Durotaxis

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Durotaxis is a form of cell migration in which cells are guided by rigidity gradients, which arise from differential structural properties of the extracellular matrix (ECM). Most normal cells migrate up rigidity gradients (in the direction of greater stiffness). [1]

Contents

History of durotaxis research

The process of durotaxis requires a cell to actively sense the environment, process the mechanical stimulus, and execute a response. Originally, this was believed to be an emergent metazoan property, as the phenomenon requires a complex sensory loop that is dependent on the communication of many different cells. However, as the wealth of relevant scientific literature grew in the late 1980s and throughout the 1990s, it became apparent that single cells possess the ability to do the same. The first observations of durotaxis in isolated cells were that mechanical stimuli could cause the initiation and elongation of axons in the sensory and brain neurons of chicks and induce motility in previously stationary fish epidermal keratocytes. [2] [3] [4] [5] ECM stiffness was also noted to influence cytoskeletal stiffness, fibronectin fibril assembly, the strength of integrin-cytoskeletal interactions, morphology and motility rate, all of which were known influence cell migration. [6] [7] [8] [9] [10]

With information from the previous observations, Lo and colleagues formulated the hypothesis that individual cells can detect substrate stiffness by a process of active tactile exploration in which cells exert contractile forces and measure the resulting deformation in the substrate. Supported by their own experiments, this team coined the term "durotaxis" in their paper in the Biophysical Journal in the year 2000. [11] More recent research supports the previous observations and the principle of durotaxis, with continued evidence for cell migration up rigidity gradients and stiffness-dependent morphological changes [1] [12] [13]

Substrate rigidity

The rigidity of the ECM is significantly different across cell types; for example, it ranges from the soft ECM of brain tissue to that of rigid bone or the stiff cell wall of plant cells. This difference in rigidity is a result of the qualitative and quantitative biochemical properties of the ECM or in other words, the concentration and categories of the various macromolecules that form the ECM meshwork. Though the ECM is composed of many intracellularly-synthesized components - including a number of glycosaminoglycans (GAGs) and fibrous proteins such as fibronectin, laminin, collagen, and elastin - it is the latter two fibers that are most influential in defining the mechanical properties of the ECM.

Collagen is the fibrous protein that gives the ECM its tensile strength, or rigidity. Elastin - as its name suggests - is a highly elastic protein with an important role in tissues that need to return to their original positions after deformation, such as skin, blood vessels, and lungs. The relative concentrations of these two main determinants, along with other less influential matrix components, determine the rigidity of the ECM. [14] For example, collagen concentration has been reported to be correlated to matrix stiffness, both in vivo and in vitro (gels). [15] [16]

Measuring rigidity

In biological research, the rigidity (or stiffness) is commonly measured using Young's modulus of elasticity, the ratio of stress to strain along an axis, in Pascals. Thus, a material with a high Young's modulus is very rigid. [17] The most precise and well-established method to measure Young's modulus of a tissue relies on instruments - such as the Instron load cell device - that directly apply a mechanical load and measure the resulting deformation. Now, the Young's modulus of a tissue can be easily and accurately estimated without excision using a variety of elastography techniques. These methods induce distortion in the tissue and measure the mechanical properties, usually with ultrasound or magnetic resonance imaging (MRI). [18]

Young's modulus has been repeatedly used to characterize the mechanical properties of many tissues in the human body. The stiffness of animal tissues varies over several orders of magnitude, for example:

Synthesizing varying rigidity

Matrices of varying stiffness are commonly engineered for experimental and therapeutic purposes (e.g. collagen matrices for wound healing [24] ). Durotactic gradients are simply made by creating 2-dimensional substrates out of polymer (e.g. acrylamide [13] or polydimethylsiloxane) in which the stiffness is controlled by cross-linking density, which in turn is controlled by cross-linker concentration. The polymer must be coated with a material that the cell can adhere to, such as collagen or fibronectin. The gradients themselves are often synthesized as hydrogels using microfluidic gradient generators followed by photopolymerization. [25]

An advancement to this technique is the use of 3D matrices, which are able to guide cell migration in conditions that are more relatable to the natural three dimensional environment of the cell. [26]

The site of cellular contact with the extracellular matrix is the focal adhesion, a large, dynamic protein complex that connects the cytoskeleton to the ECM fibers through several organized layers of interacting proteins. Integrins are the outermost proteins and the ones that bind directly to the ECM ligands. However, focal adhesions are quite more than simple anchors - their proteins have many roles in signaling. These proteins, such as focal adhesion kinase (FAK), talin, vinculin, paxillin, and α-actinin, interact with small GTPases (Rho, Rac, Cdc42) and other signaling pathways in order to relay even small changes in matrix stiffness and consequently respond with changes in cell shape, actomyosin contractility, and cytoskeletal organization. As a result, these changes can cause a cell to rearrange its cytoskeleton in order to facilitate directional migration. [27] [28]

