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

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, Rodrigo L. Dos Santos, Nicolas Lévy, James C. Smith, João Pedro de Magalhães, Alessandro Ori, Andreia Bernardo, Annachiara De Sandre-Giovannoli, Xavier Nissan, Anna Rosell and Lino Ferreira ()
Additional contact information
Patricia R. Pitrez: University of Coimbra
Luís Estronca: 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
Karim Harhouri: Aix Marseille Univ, INSERM, MMG
Daniel Thornton: University of Liverpool
Claire Navarro: Aix Marseille Univ, INSERM, MMG
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
James C. Smith: Francis Crick Institute
João Pedro de Magalhães: University of Coimbra
Alessandro Ori: Leibniz Institute on Aging - Fritz Lipmann Institute
Andreia Bernardo: Francis Crick Institute
Annachiara De Sandre-Giovannoli: Aix Marseille Univ, INSERM, MMG
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

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17901-2

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