Cells are constantly under strain from a range of external forces, including tensile and compressive forces, hydrostatic pressure and fluid shear stress.
The ability of the cell to detect these external forces is known as ‘passive’ mechanosensing and is usually conducted in a multifaceted process that incorporates various transmembrane receptors, structural elements and support proteins. Whilst cells can detect and process external forces, they are also able to exert their own internal forces as a means of ‘active’ mechanosensing. This involves structural rearrangements of the cytoskeleton and surrounding membranes to allow the detection and measurement of rigidity, surface topography or ligand density .
Cell motility is central to mechanosensing, as it positions the cell in the appropriate context for detection of its ever-changing environment. The detection and transduction of external forces results in the production of an appropriate mechanoresponse, which in itself can be in the form of cell motility, creating a feedback loop.
Although mechanical forces are exerted and detected at a cellular level, their effects are noticeable on much larger scales. The detection of mechanical forces works together with biochemical signals to drive tissue and organ development and ensure the efficient function of the bodies many systems. Current research efforts highlight the importance of mechanobiology in developmental biology, tissue repair and remodeling, the immune response and in diseases such as cancer and various vascular pathologies. Four broad areas of research in which mechanobiology has an increasingly prominent role are discussed below, with particular emphasis on mechanosensing and cell motility:
During embryogenesis mechanical stresses produced through the interaction of individual cells and the local tissue environment contribute to the direction of many of the key processes associated with development, such as stem cell differentiation, cell proliferation and organization.
Active mechanosensing appears to be especially important in the differentiation of mesenchymal stem cells, where the rigidity or stiffness of their environment determines the lineage they will commit to. It has been demonstrated that mesenchymal stem cells grown on soft matrices reflecting brain tissue, became neurogenic, whilst those grown on rigid matrices reflecting bone, became osteogenic. Similarly, stem cells grown on matrices mimicking striated muscle differentiated down a myoblast lineage . The ability of a cell to sense the rigidity of its surroundings is dependent on its ability to pull against the matrix, tissue or extracellular matrix (ECM) – a process that in mesenchmyal stem cells is shown to require non-muscle myosins .
ECM rigidity is one of several mechanical forces that direct stem cell differentiation, others include shear stress and strain. The detection of fluid shear stress by endothelial progenitor cells freely flowing in the bloodstream, has been shown to stimulate their differentiation into arterial endothelial cells . Similarly, the detection of mechanical strain by mesenchymal stem cells has been shown to regulate their differentiation into vascular smooth muscle cells .
Mechanosensing is increasingly seen as key to the correct execution of the developmental program, at cellular, tissue and whole organism levels – this relies in large part on the actin cytoskeleton ,. The cytoskeleton both senses and responds to mechanical stresses, creating a feedback loop, which when broken can interfere with important cellular processes such as migration . Cell migration and proliferation are both important during embryogenesis and tissue development and are regulated by cytoskeletal tension, mechanical stresses and changes in cell morphology ,.
Development of the extensive, network of blood vessels is influenced heavily by a mechanical force known as fluid shear stress. This is a frictional force exerted by fluid flow and research efforts have focused on understanding how this force impacts endothelial cells that line the walls of blood vessels (as reviewed in ). The detection of fluid shear stress by endothelial cells is important during angiogenesis , vascular remodeling  and pathogenesis.
Defects in the mechanotransduction of shear stress and the subsequent response to it are suggested to promote vascular diseases , such as hypertension (high blood pressure), atherosclerosis (thickening and hardening of blood vessel walls)  and thrombosis (formation of blood clots). The growing field of mechanobiology has investigated the effect of shear stress on endothelial cells in vitro, through the use of flow-loading devices that mimic both normal and disease states.
Shear stress is known to regulate endothelial cells in a variety of ways, affecting their morphology, orientation, gene expression, secretory capacity, viscoelasticity  and leukocyte adhesive properties (as reviewed in , 14]). Ultimately shear stress contributes to structural remodeling of the vascular network and the establishment of vascular tone , 14].
