A Unified Linear Viscoelastic Model of the Cell Nucleus Defines the Mechanical Contributions of Lamins and Chromatin

Oren Wintner; Nivi Hirsch-Attas; Miriam Schlossberg; Fani Brofman; Roy Friedman; Meital Kupervaser; Danny Kitsberg; Amnon Buxboim

doi:10.1002/advs.201901222

A Unified Linear Viscoelastic Model of the Cell Nucleus Defines the Mechanical Contributions of Lamins and Chromatin

Oren Wintner, Nivi Hirsch-Attas, Miriam Schlossberg, Fani Brofman, Roy Friedman, Meital Kupervaser, Danny Kitsberg, Amnon Buxboim^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

Abstract

The cell nucleus is constantly subjected to externally applied forces. During metazoan evolution, the nucleus has been optimized to allow physical deformability while protecting the genome under load. Aberrant nucleus mechanics can alter cell migration across narrow spaces in cancer metastasis and immune response and disrupt nucleus mechanosensitivity. Uncovering the mechanical roles of lamins and chromatin is imperative for understanding the implications of physiological forces on cells and nuclei. Lamin-knockout and -rescue fibroblasts and probed nucleus response to physiologically relevant stresses are generated. A minimal viscoelastic model is presented that captures dynamic resistance across different cell types, lamin composition, phosphorylation states, and chromatin condensation. The model is conserved at low and high loading and is validated by micropipette aspiration and nanoindentation rheology. A time scale emerges that separates between dominantly elastic and dominantly viscous regimes. While lamin-A and lamin-B1 contribute to nucleus stiffness, viscosity is specified mostly by lamin-A. Elastic and viscous association of lamin-B1 and lamin-A is supported by transcriptional and proteomic profiling analyses. Chromatin decondensation quantified by electron microscopy softens the nucleus unless lamin-A is expressed. A mechanical framework is provided for assessing nucleus response to applied forces in health and disease.

Original language	American English
Article number	1901222
Journal	Advanced Science
Volume	7
Issue number	8
DOIs	https://doi.org/10.1002/advs.201901222
State	Published - 1 Apr 2020

Bibliographical note

Funding Information:
The authors greatly appreciate support from the Israel Science Foundation (Grant Number 1246/14), the European Research Council (ERC‐StG 678977), and the Niedersächsisches Vorab (Grant No. ZN 3183). The authors thank S. Safran and D. Deviri (Weizmann Institute of Science), D. Harries and A. Eden (Hebrew University of Jerusalem), and Y. Shokef and H. Diamant (Tel Aviv University) for fruitful discussions. The authors are grateful for the lab of Prof. Y. Buganim (Hebrew University) for blastocyst injections and for the mES and iPS cells.

Funding Information:
The authors greatly appreciate support from the Israel Science Foundation (Grant Number 1246/14), the European Research Council (ERC-StG 678977), and the Nieders?chsisches Vorab (Grant No. ZN 3183). The authors thank S. Safran and D. Deviri (Weizmann Institute of Science), D. Harries and A. Eden (Hebrew University of Jerusalem), and Y. Shokef and H. Diamant (Tel Aviv University) for fruitful discussions. The authors are grateful for the lab of Prof. Y. Buganim (Hebrew University) for blastocyst injections and for the mES and iPS cells.

Publisher Copyright:
© 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Keywords

nuclear lamins
nucleus mechanics
nucleus mechanobiology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/advs.201901222

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title = "A Unified Linear Viscoelastic Model of the Cell Nucleus Defines the Mechanical Contributions of Lamins and Chromatin",

abstract = "The cell nucleus is constantly subjected to externally applied forces. During metazoan evolution, the nucleus has been optimized to allow physical deformability while protecting the genome under load. Aberrant nucleus mechanics can alter cell migration across narrow spaces in cancer metastasis and immune response and disrupt nucleus mechanosensitivity. Uncovering the mechanical roles of lamins and chromatin is imperative for understanding the implications of physiological forces on cells and nuclei. Lamin-knockout and -rescue fibroblasts and probed nucleus response to physiologically relevant stresses are generated. A minimal viscoelastic model is presented that captures dynamic resistance across different cell types, lamin composition, phosphorylation states, and chromatin condensation. The model is conserved at low and high loading and is validated by micropipette aspiration and nanoindentation rheology. A time scale emerges that separates between dominantly elastic and dominantly viscous regimes. While lamin-A and lamin-B1 contribute to nucleus stiffness, viscosity is specified mostly by lamin-A. Elastic and viscous association of lamin-B1 and lamin-A is supported by transcriptional and proteomic profiling analyses. Chromatin decondensation quantified by electron microscopy softens the nucleus unless lamin-A is expressed. A mechanical framework is provided for assessing nucleus response to applied forces in health and disease.",

