VULNERABILITY OF PROGEROID SMOOTH MUSCLE CELLS TO ARTERIAL SHEAR STRESS IS MEDIATED BY MMP13

Patricia Pitrez , Luis Estronca , Luis Monteiro , Guillem Colell , Helena Vazão , Deolinda Santinha , Karim Harhouri (1) , Daniel Thornton , Claire L. Navarro (1, 2) , Anne-Laure Egesipe , Tania Cavalho , Rodrigo L dos Santos , Nicolas Levy (1, 3) , James Smith , Joao-Pedro Magalhaes , Alessandro Ori , Andreia Bernardo , Annachiara de Sandre-Giovannoli (1, 3, 4) , Xavier Nissan , Anna Rosell , Lino Ferreira

1 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
2 ProGeLife [Marseille]
3 Département de génétique médicale [Hôpital de la Timone - APHM]
4 CRB TAC - Centre de ressources biologiques Tissus ADN Cellules [Hôpital de la Timone - APHM]

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.

Mots clés: Cardiovascular diseases; Stem-cell biotechnology

Domaines: Génétique

Patricia Pitrez, Luis Estronca, Luis Monteiro, Guillem Colell, Helena Vazão, et al.. VULNERABILITY OF PROGEROID SMOOTH MUSCLE CELLS TO ARTERIAL SHEAR STRESS IS MEDIATED BY MMP13. Nature Communications, 2022, 28 (1), pp.S340. ⟨10.1038/s41467-020-17901-2⟩. ⟨hal-03780360⟩