Senescence impairs successful reprogramming to pluripotent stem cells.
Somatic cells can be reprogrammed into induced pluripotent stem (iPS) cells by overexpressing combinations of factors such as Oct4, Sox2, Klf4, and c-Myc. Reprogramming is slow and stochastic, suggesting the existence of barriers limiting its efficiency. Here we identify senescence as one such barrier. Expression of the four reprogramming factors triggers senescence by up-regulating p53, p16(INK4a), and p21(CIP1). Induction of DNA damage response and chromatin remodeling of the INK4a/ARF locus are two of the mechanisms behind senescence induction. Crucially, ablation of different senescence effectors improves the efficiency of reprogramming, suggesting novel strategies for maximizing the generation of iPS cells.
Banito
Ana
A
Cell Proliferation Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London W12 0NN, United Kingdom.
Rashid
Sheikh T
ST
Acosta
Juan Carlos
JC
Li
SiDe
S
Pereira
Carlos F
CF
Geti
Imbisaat
I
Pinho
Sandra
S
Silva
Jose C
JC
Azuara
Veronique
V
Walsh
Martin
M
Vallier
Ludovic
L
Gil
Jesús
J
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D065150:Cellular Reprogramming; D016922:Cellular Senescence / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D000090062:Kruppel-Like Factor 4; D039904:Pluripotent Stem Cells / Q000166:cytology*
PLoS Genet. 2008 Sep 05;4(9):e1000170
18773085
Genes Dev. 2007 Mar 15;21(6):644-8
17369397
Nature. 2002 Apr 4;416(6880):545-8
11932748
Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2883-8
18287077
Nat Biotechnol. 2009 May;27(5):459-61
19363475
Cell Cycle. 2009 Feb 1;8(3):394-8
19176999
Science. 2008 Nov 7;322(5903):945-9
18818365
Dev Cell. 2003 Aug;5(2):351-8
12919684
Science. 2007 Dec 21;318(5858):1917-20
18029452
Cell. 2009 Jan 23;136(2):364-77
19167336
Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):157-62
19109433
Cell Stem Cell. 2009 Apr 3;4(4):301-12
19341620
Nature. 2008 Jan 10;451(7175):141-6
18157115
Cell. 2006 Aug 25;126(4):663-76
16904174
Science. 2009 May 8;324(5928):797-801
19325077
Nat Genet. 2008 Dec;40(12):1478-83
18978791
Genes Dev. 2009 May 15;23(10):1177-82
19451218
Nature. 1997 Feb 27;385(6619):810-3
9039911
Cell. 2007 Jul 27;130(2):223-33
17662938
Cell Stem Cell. 2009 May 8;4(5):381-4
19398399
Cell Stem Cell. 2008 Feb 7;2(2):151-9
18371436
Dev Biol. 2004 Jun 15;270(2):488-98
15183728
PLoS Biol. 2008 Oct 21;6(10):e253
18942890
Science. 2008 Nov 7;322(5903):949-53
18845712
Cell. 2007 Nov 30;131(5):861-72
18035408
Nature. 2009 Apr 9;458(7239):771-5
19252477
Nature. 2008 Jul 3;454(7200):49-55
18509334