Role of nuclear mechanosensitivity in determining cellular responses to forces and biomaterials

doi:10.1016/j.biomaterials.2019.01.010

Biomaterials

Volume 197, March 2019, Pages 60-71

https://doi.org/10.1016/j.biomaterials.2019.01.010 Get rights and content

Abstract

Tissue engineers use biomaterials or apply forces to alter cell behaviors and cure damaged/diseased tissues. The external physical cues perceived by cells are transduced intracellularly along the mechanosensitive machineries, including subcellular adhesion molecules and cytoskeletons. The signals are further channeled to a nucleus through the physical links of nucleoskeleton and cytoskeleton or the biochemical translocation of transcription factors. Thus, the external cues are thought to affect directly or indirectly the nucleus and the genetic transcriptional process, ultimately determining cell fate. Here we communicate the importance of such mechanotransductory processes in cell and tissue engineering where external forces- or biomaterials-related physical cues essentially regulate cellular behaviors, with an emphasis on the mechanosensing and signaling along the road to a nucleus.

Section snippets

Forces and biomaterial-generated physical cues perceived by cells

Cells in our body are always under force while the mode and degree are different with time and position. Endothelial cells in blood vessels experience constantly the pulsatile shear force of blood fluid [1]. Chondrocytes in cartilage are under dynamic compression loads whereas tendon and ligament cells experience primarily tensile forces to properly function [2]. Therefore, cells in our body (i.e. fibroblasts, adipocytes, neurons, myoblasts, chondrocytes, and osteoblasts) are keen to adopt the

Mechanosensitive machineries toward nucleus and their implications in cell fate change

The physiological forces perceived by cells are known to be in a wide range depending on the environments. For example, approximately 0.1–100 Pa (10–10000 nN/mm²) exerts on endothelial or blood cells [18] whereas a few hundreds of MPa (N/mm²) is reported for muscle, cartilage and bone [[19], [20], [21], [22]]. The external physical forces transmit through diverse sets of mechanosensitive cellular components that are physically connected, which includes integrin sets, adhesion complex,

Mechanosensitive ion channels

Apart from the integrin receptors, the mechanosensitive ion channels have long been implicated to take essential part in cellular mechanoreception of external cues (Fig. 2h). Ion channels allow the passage of ions across the cell membrane in response to a mechanical stimulus [98]. Among them, Piezo1 and Piezo2 are well-known mechanically activated cation channels that mediate cellular perception, proprioception, development and cell differentiation [99]. Mechanical stretch of cells activates

Concluding remarks

A wealth of studies has demonstrated the importance of biophysical signals of biomaterials and applied forces in cellular fate change. Mechanosensitive machineries of not only the cell surface receptors, the associated focal adhesion complex, and the actomyosin contractile machinery, but also of the LINC complex and the subnuclear mechanotransductory molecules recently discovered highlight the physical transmission of external signals toward nucleus. The translocation of transcription factors

Acknowledgments

This research was supported by the National Research Foundation of Korea (NRF) from Republic of Korea (Global Research Lab (GRL) Program 2015–0093829, NRF-2018R1A2B3003446, and Global Research Development Center (GRDC) Program NRF-2018K1A4A3A01064257).

References (136)

A.J. Engler et al.
Matrix elasticity directs stem cell lineage specification
Cell
(2006)
T. Perestrelo et al.
Metabolic and mechanical cues regulating pluripotent stem cell fate
Trends Cell Biol.
(2018)
X. Li et al.
Effects of external stress on biodegradable orthopedic materials: a review
Bioact. Mater.
(2016)
S. Park et al.
Mechanical response of bovine articular cartilage under dynamic unconfined compression loading at physiological stress levels
Osteoarthr. Cartil.
(2004)
Y. Wang et al.
Zyxin and paxillin proteins: focal adhesion plaque LIM domain proteins go nuclear
Biochim. Biophys. Acta
(2003)
E.G. Kleinschmidt et al.
Focal adhesion kinase signaling in unexpected places
Curr. Opin. Cell Biol.
(2017)
S.J. Sequeira et al.
The regulation of focal adhesion complex formation and salivary gland epithelial cell organization by nanofibrous PLGA scaffolds
Biomaterials
(2012)
E. Lyulcheva et al.
Drosophila pico and its mammalian ortholog lamellipodin activate serum response factor and promote cell proliferation
Dev. Cell
(2008)
M. Aragona et al.
A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors
Cell
(2013)
M.E. Arsenault et al.
Confinement and manipulation of actin filaments by electric fields
Biophys. J.
(2007)

J.H. Lee et al.

