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Redox-dependent BMI1 activity drives in vivo adult cardiac progenitor cell differentiation

Cell Death & Differentiationvolume 25pages807820 (2018) | Download Citation

Abstract

Accumulation of reactive oxygen species (ROS) is associated with several cardiovascular pathologies and with cell cycle exit by neonanatal cardiomyocytes, a key limiting factor in the regenerative capacity of the adult mammalian heart. The polycomb complex component BMI1 is linked to adult progenitors and is an important partner in DNA repair and redox regulation. We found that high BMI1 expression is associated with an adult Sca1+ cardiac progenitor sub-population with low ROS levels. In homeostasis, BMI1 repressed cell fate genes, including a cardiogenic differentiation program. Oxidative damage nonetheless modified BMI1 activity in vivo by derepressing canonical target genes in favor of their antioxidant and anticlastogenic functions. This redox-mediated mechanism is not restricted to damage situations, however, and we report ROS-associated differentiation of cardiac progenitors in steady state. These findings demonstrate how redox status influences the cardiac progenitor response, and identify redox-mediated BMI1 regulation with implications in maintenance of cellular identity in vivo.

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Edited by D. Aberdam

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Acknowledgements

We thank S. Gutiérrez for assistance with confocal microscopy, J.C. Oliveros and M. Franch for bioinformatics, M.C. Moreno and S. Escudero for the sorting strategy, M Serrano for G6PDtg mouse line, N. Fonseca-Balvis for her valuable input, and C. Mark for editorial support. D.H., M.T., and F.M.C. were predoctoral fellows from the Spanish Ministry of Economy and Competitiveness. This study was supported by grants to A.B. from the Spanish Ministry of Science and Innovation (PLE2009-0147), the Ministry of Economy and Competitiveness (SAF2015-70882-R), Comunidad Autónoma de Madrid (S2011/BMD-2420), Instituto de Salud Carlos III (RETICS-RD12/0018) and the European Commission (HEALTH-2009_242038), and by a grant from the Generalitat Valenciana (PROMOTEO/2016/006) to E.R. The CNB-CSIC and CNIC are supported by the Spanish Ministry of Economy and Competitiveness.

Author contributions

D.H. conceived, performed, and designed experiments, developed the project, contributed ideas, and wrote the manuscript. M.T., S.C., and F.M.C. performed and designed experiments. R.M.C., E.F., and E.R. performed experiments. A.B. conceived and developed the project, designed experiments, interpreted results, and wrote the manuscript. All authors read and approved the final manuscript.

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Affiliations

  1. Department of Immunology and Oncology, Spanish National Center for Biotechnology (CNB-CSIC), Madrid, Spain

    • Diego Herrero
    • , Susana Cañón
    • , Rosa María Carmona
    •  & Antonio Bernad
  2. Cardiovascular Development and Repair Department, Spanish National Cardiovascular Research Center (CNIC), Madrid, Spain

    • María Tomé
    • , Susana Cañón
    • , Francisco M. Cruz
    •  & Antonio Bernad
  3. CIBERobn (Physiopathology of Obesity and Nutrition CB12/03/30038), Carlos III Health Research Institute (ISCIII), Madrid, Spain

    • Enrique Roche
  4. Department of Applied Biology-Nutrition and Institute of Bioengineering, University Miguel Hernández, Institute for Health and Biomedical Research (ISABIAL-FISABIO Fundation), Alicante, Spain

    • Encarna Fuster
    •  & Enrique Roche

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The authors declare that they have no competing financial interests.

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Correspondence to Antonio Bernad.

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https://doi.org/10.1038/s41418-017-0022-2