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Research Papers

The Nuclear Option: Evidence Implicating the Cell Nucleus in Mechanotransduction

[+] Author and Article Information
Spencer E. Szczesny

Department of Orthopaedic Surgery,
University of Pennsylvania,
424 Stemmler Hall,
36th Street and Hamilton Walk,
Philadelphia, PA 19104;
Translational Musculoskeletal Research Center,
Corporal Michael J. Crescenz Veterans Affairs
Medical Center,
3900 Woodland Avenue,
Philadelphia, PA 19104

Robert L. Mauck

Department of Orthopaedic Surgery,
University of Pennsylvania,
424 Stemmler Hall,
36th Street and Hamilton Walk,
Philadelphia, PA 19104;
Translational Musculoskeletal Research Center,
Corporal Michael J. Crescenz Veterans Affairs
Medical Center,
3900 Woodland Avenue,
Philadelphia, PA 19104;
Department of Bioengineering,
University of Pennsylvania,
240 Skirkanich Hall,
210 South 33rd Street,
Philadelphia, PA 19104
e-mail: lemauck@mail.med.upenn.edu

1Corresponding author.

Manuscript received June 30, 2016; final manuscript received November 1, 2016; published online January 19, 2017. Assoc. Editor: Victor H. Barocas.

J Biomech Eng 139(2), 021006 (Jan 19, 2017) (16 pages) Paper No: BIO-16-1276; doi: 10.1115/1.4035350 History: Received June 30, 2016; Revised November 01, 2016

Biophysical stimuli presented to cells via microenvironmental properties (e.g., alignment and stiffness) or external forces have a significant impact on cell function and behavior. Recently, the cell nucleus has been identified as a mechanosensitive organelle that contributes to the perception and response to mechanical stimuli. However, the specific mechanotransduction mechanisms that mediate these effects have not been clearly established. Here, we offer a comprehensive review of the evidence supporting (and refuting) three hypothetical nuclear mechanotransduction mechanisms: physical reorganization of chromatin, signaling at the nuclear envelope, and altered cytoskeletal structure/tension due to nuclear remodeling. Our goal is to provide a reference detailing the progress that has been made and the areas that still require investigation regarding the role of nuclear mechanotransduction in cell biology. Additionally, we will briefly discuss the role that mathematical models of cell mechanics can play in testing these hypotheses and in elucidating how biophysical stimulation of the nucleus drives changes in cell behavior. While force-induced alterations in signaling pathways involving lamina-associated polypeptides (LAPs) (e.g., emerin and histone deacetylase 3 (HDAC3)) and transcription factors (TFs) located at the nuclear envelope currently appear to be the most clearly supported mechanism of nuclear mechanotransduction, additional work is required to examine this process in detail and to more fully test alternative mechanisms. The combination of sophisticated experimental techniques and advanced mathematical models is necessary to enhance our understanding of the role of the nucleus in the mechanotransduction processes driving numerous critical cell functions.

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References

Figures

Grahic Jump Location
Fig. 1

Primary sites of cellular mechanotransduction. Cells attach to the extracellular matrix via integrins and other associated proteins that form focal adhesions. Forces (F) generated by extracellular strain or active cell contraction are produced at the focal adhesions and transmitted through the cell cytoskeleton primarily by actin stress fibers (shown in red) and intermediate filaments (shown in green). Tension within the cytoskeleton transmits forces to the nucleus, which initiates nuclear remodeling and potential mechanotransduction mechanisms. Additionally, stretch of the plasma membrane and cytoskeletal tension may open stretch-activated ion channels. The resulting influx of ions alters the electrochemical potential of the cell and mediates downstream signaling. Color figures are available online.

Grahic Jump Location
Fig. 2

Extracellular forces deform the nucleus. (a)–(c) Force applied to endothelial cells by displacing an RGD-coated bead bound to integrins on the cell surface produces nuclear deformation and displacement of intranuclear nucleoli. (d) Extracellular loading also displaces fluorescently labeled YFP-coilin and CFP-SMN proteins, which are markers for Cajal bodies within the nucleus. Inset: Bright-field image of HeLa cell with RGD-coated bead in black and nucleus outlined with dotted line. Scale bar: 10 μm. (e) Prior to loading, the CFP signal is quenched by fluorescence resonance energy transfer (FRET) due to the association between coilin and SMN. With applied stress, the coilin and SMN proteins separate, resulting in an increase in CFP fluorescence. Adapted with permission from Refs. [34] and [37]. Refer to electronic document for color images.

