Netrin-1 regulates somatic cell reprogramming and pluripotency maintenance

Duygu Ozmadenci, Olivier Féraud, Suzy Markossian, Elsa Kress, Benjamin Ducarouge, Benjamin Gibert, Jian Ge, Isabelle Durand, Nicolas Gadot, Michela Plateroti, Annelise Bennaceur-Griscelli, Jean-Yves Scoazec, Jesus Gil, Hongkui Deng, Agnes Bernet, Patrick Mehlen () and Fabrice Lavial ()
Additional contact information
Duygu Ozmadenci: 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
Olivier Féraud: INSERM U935, ESTeam Paris-Sud, Université Paris-Sud
Suzy Markossian: 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
Elsa Kress: CGϕMC UMR 5534 - Université Lyon 1
Benjamin Ducarouge: 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
Benjamin Gibert: 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
Jian Ge: Center for Life Sciences, Peking University, Yiheyuan Road Haidian District
Isabelle Durand: Cytometry Facility, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard
Nicolas Gadot: Anipath, Université de Lyon, Hospices Civils de Lyon, Hôpital Edouard Herriot, Anatomie Pathologique
Michela Plateroti: CGϕMC UMR 5534 - Université Lyon 1
Annelise Bennaceur-Griscelli: INSERM U935, ESTeam Paris-Sud, Université Paris-Sud
Jean-Yves Scoazec: Anipath, Université de Lyon, Hospices Civils de Lyon, Hôpital Edouard Herriot, Anatomie Pathologique
Jesus Gil: Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, W12 0NN
Hongkui Deng: Center for Life Sciences, Peking University, Yiheyuan Road Haidian District
Agnes Bernet: 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
Patrick Mehlen: 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
Fabrice Lavial: 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

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8398

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