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NF-κB activation impairs somatic cell reprogramming in ageing

Nature Cell Biology volume 17, pages 10041013 (2015) | Download Citation

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Abstract

Ageing constitutes a critical impediment to somatic cell reprogramming. We have explored the regulatory mechanisms that constitute age-associated barriers, through derivation of induced pluripotent stem cells (iPSCs) from individuals with premature or physiological ageing. We demonstrate that NF-κB activation blocks the generation of iPSCs in ageing. We also show that NF-κB repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-κB hyperactivation impairs the generation of iPSCs by eliciting the reprogramming repressor DOT1L, which reinforces senescence signals and downregulates pluripotency genes. Genetic and pharmacological NF-κB inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Néstor–Guillermo progeria syndrome and Hutchinson–Gilford progeria syndrome patients, as well as from normal aged donors. Finally, we demonstrate that DOT1L inhibition in vivo extends lifespan and ameliorates the accelerated ageing phenotype of progeroid mice, supporting the interest of studying age-associated molecular impairments to identify targets of rejuvenation strategies.

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Change history

  • 04 October 2018

    Editor's Note: We would like to alert readers that the reliability of data presented in this manuscript has been the subject of criticisms, which we are currently considering. We will publish an update once our investigation is complete.

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Acknowledgements

We thank R. M. Schmid, H. Algül, T. Schöler, A. R. Folgueras, X. S. Puente, A. A. Ferrando, M. Serrano, H. Li, A. López-Soto, C. Bárcena, M. Gupta and D. Robinton for helpful comments and advice. We also thank F. Rodríguez and M. Roldán for excellent technical assistance, and the Servicio de Histopatología (IUOPA) for histological studies. This work was supported by grants from Ministerio de Economía y Competitividad-Spain (to C.L.-O., P.M. and C.B.), Gobierno del Principado de Asturias and Instituto de Salud Carlos III (RTICC), Spain. The Instituto Universitario de Oncología is supported by Fundación Bancaria Caja de Ahorros de Asturias. C.B. is a recipient of a ‘Miguel Servet’ fellowship from the ISCIII-FIS. P.M. is a member of the Spanish Cell Therapy Network (Tercel). C.L.-O. is an Investigator of the Botin Foundation supported by Banco Santander through its Santander Universities Global Division. This paper is dedicated to the memory of Néstor M.O.

Author information

Author notes

    • Clara Soria-Valles
    •  & Fernando G. Osorio

    These authors contributed equally to this work.

Affiliations

  1. Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006-Oviedo, Spain

    • Clara Soria-Valles
    • , Fernando G. Osorio
    • , Ana Gutiérrez-Fernández
    • , José M. P. Freije
    •  & Carlos López-Otín
  2. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Alejandro De Los Angeles
    •  & George Q. Daley
  3. Josep Carreras Leukemia Research Institute, Cell Therapy Program of the University of Barcelona, Faculty of Medicine, 08036 Barcelona, Spain

    • Clara Bueno
    •  & Pablo Menéndez
  4. Institucio Catalana de Recerca i Estudis Avançats (ICREA), 08035 Barcelona, Spain

    • Pablo Menéndez
  5. Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, IDIBAPS, 08036 Barcelona, Spain

    • José I. Martín-Subero
  6. Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA

    • George Q. Daley
  7. Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, Cambridge, Massachusetts 02138, USA

    • George Q. Daley

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Contributions

C.S.-V. and F.G.O. performed experimental work, data interpretation and preparation of the manuscript. A.G.-F., C.B. and J.I.M.-S. performed experimental work. A.D.L.A., P.M. and G.Q.D. provided critical materials and participated in the preparation of the manuscript. J.M.P.F. and C.L.-O. supervised research and project planning, data interpretation and preparation of the manuscript. All authors discussed the results and implications and commented on the manuscript at all stages.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to José M. P. Freije or Carlos López-Otín.

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DOI

https://doi.org/10.1038/ncb3207

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