title: Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency.
abstract: Pluripotent cells can be derived from fibroblasts by ectopic expression of defined transcription factors. A fundamental unresolved question is whether terminally differentiated cells can be reprogrammed to pluripotency. We utilized transgenic and inducible expression of four transcription factors (Oct4, Sox2, Klf4, and c-Myc) to reprogram mouse B lymphocytes. These factors were sufficient to convert nonterminally differentiated B cells to a pluripotent state. However, reprogramming of mature B cells required additional interruption with the transcriptional state maintaining B cell identity by either ectopic expression of the myeloid transcription factor CCAAT/enhancer-binding-protein-alpha (C/EBPalpha) or specific knockdown of the B cell transcription factor Pax5. Multiple iPS lines were clonally derived from both nonfully and fully differentiated B lymphocytes, which gave rise to adult chimeras with germline contribution, and to late-term embryos when injected into tetraploid blastocysts. Our study provides definite proof for the direct nuclear reprogramming of terminally differentiated adult cells to pluripotency.
authors.affiliation: The Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Hanna
authors.forename: Styliani
authors.initials: S
authors.lastname: Markoulaki
authors.forename: Patrick
authors.initials: P
authors.lastname: Schorderet
authors.forename: Bryce W
authors.initials: BW
authors.lastname: Carey
authors.forename: Caroline
authors.initials: C
authors.lastname: Beard
authors.forename: Marius
authors.initials: M
authors.lastname: Wernig
authors.forename: Menno P
authors.initials: MP
authors.lastname: Creyghton
authors.forename: Eveline J
authors.initials: EJ
authors.lastname: Steine
authors.forename: John P
authors.initials: JP
authors.lastname: Cassady
authors.forename: Ruth
authors.initials: R
authors.lastname: Foreman
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lengner
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Dausman
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D014157:Transcription Factors