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Vulnerability of progeroid smooth muscle cells to biomechanical forces is mediated by MMP13

Author

Listed:
  • Patricia R. Pitrez

    (University of Coimbra
    University of Coimbra)

  • Luís Estronca

    (University of Coimbra
    University of Coimbra)

  • Luís Miguel Monteiro

    (University of Coimbra)

  • Guillem Colell

    (Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona)

  • Helena Vazão

    (University of Coimbra)

  • Deolinda Santinha

    (University of Coimbra
    University of Coimbra)

  • Karim Harhouri

    (Aix Marseille Univ, INSERM, MMG)

  • Daniel Thornton

    (University of Liverpool)

  • Claire Navarro

    (Aix Marseille Univ, INSERM, MMG
    Progelife)

  • Anne-Laure Egesipe

    (CECS, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases)

  • Tânia Carvalho

    (Universidade de Lisboa)

  • Rodrigo L. Dos Santos

    (Mogrify Ltd)

  • Nicolas Lévy

    (Aix Marseille Univ, INSERM, MMG
    Department of Medical Genetics, La Timone Children’s Hospital)

  • James C. Smith

    (Francis Crick Institute)

  • João Pedro de Magalhães

    (University of Coimbra
    University of Liverpool)

  • Alessandro Ori

    (Leibniz Institute on Aging - Fritz Lipmann Institute)

  • Andreia Bernardo

    (Francis Crick Institute)

  • Annachiara De Sandre-Giovannoli

    (Aix Marseille Univ, INSERM, MMG
    Department of Medical Genetics, La Timone Children’s Hospital
    CRB Assistance Publique des Hôpitaux de Marseille (CRB AP-HM, TAC))

  • Xavier Nissan

    (CECS, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases)

  • Anna Rosell

    (Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona)

  • Lino Ferreira

    (University of Coimbra
    University of Coimbra)

Abstract

Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disease in children that leads to early death. Smooth muscle cells (SMCs) are the most affected cells in HGPS individuals, although the reason for such vulnerability remains poorly understood. In this work, we develop a microfluidic chip formed by HGPS-SMCs generated from induced pluripotent stem cells (iPSCs), to study their vulnerability to flow shear stress. HGPS-iPSC SMCs cultured under arterial flow conditions detach from the chip after a few days of culture; this process is mediated by the upregulation of metalloprotease 13 (MMP13). Importantly, double-mutant LmnaG609G/G609GMmp13−/− mice or LmnaG609G/G609GMmp13+/+ mice treated with a MMP inhibitor show lower SMC loss in the aortic arch than controls. MMP13 upregulation appears to be mediated, at least in part, by the upregulation of glycocalyx. Our HGPS-SMCs chip represents a platform for developing treatments for HGPS individuals that may complement previous pre-clinical and clinical treatments.

Suggested Citation

  • Patricia R. Pitrez & Luís Estronca & Luís Miguel Monteiro & Guillem Colell & Helena Vazão & Deolinda Santinha & Karim Harhouri & Daniel Thornton & Claire Navarro & Anne-Laure Egesipe & Tânia Carvalho , 2020. "Vulnerability of progeroid smooth muscle cells to biomechanical forces is mediated by MMP13," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17901-2
    DOI: 10.1038/s41467-020-17901-2
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    Cited by:

    1. Patricia R. Pitrez & Luis M. Monteiro & Oliver Borgogno & Xavier Nissan & Jerome Mertens & Lino Ferreira, 2024. "Cellular reprogramming as a tool to model human aging in a dish," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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