3 years ago

Coordinated increase of nuclear tension and lamin-A with matrix stiffness out-competes Lamin-B Receptor which favors soft tissue phenotypes.

Discher, Swift, Buxboim, Shin, Athirasala, Rehfeldt, Irianto
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 micro-elasticity, 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 the differentiation potential of MSCs. Nuclear envelope fluctuations are suppressed on stiff matrix relative to soft and are used to determine a nuclear tension that agrees with trends from traction force microscopy and from increased lamin-A,C. Transcriptomes of diverse tissues and MSCs further show that stiffness-associated increases in lamin-A,C are accompanied by decreases in lamin-B receptor (LBR), which contributes to lipid biosynthesis. Adipogenesis (soft) of MSCs increases LBR:lamin-A,C protein stoichiometry relative to osteogenesis (stiff), with competitive interactions of LBR and lamin-A,C for lamin-B explaining responses to matrix elasticity, knockdowns, myosin-II inhibition, and constricted migration. Matrix stiffness-driven contractility thus tenses the nucleus to favor lamin-A,C accumulation and oppose soft tissue phenotypes.

Publisher URL: http://doi.org/10.1091/mbc.E17-06-0393

DOI: 10.1091/mbc.E17-06-0393

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