Electrical stimulation by enzymatic biofuel cell to promote proliferation, migration and differentiation of muscle precursor cells

Biomaterials

(2015)

J. Du et al.

Optimal electrical stimulation boosts stem cell therapy in nerve regeneration

Biomaterials

(2018)

H.-S. Ahn et al.

Carbon-nanotube-interfaced glass fiber scaffold for regeneration of transected sciatic nerve

Acta Biomater.

(2015)

D.-H. Kim et al.

Cytoskeletal tension induces the polarized architecture of the nucleus

Biomaterials

(2015)

S. Alam et al.

Nuclear forces and cell mechanosensing

Prog. Mol. Biol. Transl. Sci.

(2014)

A. Buxboim et al.

Matrix elasticity regulates lamin-A,C phosphorylation and turnover with feedback to actomyosin

Curr. Biol.

(2014)

Wendy A. Bickmore et al.

Genome architecture: domain organization of interphase chromosomes

Cell

(2013)

P.R. Cook

A model for all genomes: the role of transcription factories

J. Mol. Biol.

(2010)

R. McBeath et al.

Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment

Dev. Cell

(2004)

T. Miyamoto et al.

Functional role for Piezo1 in stretch-evoked Ca(2)(+) influx and ATP release in urothelial cell cultures

J. Biol. Chem.

(2014)

E. Dejana et al.

The molecular basis of endothelial cell plasticity

Nat. Commun.

(2017)

K.H. Vining et al.

Mechanical forces direct stem cell behaviour in development and regeneration

Nat. Rev. Mol. Cell Biol.

(2017)

L. Wang et al.

Nanofiber Yarn/hydrogel core–shell scaffolds mimicking native skeletal muscle tissue for guiding 3D myoblast alignment, elongation, and differentiation

ACS Nano

(2015)

T.M. Bedair et al.

Recent advances to accelerate re-endothelialization for vascular stents

J. Tissue Eng.

(2017)

J.-H. Lee et al.

Emerging properties of hydrogels in tissue engineering

J. Tissue Eng.

(2018)

J.H. Lee et al.

Artificial control of cell signaling and growth by magnetic nanoparticles

Angew. Chem. Int. Ed.

(2010)

B. Suki et al.

A microfluidic chamber-based approach to map the shear moduli of vascular cells and other soft materials

Sci. Rep.

(2017)

V. Zablotskii et al.

How a high-gradient magnetic field could affect cell life

Sci. Rep.

(2016)

O. Chaudhuri et al.

Hydrogels with tunable stress relaxation regulate stem cell fate and activity

Nat. Mater.

(2015)

M. Guvendiren et al.

Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics

Nat. Commun.

(2012)

Z.A. Cheng et al.

Bioactive chemical nanopatterns impact human mesenchymal stem cell fate

Nano Lett.

(2013)

C. Allan et al.

Osteoblast response to disordered nanotopography

J. Tissue Eng.

(2018)

M. Kolster et al.

Outgrowing endothelial and smooth muscle cells for tissue engineering approaches

J. Tissue Eng.

(2017)

M. Maekawa et al.

Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase

Science

(1999)

O. Valiron et al.

Cellular disorders induced by high magnetic fields

J. Magn. Reson. Imag.

(2005)

S. Chatterjee

Endothelial mechanotransduction, redox signaling and the regulation of vascular inflammatory pathways

Front. Physiol.

(2018)

A.D. Lantada et al.

Novel system for bite-force sensing and monitoring based on magnetic near field communication

Sensors (Basel)

(2012)

C.D. Kuthe et al.

Experimental evaluation of fiber orientation based material properties of skeletal muscle in tension

Mol. Cell. BioMech.

(2014)

N. Wang et al.

Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus

Nat. Rev. Mol. Cell Biol.

(2009)

F. Falleroni et al.

Cell mechanotransduction with piconewton forces applied by optical tweezers

Front. Cell. Neurosci.

(2018)

K. Haase et al.

Extracellular forces cause the nucleus to deform in a highly controlled anisotropic manner

Sci. Rep.

(2016)

C. Guilluy et al.

Isolated nuclei adapt to force and reveal a mechanotransduction pathway in the nucleus

Nat. Cell Biol.

(2014)

T.J. Kirby et al.

