4.8 Article

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

期刊

NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -

出版社

NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-17901-2

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资金

  1. FEDER through the Program COMPETE [EXPL/BIM-MED/2267/2013, POCI01-0145-FEDER-029229]
  2. Portuguese fund through FCT [EXPL/BIM-MED/2267/2013, POCI01-0145-FEDER-029229]
  3. European project ERAatUC [669088]
  4. FCT [SFRH/BD/71042/2010]
  5. Miguel Servet research contract from Instituto de Salud Carlos III, Spain [CPII15/00003]
  6. Federal Government of Germany
  7. State of Thuringia
  8. FLI proteomics core facility
  9. Fundação para a Ciência e a Tecnologia [EXPL/BIM-MED/2267/2013, SFRH/BD/71042/2010] Funding Source: FCT

向作者/读者索取更多资源

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. Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disease and smooth muscle cells are the most affected cells in HGPS individuals. Here, the authors report a microfluidics platform with HGPS induced pluripotent stem cells and show that inhibition of metalloprotease 13 may reduce smooth muscle cell loss.

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