Vulnerability of progeroid smooth muscle cells to biomechanical forces is mediated by MMP13
Pitrez, Patricia R. (University of Coimbra)
Estronca, Luís (University of Coimbra)
Monteiro, Luís Miguel (University of Coimbra)
Colell, Guillem (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Vazão, Helena (University of Coimbra)
Santinha, Deolinda (University of Coimbra)
Harhouri, Karim (Aix Marseille Univ)
Thornton, Daniel (University of Liverpool)
Navarro, Claire (Progelife (França))
Egesipe, Anne-Laure (Institute for Stem Cell Therapy and Exploration of Monogenic Diseases)
Carvalho, Tânia (Universidade de Lisboa)
Dos Santos, Rodrigo L. (Cambridge Science Park)
Lévy, Nicolas (La Timone Children's Hospital)
Smith, James C. (Francis Crick Institute)
de Magalhaes, Joao Pedro (University of Liverpool. Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease)
Ori, Alessandro (Leibniz Institute on Aging)
Bernardo, Andreia (Francis Crick Institute)
De Sandre-Giovannoli, Annachiara (CRB Assistance Publique des Hôpitaux de Marseille)
Nissan, Xavier (Institute for Stem Cell Therapy and Exploration of Monogenic Diseases (França))
Rosell Novel, Anna (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Ferreira, Lino (University of Coimbra)
Universitat Autònoma de Barcelona

Date:	2020
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 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. Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disease and smooth muscle cells are the most affected cells in HGPS individuals. Here, the authors report a microfluidics platform with HGPS induced pluripotent stem cells and show that inhibition of metalloprotease 13 may reduce smooth muscle cell loss.
Grants:	Ministerio de Economía y Competitividad CPII15/00003 European Commission. Horizon 2020 669088
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Stem-cell biotechnology ; Cardiovascular diseases
Published in:	Nature communications, Vol. 11 (august 2020) , ISSN 2041-1723

DOI: 10.1038/s41467-020-17901-2
PMID: 32807790

16 p, 3.7 MB

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