Coordinated increase of nuclear tension and lamin-A with matrix stiffness outcompetes lamin-B receptor that favors soft tissue phenotypes

Amnon Buxboim, Jerome Irianto, Joe Swift, Avathamsa Athirasala, Jae Won Shin, Florian Rehfeldt, Dennis E. Discher*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

Matrix stiffness that is sensed by a cell or measured by a purely physical probe reflects the intrinsic elasticity of the matrix and also how thick or thin the matrix is. Here, mesenchymal stem cells (MSCs) and their nuclei spread in response to thickness-corrected matrix microelasticity, with increases in nuclear tension and nuclear stiffness resulting from increases in myosin-II and lamin-A,C. Linearity between the widely varying projected area of a cell and its nucleus across many matrices, timescales, and myosin-II activity levels indicates a constant ratio of nucleus-To-cell volume, despite MSCs' lineage plasticity. Nuclear envelope fluctuations are suppressed on the stiffest matrices, and fluctuation spectra reveal a high nuclear tension that matches trends from traction force microscopy and from increased lamin-A,C. Transcriptomes of many diverse tissues and MSCs further show that lamin-A,C's increase with tissue or matrix stiffness anti-correlates with lamin-B receptor (LBR), which contributes to lipid/sterol biosynthesis. Adipogenesis (a soft lineage) indeed increases LBR:lamin-A,C protein stoichiometry in MSCs versus osteogenesis (stiff). The two factors compete for lamin-B in response to matrix elasticity, knockdown, myosin-II inhibition, and even constricted migration that disrupts and segregates lamins in situ. Matrix stiffness-driven contractility thus tenses the nucleus to favor lamin-A,C accumulation and suppress soft tissue phenotypes.

Original languageAmerican English
Pages (from-to)3333-3348
Number of pages16
JournalMolecular Biology of the Cell
Volume28
Issue number23
DOIs
StatePublished - 7 Nov 2017

Bibliographical note

Funding Information:
We thank Yun-Ruei C. Kao and Takamasa Harada for considerable technical assistance. The research was supported by National Institutes of Health/National Cancer Institute PSOC Award U54 CA193417, National Heart Lung and Blood Institute Awards R01 HL124106 and R21 HL128187, the US–Israel Binational Science Foundation, and a National Science Foundation Materials Science and Engineering Center grant to the University of Pennsylvania. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other granting agencies.

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