A cell's cytoskeleton is a constantly fluctuating network of polymers whose organization greatly depends on the physical environment of the cell. At the focal adhesions, a cell exerts a traction force. In other words, it pulls on the ECM. Thus, the cell maintains a mechanical homeostasis between ECM stiffness and cytoskeletal tension across its focal adhesions. This homeostasis is dynamic, as the focal adhesion complexes are continuously constructed, remodeled, and disassembled. This leads to changes in signal transduction and downstream cellular responses. [29] Cell signaling is a product of both the physical and biochemical properties of the ECM and interaction between these two pathways is crucial to understand cellular responses. For example, bone morphogenetic protein (BMP) - a growth factor - is unable to induce osteogenesis under insufficient cytoskeletal tension. [30]

The source of cytoskeletal traction is actomyosin contractility. Increased external stiffness leads to a signal transduction cascade that activates the small GTPase Rho and Rho-associated kinase (ROCK). ROCK, in turn, controls myosin light chain phosphorylation, an event that triggers myosin ATPase activity and the shortening of actin fibers, causing contraction and pulling on the ECM. [31] Though the precise pathway that connects ECM stiffness to ROCK activity is unknown, the observation of increased traction in response to increased ECM stiffness is sufficient to explain the phenomenon of durotaxis. The stronger mechanical feedback would pull the cell towards the stiffer region and cause a bias in directional movement and have other consequences on cytoskeletal and focal adhesion organization. [11]

Consequently, durotaxis must rely on continuous sampling of ECM stiffness over space and time in a process called rigidity mechanosensing. [32] Recent research has revealed that individual focal adhesions do not necessarily exert stable traction forces in response to unchanging ECM stiffness. In fact, while some individual focal adhesions may display stable traction forces, others exhibit tugging traction in the manner of a repeated cycle of tugging and release. The properties of focal adhesions - whether stable or tugging - are independent of their neighbors and as such, each focal adhesion acts autonomously. This tugging traction has been shown to be dispensable to other forms of cell migration, such as chemotaxis and haptotaxis, but required for durotaxis. The focal adhesion proteins (FAK/paxillin/vinculin) - and their phosphorylation-dependent interactions as well as their asymmetrical distribution within the cell (i.e. YAP activation and nuclear translocation via stiffness activated pFAK) [33] - are required in order to exhibit high traction and tugging traction across a wide range of ECM rigidities. Furthermore, a reduction in focal adhesion tension by transferring cells to softer ECM or by inhibiting ROCK results in focal adhesion switching from stable to tugging states. Thus, rigidity mechanosensing allows a cell to sample matrix stiffness at the resolution of focal adhesion spacing within a cell (≈1-5μm). [1]

The integration of biochemical and mechanical cues may allow fine-tuning of cell migration. However, the physiological reasoning behind durotaxis—and specifically the tendency of cells to migrate up rigidity gradients—is unknown.

Measuring traction

The most prevalent and accurate modern method for measuring the traction forces that cells exert on the substrate relies on traction force microscopy (TFM). The principle behind this method is to measure deformation in the substrate by calculating 2-dimensional displacement of fluorescent beads that are embedded in the matrix. High-resolution TFM allows the analysis of traction forces at much smaller structures, such as focal adhesions, at a spatial resolution of ~1 μm. [34]

Clinical significance

The role of durotaxis under physiological conditions remains unknown. It may serve a purpose in fine-tuning the movement response of a cell to extracellular biochemical cues, though the relative contribution of durotaxis in a physiological environment where a cell is subject to other taxes (e.g. chemotaxis) is unknown, and may in fact prove to be wholly dispensable for cell migration in vivo. The phenomenon might also have a role in several disease states that include the stiffening of tissues, as outlined below.

