Suchergebnisse

© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License. ; 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. ; This work was funded by FEDER through the Program COMPETE and by Portuguese fund through FCT in context of the projects EXPL/BIM-MED/2267/2013 and POCI-01-0145-FEDER-029229, as well as the European project ERAatUC (ref. 669088).PRP wishes to thank FCT for a BD fellowship (SFRH/BD/71042/2010). AR is supported by the Miguel Servet research contract CPII15/00003 from Instituto de Salud Carlos III, Spain. The FLI is a member of the Leibniz Association and is financiallysupported by the Federal Government of Germany and the State of Thuringia. The authors gratefully acknowledge support from the FLI proteomics core facility. ; info:eu-repo/semantics/publishedVersion