A variety of shear stress responsive proteins have been proposed to be responsible for mechanosensing in this context (as reviewed in ), including calcium-permeable ion channels, tyrosine kinase receptors, G protein coupled receptors and adhesion proteins – all of which are suggested to undergo conformational changes in response to shear stress. At a macromolecular level, the glycocalyx of the plasma membrane is suggested to sense shear stress , whilst at the cellular level, primary cilia are implicated .
The detection of extracellular matrix (ECM) stiffness also has a role to play in vascular biology, specifically during angiogenesis. Specialized endothelial cells, called tip cells, are responsible for leading a trail of endothelial through the ECM during angiogenesis. These cells detect the stiffness of surrounding ECM through the extension of cellular branches. Following detection, the growth rate of microtubules is altered in a myosin II-dependent manner. The persistence of microtubules is also affected, however this is dependent on whether mechanosensors are engaged in a 2D or 3D ECM environment .
Collectively the studies mentioned above reveal the importance of mechanobiology in the development, maintenance and abrogation of the vascular network at both a cellular and tissue level.
The immune system is the first line of defense against pathogens and unwanted foreign bodies. To produce an efficient defense, the cells involved must be able to travel to the site of attack as directed by various chemical and mechanical stimuli. Indeed it is known that leukocytes (the blood cells involved in the immune response) move through the body up to 100 times faster than mesenchymal cells  and often through all manner of physiological environments.
Leukocytes are non-adherent cells and therefore the mechanics of their migration differs significantly from other cell types. They are able to migrate without the use of adhesion receptors and so do not rely on actin treadmilling. Nor do they utilize blebbing as a means to migrate. Furthermore leukocytes require far lower levels of traction to move, due to the absence of adhesions that in adherent cells must be forcefully detached to allow movement. Leukocytes in a 3D environment are instead suggested to migrate via internally induced deformations of the cell body, facilitated by actin polymerization .
A growing amount of evidence suggests mechanical forces also influence leukocyte activation, particularly at the immunological synapse; a site between the T-cell receptor and the antigen-presenting cell (APC). It is well established that actin polymerization is crucial in the formation of the immunological synapse, facilitating the clustering of TCRs and adhesion proteins, whilst maintaining a spatial segregation between them . Recently, an additional role in T-cell activation was revealed when a mechanical, ‘push-pull’ effect driven by T-cell actin polymerization against the APC was observed. Although the exact reasons for this interaction are yet to be defined, it was proposed that these force generation events promote mechanosensing of APC stiffness. The detection and subsequent response to this stiffness may alter the accessibility to and so detection of antigen presented on the surface of the APC .
Defects in mechanosensing, mechanotransduction and subsequent cell motility occur in several disease states. These include muscular dystrophy, cardiomyopathy, axial myopia, glaucoma, asthma, lung dysfunction, premature aging, cancer (as reviewed in ) and polycystic kidney disease (PKD) ,. In some cases these defects are a consequence of the disease, however in several instances they are suggested to be causative, contributing to disease progression and prognosis.
Evidence for the latter is building in the case of autosomal dominant PKD (ADPKD). Mutations in polycystin genes, Pkd1 and Pkd2, are known to cause ADPKD in humans, which results in the formation of kidney cysts. Experiments in mice have shown polycystin-1 and polycystin-2, encoded by mouse orthologues of Pkd1 and Pkd2, to localize to primary cilia – sensory structures present in almost all mammalian cells. Furthermore, loss of polycystin-1 or dysfunction of polycystin-2 perturbed the ability of these cilia to sense the shear stress of physiological fluid flow . It is currently still unknown how this failure in mechanotransduction could result in cyst formation. However it is speculated that an inability to detect mechanical stimuli impinges on subsequent tissue morphogenesis, with polycystin-1 acting as a mechanosensor and polycystin-2 as a means to transduce the signal via its cation channel ,.
Defects in mechanosensing and cell motility are also suggested to be causative in cancer, whose etiology covers a broad spectrum of defects from altered cell adhesion and migration to deregulated gene expression, inefficient DNA repair mechanisms and inhibition of apoptosis. Metastatic cancer cells lose their dependency to adhere to the tissue surface and instead acquire the ability to translocate through all manner of environments. Although the tumour mass is generally more rigid than its surrounding tissue, individual cells are more pliable, a property that sustains their ability to pass through narrow pores and blood vessels (as reviewed in ). Furthermore, recent work has shown that the stiffness of cancer cells is inversely related to their invasiveness, as measured by their ability to migrate through basement membrane. This was shown to be dependent on the actomyosin network, specifically myosin II .