Emerging views of the nucleus as a cellular mechanosensor

Nat. Cell Biol.

(2018)

S. Li et al.

Hydrogels with precisely controlled integrin activation dictate vascular patterning and permeability

Nat. Mater.

(2017)

N.I. Reed et al.

The αvβ1 integrin plays a critical in vivo role in tissue fibrosis

Sci. Transl. Med.

(2015)

V.D.L. G et al.

Inhibition of focal adhesion kinase signaling by integrin α6β1 supports human pluripotent stem cell self‐renewal

Stem Cell.

(2016)

S.J. Shattil

Signaling through platelet integrin alpha IIb beta 3: inside-out, outside-in, and sideways

Thromb. Haemost.

(1999)

M.J. Dalby et al.

Harnessing nanotopography and integrin–matrix interactions to influence stem cell fate

Nat. Mater.

(2014)

M.J. Paszek et al.

The cancer glycocalyx mechanically primes integrin-mediated growth and survival

Nature

(2014)

J.J. Northey et al.

Tissue force programs cell fate and tumor aggression

Cancer Discov.

(2017)

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ReviewRole of nuclear mechanosensitivity in determining cellular responses to forces and biomaterials

Abstract

Section snippets

Forces and biomaterial-generated physical cues perceived by cells

Mechanosensitive machineries toward nucleus and their implications in cell fate change

Mechanosensitive ion channels

Concluding remarks

Acknowledgments

Cell

Trends Cell Biol.

Bioact. Mater.

Osteoarthr. Cartil.

Biochim. Biophys. Acta

Curr. Opin. Cell Biol.

Biomaterials

Dev. Cell

Cell

Biophys. J.

Biomaterials

Biomaterials

Acta Biomater.

Biomaterials

Prog. Mol. Biol. Transl. Sci.

Curr. Biol.

Cell

J. Mol. Biol.

Dev. Cell

J. Biol. Chem.

The molecular basis of endothelial cell plasticity

Nat. Commun.

Mechanical forces direct stem cell behaviour in development and regeneration

Nat. Rev. Mol. Cell Biol.

Nanofiber Yarn/hydrogel core–shell scaffolds mimicking native skeletal muscle tissue for guiding 3D myoblast alignment, elongation, and differentiation

ACS Nano

Recent advances to accelerate re-endothelialization for vascular stents

J. Tissue Eng.

Emerging properties of hydrogels in tissue engineering

J. Tissue Eng.

Artificial control of cell signaling and growth by magnetic nanoparticles

Angew. Chem. Int. Ed.

A microfluidic chamber-based approach to map the shear moduli of vascular cells and other soft materials

Sci. Rep.

How a high-gradient magnetic field could affect cell life

Sci. Rep.

Hydrogels with tunable stress relaxation regulate stem cell fate and activity

Nat. Mater.

Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics

Nat. Commun.

Bioactive chemical nanopatterns impact human mesenchymal stem cell fate

Nano Lett.

Osteoblast response to disordered nanotopography

J. Tissue Eng.

Outgrowing endothelial and smooth muscle cells for tissue engineering approaches

J. Tissue Eng.

Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase

Science

Cellular disorders induced by high magnetic fields

J. Magn. Reson. Imag.

Endothelial mechanotransduction, redox signaling and the regulation of vascular inflammatory pathways

Front. Physiol.

Novel system for bite-force sensing and monitoring based on magnetic near field communication

Sensors (Basel)

Experimental evaluation of fiber orientation based material properties of skeletal muscle in tension

Mol. Cell. BioMech.

Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus

Nat. Rev. Mol. Cell Biol.

Cell mechanotransduction with piconewton forces applied by optical tweezers

Front. Cell. Neurosci.

Extracellular forces cause the nucleus to deform in a highly controlled anisotropic manner

Sci. Rep.

Isolated nuclei adapt to force and reveal a mechanotransduction pathway in the nucleus

Nat. Cell Biol.

Emerging views of the nucleus as a cellular mechanosensor

Nat. Cell Biol.

Hydrogels with precisely controlled integrin activation dictate vascular patterning and permeability

Nat. Mater.

The αvβ1 integrin plays a critical in vivo role in tissue fibrosis

Sci. Transl. Med.

Inhibition of focal adhesion kinase signaling by integrin α6β1 supports human pluripotent stem cell self‐renewal

Stem Cell.

Review
Role of nuclear mechanosensitivity in determining cellular responses to forces and biomaterials