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

• Published in: Aging cell Vol. 19; no. 8; pp. e13152 - n/a
• Main Authors: Mu, Xiaodong, Tseng, Chieh, Hambright, William S., Matre, Polina, Lin, Chih‐Yi, Chanda, Palas, Chen, Wanqun, Gu, Jianhua, Ravuri, Sudheer, Cui, Yan, Zhong, Ling, Cooke, John P., Niedernhofer, Laura J., Robbins, Paul D., Huard, Johnny
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.08.2020; John Wiley and Sons Inc
• Subjects: accelerated aging; Actin; Aging; Animals; Cell activation; cell nucleus; cellular senescence; Cellular Senescence - immunology; Cytoskeleton; Cytoskeleton - immunology; Deoxyribonucleic acid; DNA; DNA damage; Fibroblasts; Gene expression; Gene mutations; Genetic aspects; Humans; Immune response; Immunity, Innate - immunology; Innate immunity; Mechanical properties; Mesenchyme; Mice; Micronuclei; Musculoskeletal system; Mutation; Original; Phenotypes; Progeria; Progeria - immunology; Proteins; Rho-associated kinase; RhoA protein; Senescence; siRNA; skeletal muscle; Stem cell transplantation; Stem cells; accelerated aging; stem cells; cell nucleus; cellular senescence; skeletal muscle
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.13152

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. There is increased RhoA activation and cytoskeleton stiffness in progeria cells, which mediates increased nuclear blebbing, micronuclei formation, innate immune response, and cellular senescence. RhoA activation is coupled with elevated Sun2 expression, but not Sun1, especially in nucleus with blebbing and micronuclei. Repression of RhoA and Sun2 activation was able to reduce cytoskeleton stiffness, nuclear blebbing, and micronuclei formation and delay the progression of cellular senescence.