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

2020; Nature Portfolio; Volume: 11; Issue: 1 Linguagem: Inglês

10.1038/s41467-020-17901-2

2041-1723

Patrícia R. Pitrez, Luı́s M.B.B. 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 S. Bernardo, Annachiara De Sandre‐Giovannoli, Xavier Nissan, Anna Rosell, Lino Ferreira,

Renal and related cancers

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.