Reprogramming to Pluripotency Can Conceal Somatic Cell Chromosomal Instability 英文参考文献.docVIP

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Reprogramming to Pluripotency Can Conceal Somatic Cell Chromosomal Instability 英文参考文献.doc

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Reprogramming to Pluripotency Can Conceal Somatic Cell Chromosomal Instability 英文参考文献

ReprogrammingtoPluripotencyCanConcealSomatic CellChromosomalInstability MasakazuHamada1.,LiviuA.Malureanu1,2.,TobiasWijshake2,WeiZhou2,JanM.vanDeursen1,2* 1DepartmentofBiochemistryandMolecularBiology,MayoClinic,Rochester,Minnesota,UnitedStatesofAmerica,2DepartmentofPediatricandAdolescentMedicine, MayoClinic,Rochester,Minnesota,UnitedStatesofAmerica Abstract The discovery that somatic cells are reprogrammable to pluripotency by ectopic expression of a small subset of transcriptionfactorshascreatedgreatpotentialforthedevelopmentofbroadlyapplicablestem-cell-basedtherapies.One of the concerns regarding the safe use of induced pluripotent stem cells (iPSCs) in therapeutic applications is loss of genomicintegrity,ahallmarkofvarioushumanconditionsanddiseases,includingcancer.Structuralchromosomedefects such as short telomeres and double-strand breaks are known to limit reprogramming of somatic cells into iPSCs, but whether defects that cause whole-chromosome instability (W-CIN) preclude reprogramming is unknown. Here we demonstrate,usinganeuploidy-pronemouseembryonicfibroblasts(MEFs)inwhichchromosomemissegregationisdriven byBubR1orRanBP2insufficiency,thatW-CINisnotabarriertoreprogramming.Unexpectedly,thetwoW-CINdefectshad contrastingeffectsoniPSCgenomicintegrity,withBubR1hypomorphicMEFsalmostexclusivelyyieldinganeuploidiPSC clonesand RanBP2hypomorphicMEFs karyotypically normal iPSC clones.Moreover, BubR1-insufficientiPSC clones were karyotypicallyunstable,whereasRanBP2-insufficientiPSCcloneswereratherstable.Thesefindingssuggestthataneuploid cells canbe selected for or against during reprogramming depending on the W-CIN gene defect and present the novel conceptthatsomaticcellW-CINcanbeconcealedinthepluripotentstate.Thus,karyotypicanalysisofsomaticcellsoforigin inadditiontoiPSClinesisnecessaryforsafeapplicationofreprogrammingtechnology. Citation: Hamada M, Malureanu LA, Wijshake T, Zhou W, van Deursen JM (2012) Reprogramming to Pluripotency Can Conceal Somatic Cell Chromos