Cytoskeleton stiffness regulates cellular senescence and innate immune response in Hutchinson–Gilford Progeria Syndrome

Xiaodong Mu, Chieh Tseng, William S. Hambright, Polina Matre, Chih Yi Lin, Palas Chanda, Wanqun Chen, Jianhua Gu, Sudheer Ravuri, Yan Cui, Ling Zhong, John P. Cooke, Laura J. Niedernhofer, Paul D. Robbins, Johnny Huard

Research output: Contribution to journalArticle

Abstract

Hutchinson–Gilford progeria syndrome (HGPS) is caused by the accumulation of mutant prelamin A (progerin) in the nuclear lamina, resulting in increased nuclear stiffness and abnormal nuclear architecture. Nuclear mechanics are tightly coupled to cytoskeletal mechanics via lamin A/C. However, the role of cytoskeletal/nuclear mechanical properties in mediating cellular senescence and the relationship between cytoskeletal stiffness, nuclear abnormalities, and senescent phenotypes remain largely unknown. Here, using muscle-derived mesenchymal stromal/stem cells (MSCs) from the Zmpste24−/− (Z24−/−) mouse (a model for HGPS) and human HGPS fibroblasts, we investigated the mechanical mechanism of progerin-induced cellular senescence, involving the role and interaction of mechanical sensors RhoA and Sun1/2 in regulating F-actin cytoskeleton stiffness, nuclear blebbing, micronuclei formation, and the innate immune response. We observed that increased cytoskeletal stiffness and RhoA activation in progeria cells were directly coupled with increased nuclear blebbing, Sun2 expression, and micronuclei-induced cGAS-Sting activation, part of the innate immune response. Expression of constitutively active RhoA promoted, while the inhibition of RhoA/ROCK reduced cytoskeletal stiffness, Sun2 expression, the innate immune response, and cellular senescence. Silencing of Sun2 expression by siRNA also repressed RhoA activation, cytoskeletal stiffness and cellular senescence. Treatment of Zmpste24/ mice with a RhoA inhibitor repressed cellular senescence and improved muscle regeneration. These results reveal novel mechanical roles and correlation of cytoskeletal/nuclear stiffness, RhoA, Sun2, and the innate immune response in promoting aging and cellular senescence in HGPS progeria.

Original languageEnglish (US)
Article numbere13152
JournalAging Cell
Volume19
Issue number8
DOIs
StatePublished - Jul 25 2020

Keywords

  • accelerated aging
  • cell nucleus
  • cellular senescence
  • skeletal muscle
  • stem cells

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Fingerprint Dive into the research topics of 'Cytoskeleton stiffness regulates cellular senescence and innate immune response in Hutchinson–Gilford Progeria Syndrome'. Together they form a unique fingerprint.

Cite this