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author = "Oren Wintner and Nivi Hirsch-Attas and Miriam Schlossberg and Fani Brofman and Roy Friedman and Meital Kupervaser and Danny Kitsberg and Amnon Buxboim",

note = "Funding Information: The authors greatly appreciate support from the Israel Science Foundation (Grant Number 1246/14), the European Research Council (ERC‐StG 678977), and the Nieders{\"a}chsisches Vorab (Grant No. ZN 3183). The authors thank S. Safran and D. Deviri (Weizmann Institute of Science), D. Harries and A. Eden (Hebrew University of Jerusalem), and Y. Shokef and H. Diamant (Tel Aviv University) for fruitful discussions. The authors are grateful for the lab of Prof. Y. Buganim (Hebrew University) for blastocyst injections and for the mES and iPS cells. Funding Information: The authors greatly appreciate support from the Israel Science Foundation (Grant Number 1246/14), the European Research Council (ERC-StG 678977), and the Nieders?chsisches Vorab (Grant No. ZN 3183). The authors thank S. Safran and D. Deviri (Weizmann Institute of Science), D. Harries and A. Eden (Hebrew University of Jerusalem), and Y. Shokef and H. Diamant (Tel Aviv University) for fruitful discussions. The authors are grateful for the lab of Prof. Y. Buganim (Hebrew University) for blastocyst injections and for the mES and iPS cells. Publisher Copyright: {\textcopyright} 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim",

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AU - Brofman, Fani

AU - Friedman, Roy

AU - Kupervaser, Meital

AU - Kitsberg, Danny

AU - Buxboim, Amnon

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N2 - The cell nucleus is constantly subjected to externally applied forces. During metazoan evolution, the nucleus has been optimized to allow physical deformability while protecting the genome under load. Aberrant nucleus mechanics can alter cell migration across narrow spaces in cancer metastasis and immune response and disrupt nucleus mechanosensitivity. Uncovering the mechanical roles of lamins and chromatin is imperative for understanding the implications of physiological forces on cells and nuclei. Lamin-knockout and -rescue fibroblasts and probed nucleus response to physiologically relevant stresses are generated. A minimal viscoelastic model is presented that captures dynamic resistance across different cell types, lamin composition, phosphorylation states, and chromatin condensation. The model is conserved at low and high loading and is validated by micropipette aspiration and nanoindentation rheology. A time scale emerges that separates between dominantly elastic and dominantly viscous regimes. While lamin-A and lamin-B1 contribute to nucleus stiffness, viscosity is specified mostly by lamin-A. Elastic and viscous association of lamin-B1 and lamin-A is supported by transcriptional and proteomic profiling analyses. Chromatin decondensation quantified by electron microscopy softens the nucleus unless lamin-A is expressed. A mechanical framework is provided for assessing nucleus response to applied forces in health and disease.

AB - The cell nucleus is constantly subjected to externally applied forces. During metazoan evolution, the nucleus has been optimized to allow physical deformability while protecting the genome under load. Aberrant nucleus mechanics can alter cell migration across narrow spaces in cancer metastasis and immune response and disrupt nucleus mechanosensitivity. Uncovering the mechanical roles of lamins and chromatin is imperative for understanding the implications of physiological forces on cells and nuclei. Lamin-knockout and -rescue fibroblasts and probed nucleus response to physiologically relevant stresses are generated. A minimal viscoelastic model is presented that captures dynamic resistance across different cell types, lamin composition, phosphorylation states, and chromatin condensation. The model is conserved at low and high loading and is validated by micropipette aspiration and nanoindentation rheology. A time scale emerges that separates between dominantly elastic and dominantly viscous regimes. While lamin-A and lamin-B1 contribute to nucleus stiffness, viscosity is specified mostly by lamin-A. Elastic and viscous association of lamin-B1 and lamin-A is supported by transcriptional and proteomic profiling analyses. Chromatin decondensation quantified by electron microscopy softens the nucleus unless lamin-A is expressed. A mechanical framework is provided for assessing nucleus response to applied forces in health and disease.

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VL - 7

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A Unified Linear Viscoelastic Model of the Cell Nucleus Defines the Mechanical Contributions of Lamins and Chromatin

Abstract

Bibliographical note

Keywords

UN SDGs

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