Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres

  1. Juan Manuel Povedano
  2. Paula Martinez
  3. Rosa Serrano
  4. Águeda Tejera
  5. Gonzalo Gómez-López
  6. Maria Bobadilla
  7. Juana Maria Flores
  8. Fátima Bosch
  9. Maria A Blasco  Is a corresponding author
  1. Spanish National Cancer Centre (CNIO), Spain
  2. F. Hoffmann-La Roche Ltd, Switzerland
  3. Complutense University of Madrid, Spain
  4. Autonomous University of Barcelona, Spain

Abstract

Pulmonary fibrosis is a fatal lung disease characterized by fibrotic foci and inflammatory infiltrates. Short telomeres can impair tissue regeneration and are found both in hereditary and sporadic cases. We show here that telomerase expression using AAV9 vectors shows therapeutic effects in a mouse model of pulmonary fibrosis owing to a low-dose bleomycin insult and short telomeres. AAV9 preferentially targets regenerative alveolar type II cells (ATII). AAV9-Tert-treated mice show improved lung function and lower inflammation and fibrosis at 1-3 weeks after viral treatment, and improvement or disappearance of the fibrosis at 8 weeks after treatment. AAV9-Tert treatment leads to longer telomeres and increased proliferation of ATII cells, as well as lower DNA damage, apoptosis, and senescence. Transcriptome analysis of ATII cells confirms downregulation of fibrosis and inflammation pathways. We provide a proof-of-principle that telomerase activation may represent an effective treatment for pulmonary fibrosis provoked or associated with short telomeres.

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Article and author information

Author details

  1. Juan Manuel Povedano

    Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain
    Competing interests
    No competing interests declared.
  2. Paula Martinez

    Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain
    Competing interests
    No competing interests declared.
  3. Rosa Serrano

    Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain
    Competing interests
    No competing interests declared.
  4. Águeda Tejera

    Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain
    Competing interests
    No competing interests declared.
  5. Gonzalo Gómez-López

    Structural Biology and Biocomputing Program, Spanish National Cancer Centre (CNIO), Madrid, Spain
    Competing interests
    No competing interests declared.
  6. Maria Bobadilla

    Roche Pharma Research and Early Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland
    Competing interests
    Maria Bobadilla, is an employee for F. Hoffmann-La Roche Ltd, and the author declares no other competing financial interests.
  7. Juana Maria Flores

    Animal Surgery and Medicine Department, Complutense University of Madrid, Madrid, Spain
    Competing interests
    No competing interests declared.
  8. Fátima Bosch

    Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, Barcelona, Spain
    Competing interests
    No competing interests declared.
  9. Maria A Blasco

    Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain
    For correspondence
    mblasco@cnio.es
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4211-233X

Funding

Ministerio de Economía y Competitividad (SAF2013-45111-R)

  • Paula Martinez

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal procedures were approved by the CNIO-ISCIII Ethics Committee for Research and Animal Welfare (CEIyBA) and conducted in accordance to the recommendations of the Federation of European Laboratory Animal Science Associations (FELASA).

Reviewing Editor

  1. Kathleen Collins, University of California, Berkeley, United States

Publication history

  1. Received: August 16, 2017
  2. Accepted: January 23, 2018
  3. Accepted Manuscript published: January 30, 2018 (version 1)
  4. Version of Record published: February 19, 2018 (version 2)

Copyright

© 2018, Povedano et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Juan Manuel Povedano
  2. Paula Martinez
  3. Rosa Serrano
  4. Águeda Tejera
  5. Gonzalo Gómez-López
  6. Maria Bobadilla
  7. Juana Maria Flores
  8. Fátima Bosch
  9. Maria A Blasco
(2018)
Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres
eLife 7:e31299.
https://doi.org/10.7554/eLife.31299
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