Reprogramming Primordial Germ Cells into Pluripotent Stem Cells 英文参考文献.docVIP

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Reprogramming Primordial Germ Cells into Pluripotent Stem Cells 英文参考文献.doc

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Reprogramming Primordial Germ Cells into Pluripotent Stem Cells 英文参考文献

ReprogrammingPrimordialGermCellsintoPluripotent StemCells GabrielaDurcova-Hills1*,FuchouTang1,GinaDoody2,ReubenTooze2,M.AzimSurani1* 1Wellcome Trust/Cancer Research UK Gurdon Institute of Cancer and Developmental Biology, University of Cambridge, Cambridge, United Kingdom, 2Division of ExperimentalHaematology,LeedsInstituteofMolecularMedicine,UniversityofLeeds,Leeds,UnitedKingdom Abstract Background: Specification of primordial germ cells (PGCs) results in the conversion of pluripotent epiblast cells into monopotentgermcelllineage.Blimp1/Prmt5complexplaysacriticalroleinthespecificationandmaintenanceoftheearly germcelllineage.However,PGCscanbeinducedtodedifferentiatebacktoapluripotentstateasembryonicgerm(EG)cells whenexposedtoexogenoussignalingmolecules,FGF-2,LIFandSCF. Methodology and Principal Findings: Here we show that Trichostatin A (TSA), an inhibitor of histone deacetylases, is a highly potent agent that can replace FGF-2 to induce dedifferentiation of PGCs into EG cells. A key early event during dedifferentiation of PGCs in response to FGF-2 or TSA is the down-regulation of Blimp1, which reverses and apparently relievesthecellfaterestrictionimposedbyit.Notably,thetargetsofBlimp1,whichincludec-MycandKlf-4,whichrepresent twoofthekeyfactorsknowntopromotereprogrammingofsomaticcellstopluripotentstate,areup-regulated.Wealso foundearlyactivationoftheLIF/Stat-3signalingpathwaywiththetranslocationofStat-3intothenucleus.Bycontrast,while Prmt5isretainedinEGcells,ittranslocatesfromthenucleustothecytoplasmwhereitprobablyhasanindependentrolein regulatingpluripotency. Conclusions/Significance: We propose that dedifferentiation of PGCs into EG cells may provide significant mechanistic insightsonearlyeventsassociatedwithreprogrammingofcommittedcellstoapluripotentstate. Citation:Durcova-HillsG,TangF,DoodyG,ToozeR,SuraniMA(2008)ReprogrammingPrimordialGermCellsintoPluripotentStemCells.PLoSONE3(10):e3531. doi:10.1371/journal.pone.0003531 Editor:Jean-NicolasVolff,EcoleNormaleSup