Vulnerability of progeroid smooth muscle cells to biomechanical forces is mediated by MMP13
More about Open Access at the CrickAuthors list
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 Jim Smith João Pedro de Magalhães Alessandro Ori Andreia Bernardo Annachiara De Sandre-Giovannoli Xavier Nissan Anna Rosell Lino FerreiraAbstract
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.
Journal details
Journal Nature Communications
Volume 11
Issue number 1
Pages 4110
Available online
Publication date
Full text links
Publisher website (DOI) 10.1038/s41467-020-17901-2
Figshare View on figshare
Europe PubMed Central 32807790
Pubmed 32807790
Keywords
Related topics
Type of publication