Grahic Jump Location
Fig. 3

Schematic illustrating the structure of the nuclear envelope. Adjacent to the inner nuclear membrane is the nuclear lamina, which is a meshwork of intermediate filaments that are the primary structural support for the nucleus. Heterochromatic lamina-associated domains (LADs) bind to the lamina and other proteins associated with the nuclear envelope (e.g., emerin). Linker of the nucleoskeleton and cytoskeleton (LINC) complexes are composed of nesprins and SUN proteins as well as other associated molecules (e.g., emerin, FHOD1, and Samp1) and connect the nuclear lamina with the cytoplasmic cytoskeleton. Color figures are available online.

Grahic Jump Location
Fig. 4

Compressive loading of the apical nuclear surface. (a) Apical actin stress fibers (green) form deep indentations within the nucleus, which deform the nuclear lamina (red) and intranuclear chromatin (blue). Scale bar: 3 μm. (b) and (c) Cross-sectional images of nucleus showing actin stress fibers within nuclear indentations and substantial local nuclear deformations. Scale bars: 1.5 μm. Adapted with permission from Ref. [92]. Color figures are available online.

Grahic Jump Location
Fig. 5

Relocation of gene loci within the nucleus during stem cell differentiation. (a) In stem cells, pluripotent and housekeeping genes are actively transcribed within the nuclear interior while lineage-specific genes are silenced at the nuclear periphery. (b) With lineage commitment, lineage-specific genes are detached from the nuclear lamina and relocated to the nuclear interior. In contrast, pluripotent genes are silenced and attach to the nuclear lamina. (c) Additionally, some lineage-specific genes remain inactive despite being displaced from the nuclear envelope and are transcribed only after terminal differentiation. Adapted with permission from Ref. [78]. Color figures are available online.

Grahic Jump Location
Fig. 6

A stiff nuclear lamina prevents large deformations of the nucleus. (a) Kymographs of the nuclear envelope demonstrate that elongated cells on rectangular micropatterned islands (gray lines) have significantly smaller local perturbations of the nuclear surface compared to round cells on circular islands (red lines). These differences in the stability of the nuclear envelope are due to remodeling of the nuclear lamina, since (b) knockout of lamin A/C in elongated cells produces larger fluctuations in the nuclear surface, whereas (c) overexpression of lamin A/C in round cells has the opposite effect. Adapted with permission from Ref. [154]. Color figures are available online.

Grahic Jump Location
Fig. 7

Proteins associated with the nuclear lamina. In addition to the components of the LINC complex, numerous lamina-associated polypeptides (LAPs) bind to the nuclear lamina and serve various functions. Emerin, LAP2β, and MAN1 help connect heterochromatic LADs to the nuclear lamina via their interaction with BAF. In addition, HDAC3 and LBR directly bind chromatin. These proteins, as well as the nuclear lamina itself, also bind various transcription factors (TFs) involved in important signaling pathways (e.g., c-Fos, SREB1, β-catenin, and Smads). CTCF helps position chromatin at the nuclear envelope and also flanks regions of histone modifications associated with gene silencing (i.e., H3K9me3 and H3K27me3). Soluble lamin A/C dimers associate with actively transcribed euchromatin within the nuclear interior via LAP2α. Lamin A/C and emerin are also likely involved in the actomyosin machinery potentially responsible for relocating gene loci to the nuclear interior upon activation. Color figures are available online.

Grahic Jump Location
Fig. 8

Changes in biophysical stimuli dynamically modulate nuclear and cytoskeletal structure. (Left) Force applied to the nucleus promotes assembly of the lamina and nuclear stiffening. This in turn increases the forces at focal adhesions generated by actomyosin contractility, which leads to further growth of focal adhesions and stress fibers. Increased actin polymerization and nuclear loading induce import of transcription factors (e.g., MKL1 and YAP), which drive further structural remodeling in the cytoplasm via upregulation of several cytoskeletal proteins (e.g., myosin-IIA). (Right) Loss of nuclear loading causes disassembly and degradation of lamin A/C. This softens the nucleus and disrupts existing LINC complexes, causing reductions in stress fiber and focal adhesion size as well as cytoskeletal tension. Increased levels of G-actin and loss of nuclear loading lead to sequestration of MKL1 and YAP within the cytoplasm and downregulation of cytoskeletal proteins.

Grahic Jump Location
Fig. 9

Simple calculation of forces required to locally deform nuclear lamina and decondense chromatin. (a) Application of local force (F) via micropipette aspiration of isolated nuclei displaces the nuclear lamina a distance L, while the intranuclear chromatin is excluded from the pipette lumen. This provides an estimate of the network elastic modulus of the nuclear lamina. (b) Force applied to the nuclear envelope is transmitted to the nuclear lamina and attached chromatin fiber, which act in parallel and have stiffnesses Knl and Kchr, respectively. (c) Micropipette aspiration of live adherent fibroblasts produces substantial local deformation of the nucleus, which is more than sufficient to decondense chromatin and potentially initiate gene transcription. Adapted with permission from Refs. [33] and [239].

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