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

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 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_name

Nat Commun

journal_title

Nature communications

authors

Pitrez PR,Estronca L,Monteiro LM,Colell G,Vazão H,Santinha D,Harhouri K,Thornton D,Navarro C,Egesipe AL,Carvalho T,Dos Santos RL,Lévy N,Smith JC,de Magalhães JP,Ori A,Bernardo A,De Sandre-Giovannoli A,Nissan X,Rosel

doi

10.1038/s41467-020-17901-2

subject

Has Abstract

pub_date

2020-08-17 00:00:00

pages

4110

issue

1

issn

2041-1723

pii

10.1038/s41467-020-17901-2

journal_volume

11

pub_type

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