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Nat Commun. 2015 Jul 8;6:7398. doi: 10.1038/ncomms8398.

Netrin-1 regulates somatic cell reprogramming and pluripotency maintenance.

Author information

1
Apoptosis, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
2
INSERM U935, ESTeam Paris-Sud, Université Paris-Sud, Villejuif, France.
3
Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique, École Normale Supérieure de Lyon, 69364 Lyon, France.
4
CGϕMC UMR 5534 - Université Lyon 1, Campus de la Doua, Bâtiment Gregor Mendel 16, Rue Dubois, 69622 Villeurbanne, France.
5
Center for Life Sciences, Peking University, Yiheyuan Road Haidian District, Beijing 100871, P.R. China.
6
Cytometry Facility, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
7
Anipath, Université de Lyon, Hospices Civils de Lyon, Hôpital Edouard Herriot, Anatomie Pathologique, 69437 Lyon, France.
8
Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, W12 0NN, London, UK.
9
1] Apoptosis, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France [2] Cellular Reprogramming and Oncogenesis Laboratory, ATIP/Avenir Laboratory, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.

Abstract

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.

PMID:
26154507
PMCID:
PMC4510695
DOI:
10.1038/ncomms8398
[Indexed for MEDLINE]
Free PMC Article

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