Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency.
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.
Hanna
Jacob
J
The Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Markoulaki
Styliani
S
Schorderet
Patrick
P
Carey
Bryce W
BW
Beard
Caroline
C
Wernig
Marius
M
Creyghton
Menno P
MP
Steine
Eveline J
EJ
Cassady
John P
JP
Foreman
Ruth
R
Lengner
Christopher J
CJ
Dausman
Jessica A
JA
Jaenisch
Rudolf
R
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
C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D014157:Transcription Factors