The rigidity of the extracellular matrix (ECM) has also been shown to influence cancer cell malignancy. ECM stiffness was shown to promote clustering of integrin receptors, resulting in the increased formation and stability of focal adhesions, which are known to act as mechanosensing protein complexes . ECM stiffness also promoted increased cellular tension and contractility. Collectively these properties indicated increased malignancy . Importantly, it has been suggested that increased cellular tension exerts further pressure on the ECM. This increases ECM rigidity, which is once again detected by integrin receptors that signal to promote cellular tension – so creating a positive feedback loop .
Currently, over 300 genetic mutations of several nuclear membrane components and lamins, are known to be associated with human diseases. As these structural proteins contribute to mechanical properties of the nucleus such as stiffness, position and integrity, their defects affect a large spectrum of tissues (reviewed in ,).
Diseases due to mutations in lamins (LMNA and LMNB genes), collectively known as laminopathies, are commonly characterized by varying degrees of defects in different muscle systems. The nervous system and adipose tissues are also affected. Some of the well-known conditions include autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD) , Dilated cardiomyopathy with conduction system defects disease (DCM- CD) , Dunnigan-type familial partial lipodystrophy (FPLD) , atypical Werner syndrome  and Hutchinson-Gilford progeria syndrome (HGPS) ,. Accelerated aging observed in HGPS patients has recently been associated with stem cell dysfunction due to lamin mutation besides tissue deterioration .
Recent studies have revealed that rather than affecting the assembly of the LINC complexes, LMNA mutations inhibit cytoskeleton-dependent nuclear movement . In other words, whilst the localization of LINC complexes were not affected, their association with mutated lamins were weak  and this lead to less stable interactions with actin cables in muscles diseases . In the case of adipose tissues, similar inhibition of microtubule-mediated centrosome positioning was observed . Thus lamins act as anchorage devices ensuring proper nuclear positioning and movement.
Perturbations in nuclear membrane proteins such as nesprin, emerin, MAN1 and lamin B receptor (LBR) lead to defects in organization of the nuclear-cytoskeletal links (reviewed in ). These mutations can result in musculoskeletal weakness and abnormalities ,, joint contractures , autosomal recessive cerebellar ataxia  and blood cell anamolies ,.
Genome organization also plays a key role in aging and cancer (reviewed in ). Aging is characterized by global changes in chromatin structure and function such as loss of heterochromatin regions (due to a loss of heterochromatin protein HP1 and trimethylation in these regions) , global increase in H4 trimethylation , global decrease in DNA methylation and changes in levels of acetylating enzymes ,. Both normally aging or HGPS cells show high levels of DNA damage and chaotic transcriptional patterns. These epigenetic modifications have been suggested to be driven by random DNA damage leading to redistribution  (reviewed in ) or loss of histone modifiers , 48], which in turn misregulate DNA repair and transcription programs. However, it is believed that aging results from an interplay of chromatin structure, DNA repair and epigenetic status, that are all linked by feedback mechanisms rather than by defined pathways.
Chromomosal translocations, a hallmark of cancer cells, are attributed to the nonrandom spatial arrangement of chromosomes within the nuclear space, which is tissue-specific (reviewed in ,,). The frequency of translocation seems to be high in chromosomal regions that are in close physical proximity such as the ones in nucleolar  and peripheral regions . Furthermore, evidence exists that inter- or intra-chromosomal translocations often occur at specific regions due to immobile double strand beaks (DSBs). Examples of such juxtaposing gene loci include BCR (chr9) and ABL (chr22) in hematopoietic stem cells leading to chronic myeloid leukemia ,, PML (chr15) and RAR-alpha (chr17) in B-cells causing promyelocytic leukemia , MYC (chr8) and IGH (chr14) causal in Burkitts lymphoma  as well as the RET (chr 10) and H4 (chr10) genes in thyroid tumors .
The changes to mechanosensing and mechanotransduction pathways that are associated with various disease states have been reviewed thoroughly by Jaalouk and Lammerding .