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

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 rol...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431831/
https://www.ncbi.nlm.nih.gov/pubmed/32710480
http://dx.doi.org/10.1111/acel.13152
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author 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
author_facet 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
author_sort Mu, Xiaodong
collection PubMed
description 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.
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spelling pubmed-74318312020-08-20 Cytoskeleton stiffness regulates cellular senescence and innate immune response in Hutchinson–Gilford Progeria Syndrome 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 Aging Cell Original Articles 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. John Wiley and Sons Inc. 2020-07-25 2020-08 /pmc/articles/PMC7431831/ /pubmed/32710480 http://dx.doi.org/10.1111/acel.13152 Text en © 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
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
Cytoskeleton stiffness regulates cellular senescence and innate immune response in Hutchinson–Gilford Progeria Syndrome
title Cytoskeleton stiffness regulates cellular senescence and innate immune response in Hutchinson–Gilford Progeria Syndrome
title_full Cytoskeleton stiffness regulates cellular senescence and innate immune response in Hutchinson–Gilford Progeria Syndrome
title_fullStr Cytoskeleton stiffness regulates cellular senescence and innate immune response in Hutchinson–Gilford Progeria Syndrome
title_full_unstemmed Cytoskeleton stiffness regulates cellular senescence and innate immune response in Hutchinson–Gilford Progeria Syndrome
title_short Cytoskeleton stiffness regulates cellular senescence and innate immune response in Hutchinson–Gilford Progeria Syndrome
title_sort cytoskeleton stiffness regulates cellular senescence and innate immune response in hutchinson–gilford progeria syndrome
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431831/
https://www.ncbi.nlm.nih.gov/pubmed/32710480
http://dx.doi.org/10.1111/acel.13152
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