,similartomousePSCsThisarticleispartoftheTopicalCollectiononMetabolismandStem(mPSCs)[8–11].Moreover,theefficienciesofdifferentiationCellsintocardiomyocytescouldbegreatlyimprovedwiththeuseofbinant*******@[12,13].Furthermore,fluorescence-activatedcellsorting(FACS)-basedmethodsortoxin-basedmethodshave1DepartmentofCardiology,KeioUniversitySchoolofMedicine,35beendevelopedfortheeliminationofresidualPSCsafterdif-ShinanomachiShinjuku-ku,Tokyo160-8582,Japanferentiation[14–17].However,moreimprovementsarere-anFabrication,KeioUniversitySchoolofquiredtorealizetheclinicalapplicationofPSCsintermsofMedicine,35ShinanomachiShinjuku-ku,Tokyo160-8582,(2017)3:28–3429PSCsshowuniquemetabolicfeaturestomaintaintheir(LIF),whichmaintainsthecellsinana?vestateofpluripotencyandproliferativeability,andtheirmetabolismpluripotency,althoughtheycanswitchtoactivin/nodal-changesdramaticallyduringtheprocessesofreprogrammingdependentepiblaststemcells(EpiSCs)whosestate(,methodstoimprovemeta-state)isalittledownstreamfromana?-,proteomics,andtranscriptomicshavebeende-hypoxia-induciblefactor1α[28]().Inaddition,tran-velopedtoobtainmetabolicprofiles[18–20],whichcanbescriptionfactorSTAT3,downstreamoftheLIF-dependentusedtodramaticallyadvanceanalysesofthemetabolicfea-pathway,,we[29].(GSK3)andmitogen-activatedproteinkinase(MAPK)/extracellularMetabolismforSelf-RenewalandPluripotencyinPSCssignal-relatedkinase(ERK)inhibitors(2i)plusLIF[8].Astheground-statemESCs(culturedin2iplusLIF)maintainaMetabolisminmPSCshighα-ketoglutarate(αKG)level,whichisproducedfromglucoseandglutamine,,mESCs(culturedinserum[21,22]().Specifically,intheprocessofreprogrammingplusLIF)couldnotproliferatewithoutglutamine,becausemouseembryonicfibroblastsintomiPSCs,thedegreeofdepen-αKGismainlyproducedfromglutamine[30??].Thedenceonglycolysisgreatlyincreasesandthatonoxidativephos-ground-statemESCs(culturedin2iplusLIF)exhibitedanphorylation(OXPHOS)decreases,similartothehighdepen-elevatedαKG-to-inateratio,whichpromotedhistonedenceofmouseESCs(mESCs),includinghistone3lysine27ursduringtrimethylation(H3K27me3)andten-,glycolyticgene(Tet)-,pluripotencyexpressionwasfoundtoprecedepluripotentmarkerinductionwasmaintainedbecauseαKGisacofactorofFe(II)-andduringreprogramming[23].Infact,inhibitionofglucosemetab-αKG-dependentdioxygenases,-domain-,vatedglycolyticfeaturesofmESCs,itisreasonablethattheytheintracellularαKGlevelwasreportedtobeaffectedbyonditionphosphoserineaminotransferase1(PSAT1),anenzymein-[24].,,ursbyundifferentiatedstate,OCT4,SOX2,andNANOGbindtotheinductionofestrogen-relatednuclearreceptorssuchasERRαPSAT1enhancerregiontoregulatePSAT1expression[31?].andERRγandtheirco-factorssuchasPGC1αandPGC1βMoreover,mESCsarealsohighlydependentonthreonine[25].Bycontrast,depletionofthesefactorsreducesthecatabolism,whichproducesglycineandacetyl-CoAviathre-reprogrammingefficiencyinmouseembryonicfibroblastsoninedehydrogenase(TDH)thatarerequiredforS-[25].Moreover,thepentosephosphatepathway(PPP)andsyn-adenosylmethionine(SAM)synthesis[32??,33?].AsSAMthesisofaminoacidsarealsoactivatedinmESCsbecauseoftheproductionisimportantforhistonemethylation,cellcultureneedtoproducenucleotidesandaminoacidsforproliferationinthreonine-depletedconditionsleadstoadecreaseinthe[26??].Takentogether,thesestudiessuggestthatmPSCsarede-SAMlevel,which,inturn,reducesthedegreeofhistoneH3pendentonglycolysisnotonlyforATPproduction,butalsoforlysine4trimethylation(H3K4me3),resultingindifficultyofbiomassproduction,,-MetabolisminhPSCsizedbyahighreduced-to-oxidizedglutathioneratioandabun-,hPSCsarealsodependentonglycolysisforATPgeneration,andinhibitionoftheeicosanoidsignalingpathway,awell-knownshowdecreasedpyruvateoxidationduetothehighexpressionofpro-oxidativecascade,couldpromotepluripotencybymaintain-uncouplingprotein2(UCP2),amitochondrialinnermembraneingthelevelsofunsaturatedfattyacids[27?].protein[34].hPSCsalsohighlyconsumeseveralaminoacids,Pluripotencyshowsdiversestates,andeachstatehasdif--,inmediumcontainingserumplusleukemiainhibitoryfactorandglutaminemetabolismwasmorestronglyactivatedunder30CurrStemCellRep(2017)3:28–-coenzymeA(CoA)contributestohistoneacetylationNa?ve-statePSCslikemESCsdependonglucoseandglutamineforpluripotencyaswellastolipidsynthesisforproliferation,-derivedαKGisimportantforthreonine-ormethionine--stateH3K4me3,whichisalsoimportantforthemaintenanceofpluripotencyparedtona?ve-,,;NNMTnicotinamideN-(GSH);GSHreducedglutathione;SAMS-pluripotencybecauseglutamine-derivedGSHplaysasascavengerforadenosylmethionine;,glucose-mediatedglucose-depletedconditions[35?]().Inaddition,glutaminePSCsintermsoftheircontributionstoenergetics,ics,,itfollowsthatmanipulationofonlyessentialtomaintaintheredoxstatebutalsopreventstheglucose,glutamine,andmethioninemetabolismcanbeuseddegradationofOCT4[36].UnlikemPSCs,hPSCsarenotdepen-,,hPSCsdependonmethioninecatabo-lismforSAMproduction[37?].Moreover,hPSCsutilizeglucoseSeveralstudieshavedemonstratedtheessentialrolesofcellularfortheproductionofcytosolicacetyl-CoA,whichpromoteshis--toneacetylationinapluripotentstate[38?].Recently,hPSCswereation,PSCsshowreducedrelianceonglycolysisandincreasedbinationmitochondrialnumbersandmaturation[40],leadingtorepres-ofsmallmoleculessuchasGSK3inhibitor(CHIR99021),sionofUCP2expressionandaconsequentincreaseinoxidativeMAPK/ERKkinase(MEK)inhibitor(PD0325901),c-JunN-ter-phosphorylationandreactiveoxygenspecies(ROS)generationminalkinase(JNK)inhibitor(SP600125),p38inhibitor[41,42].ItiswellknownthatROSenhancethedifferentiation(BIRB796),humanLIF,insulin-likegrowthfactor(IGF),andefficiencyofhESCsintocardiomyocytesviaactivationofp38basicfibroblastgrowthfactor(bFGF)[9–11].-MAPKand/orphosphoinositol3-kinase[43,44].Asupra-onstratedthatnicotinamideN-methyltransferase(NNMT)wasphysiologicalconcentrationofglucoseintheculturemediumupregulatedinna?vehPSCs[39].Inna?vehPSCs,NNMTcon-wasshowntoresultinincreasedROSproduction,leadingtosumesSAM,whichleadstomaintenanceoflowSAMlevelsandenhancedcardiomyocytedifferentiation[45].Intriguingly,sup-theH3K27me3--lularpolyunsaturatedfattyacids,whichdecreaseafterdifferenti-Glucose,glutamine,andmethioninemetabolismareindis-,un-pensablefortheself-renewal,pluripotency,andsurvivalofsaturatedfattyacidsareoxidized,leadingtoanincreasedCurrStemCellRep(2017)3:28–,,capricacid,andpalmitoylcarnitinepro-Accordingly,agivenpopulationofPSC-derivedcellsgener-motethedifferentiationofmESCsintoneuronsorallycontainsresidualundifferentiatedPSCs,whicharethecardiomyocytes[27?].Inaddition,-acidcouldenhancecardiomyocytedifferentiationfromPSCsmationwasreportedtobehigherwithacontaminationrateof[46,47].AlthoughascorbicacidisknownforitsantioxidantresidualPSCso