TY - JOUR
T1 - Netrin-1 regulates somatic cell reprogramming and pluripotency maintenance
AU - Ozmadenci, Duygu
AU - Féraud, Olivier
AU - Markossian, Suzy
AU - Kress, Elsa
AU - Ducarouge, Benjamin
AU - Gibert, Benjamin
AU - Ge, Jian
AU - Durand, Isabelle
AU - Gadot, Nicolas
AU - Plateroti, Michela
AU - Bennaceur-Griscelli, Annelise
AU - Scoazec, Jean Yves
AU - Gil, Jesus
AU - Deng, Hongkui
AU - Bernet, Agnes
AU - Mehlen, Patrick
AU - Lavial, Fabrice
N1 - Funding Information:
We are grateful to Hervé Acloque for the STN cell line, and to Michelle Percharde for reagents and protocols. We thank Jose Silva and Rodrigo Santos for Oct4/GFP MEF. We thank the contribution of AniRA-PBES platform (SFR Biosciences-UMS3444/US8), especially Sophie Blanc, Marie Teixeira and Denise Aubert for technical advice and support regarding characterisation of stem cells. We also thank Frederic Flamant. We are grateful to Veronique Azuara for discussions and critical reading of the manuscript. This work was supported by institutional grants from CNRS, INSERM, University of Lyon, Centre Léon Bérard, from the Fondation pour la Recherche Médicale, ATIP/AVENIR (F.L.) and from the Ligue Contre le Cancer, INCA, ANR, ERC, FRM, EU FP7 Hermione-2man and Fondation Bettencourt (P.M.).
PY - 2015/7/8
Y1 - 2015/7/8
N2 - The generation of induced pluripotent stem (iPS) cells holds great promise in regenerative medicine. The use of the transcription factors Oct4, Sox2, Klf4 and c-Myc for reprogramming is extensively documented, but comparatively little is known about soluble molecules promoting reprogramming. Here we identify the secreted cue Netrin-1 and its receptor DCC, described for their respective survival/death functions in normal and oncogenic contexts, as reprogramming modulators. In various somatic cells, we found that reprogramming is accompanied by a transient transcriptional repression of Netrin-1 mediated by an Mbd3/Mta1/Chd4-containing NuRD complex. Mechanistically, Netrin-1 imbalance induces apoptosis mediated by the receptor DCC in a p53-independent manner. Correction of the Netrin-1/DCC equilibrium constrains apoptosis and improves reprogramming efficiency. Our work also sheds light on Netrin-1 € s function in protecting embryonic stem cells from apoptosis mediated by its receptor UNC5b, and shows that the treatment with recombinant Netrin-1 improves the generation of mouse and human iPS cells.
AB - The generation of induced pluripotent stem (iPS) cells holds great promise in regenerative medicine. The use of the transcription factors Oct4, Sox2, Klf4 and c-Myc for reprogramming is extensively documented, but comparatively little is known about soluble molecules promoting reprogramming. Here we identify the secreted cue Netrin-1 and its receptor DCC, described for their respective survival/death functions in normal and oncogenic contexts, as reprogramming modulators. In various somatic cells, we found that reprogramming is accompanied by a transient transcriptional repression of Netrin-1 mediated by an Mbd3/Mta1/Chd4-containing NuRD complex. Mechanistically, Netrin-1 imbalance induces apoptosis mediated by the receptor DCC in a p53-independent manner. Correction of the Netrin-1/DCC equilibrium constrains apoptosis and improves reprogramming efficiency. Our work also sheds light on Netrin-1 € s function in protecting embryonic stem cells from apoptosis mediated by its receptor UNC5b, and shows that the treatment with recombinant Netrin-1 improves the generation of mouse and human iPS cells.
UR - http://www.scopus.com/inward/record.url?scp=84953896587&partnerID=8YFLogxK
U2 - 10.1038/ncomms8398
DO - 10.1038/ncomms8398
M3 - Article
C2 - 26154507
AN - SCOPUS:84953896587
SN - 2041-1723
VL - 6
JO - Nature Communications
JF - Nature Communications
M1 - 7398
ER -