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

Autor: Pitrez PR; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.; Faculty of Medicine, University of Coimbra, Coimbra, Portugal., Estronca L; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.; Faculty of Medicine, University of Coimbra, Coimbra, Portugal., Monteiro LM; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal., Colell G; Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain., Vazão H; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal., Santinha D; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.; Faculty of Medicine, University of Coimbra, Coimbra, Portugal., Harhouri K; Aix Marseille Univ, INSERM, MMG, Marseille, France., Thornton D; Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, L7 8TX, UK., Navarro C; Aix Marseille Univ, INSERM, MMG, Marseille, France.; Progelife, Marseille, France., Egesipe AL; CECS, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, Evry Cedex, France., Carvalho T; IMM, Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal., Dos Santos RL; 25 Cambridge Science Park, Mogrify Ltd, Milton Road, Cambridge, CB4 0FW, UK., Lévy N; Aix Marseille Univ, INSERM, MMG, Marseille, France.; Molecular Genetics Laboratory, Department of Medical Genetics, La Timone Children's Hospital, Marseille, France., Smith JC; Developmental Biology Laboratory, Francis Crick Institute, London, NW1 1AT, UK., de Magalhães JP; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.; Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, L7 8TX, UK., Ori A; Leibniz Institute on Aging - Fritz Lipmann Institute, 07745, Jena, Germany., Bernardo A; Developmental Biology Laboratory, Francis Crick Institute, London, NW1 1AT, UK., De Sandre-Giovannoli A; Aix Marseille Univ, INSERM, MMG, Marseille, France.; Molecular Genetics Laboratory, Department of Medical Genetics, La Timone Children's Hospital, Marseille, France.; CRB Assistance Publique des Hôpitaux de Marseille (CRB AP-HM, TAC), Marseille, France., Nissan X; CECS, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, Evry Cedex, France., Rosell A; Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain., Ferreira L; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. lino@uc-biotech.pt.; Faculty of Medicine, University of Coimbra, Coimbra, Portugal. lino@uc-biotech.pt.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2020 Aug 17; Vol. 11 (1), pp. 4110. Date of Electronic Publication: 2020 Aug 17.
DOI: 10.1038/s41467-020-17901-2
Abstrakt: 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 Lmna G609G/G609G Mmp13 -/- mice or Lmna G609G/G609G Mmp13 +/+ 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.
Databáze: MEDLINE
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