Cancer

It is a common observation that tumors are stiffer than the surrounding tissue, and even serves as the basis for breast cancer self-examination. In fact, breast cancer tissue has been reported to be as much as ten times stiffer than normal tissue. Furthermore, a growing and metastasizing tumor involves the cooperation of many different cell types, like fibroblasts and endothelial cells, that possess different rigidities and could result in local stiffness gradients that guide cell migration. [35] There is increasing evidence that durotaxis plays a role in cancer metastasis. Experiments in mice have demonstrated that tumor cells preferentially invade into the adjacent stroma along stiff collagen fibers. [36] These stiff collagen alignments can be used to identify focal sites of breast tumor cell microinvasion. [37] Pregnancy, which has various links to breast cancer incidence and prognosis, involves postpartum breast involution that relies on collagen remodeling and inflammation that converts these collagen fibers into stiffer counterparts, thus establishing a potential link between pregnancy and metastatic properties. [38] Though some research shows that stiffer tumors are indicative of increased metastasis and decreased survival (which contradicts the concept that durotactic cells should be more attracted to the tumor and metastasize less), this is not counter intuitive because collagen-dependent integrin signaling has a wide range of consequences beyond durotaxis, including inhibition of the tumor suppressor PTEN via upregulation of the miRNA miR-18a. [39] Moreover, there is evidence that increased tumor stiffness does in fact correlate with decreased metastasis, as the principle of durotaxis would suggest. [15]

Liver fibrosis

Fibrosis of the liver is the accumulation of ECM proteins, such as collagen, that occurs in many chronic liver diseases. [40] Increased liver stiffness (of existing collagen) has actually been shown to precede fibrosis and to be required for the activation of fibrogenic myofibroblasts. [41] Fibroblasts move towards the stiffer tissue via durotaxis, [33] and upon reaching it, will differentiate into fibrogenic myofibroblasts. [42] This vicious positive feedback loop of durotaxis-dependent fibrosis could potentially be a therapeutic target for the prevention of liver fibrosis.

Atherosclerosis

A diagram of the formation of an atherosclerotic plaque. Note the blue vascular smooth muscle cells, which migrate from the tunica media into the tunica intima, where the stiff plaque is forming. Aterorojenez-hucresel-tr.JPG
A diagram of the formation of an atherosclerotic plaque. Note the blue vascular smooth muscle cells, which migrate from the tunica media into the tunica intima, where the stiff plaque is forming.

The pathology of atherosclerosis is largely dependent on the migration of vascular smooth muscle cells (VSMCs) into the tunica intima layer of the blood vessel, where they can accumulate lipids, undergo necrosis, and elaborate the ECM (fibrosis). [43] The migration of these cells has also been demonstrated to be rigidity-dependent, and matrix stiffness further affects their proliferation in response to growth factors. [44] [45]

Mathematical models

Several mathematical models have been used to describe durotaxis, including:

See also

Related Research Articles

<span class="mw-page-title-main">Integrin</span> Instance of a defined set in Homo sapiens with Reactome ID (R-HSA-374573)

Integrins are transmembrane receptors that help cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, organization of the intracellular cytoskeleton, and movement of new receptors to the cell membrane. The presence of integrins allows rapid and flexible responses to events at the cell surface.

Morphogenesis is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of developmental biology along with the control of tissue growth and patterning of cellular differentiation.

<span class="mw-page-title-main">Extracellular matrix</span> Network of proteins and molecules outside cells that provides structural support for cells

In biology, the extracellular matrix (ECM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and biochemical support to surrounding cells. Because multicellularity evolved independently in different multicellular lineages, the composition of ECM varies between multicellular structures; however, cell adhesion, cell-to-cell communication and differentiation are common functions of the ECM.

Haptotaxis is the directional motility or outgrowth of cells, e.g. in the case of axonal outgrowth, usually up a gradient of cellular adhesion sites or substrate-bound chemoattractants. These gradients are naturally present in the extracellular matrix (ECM) of the body during processes such as angiogenesis or artificially present in biomaterials where gradients are established by altering the concentration of adhesion sites on a polymer substrate.

Mechanotaxis refers to the directed movement of cell motility via mechanical cues. In response to fluidic shear stress, for example, cells have been shown to migrate in the direction of the fluid flow. Mechanotaxis is critical in many normal biological processes in animals, such as gastrulation, inflammation, and repair in response to a wound, as well as in mechanisms of diseases such as tumor metastasis.

<span class="mw-page-title-main">Focal adhesion</span>

In cell biology, focal adhesions are large macromolecular assemblies through which mechanical force and regulatory signals are transmitted between the extracellular matrix (ECM) and an interacting cell. More precisely, focal adhesions are the sub-cellular structures that mediate the regulatory effects of a cell in response to ECM adhesion.

Intravasation is the invasion of cancer cells through the basement membrane into a blood or lymphatic vessel. Intravasation is one of several carcinogenic events that initiate the escape of cancerous cells from their primary sites. Other mechanisms include invasion through basement membranes, extravasation, and colonization of distant metastatic sites. Cancer cell chemotaxis also relies on this migratory behavior to arrive at a secondary destination designated for cancer cell colonization.

Talin is a high-molecular-weight cytoskeletal protein concentrated at regions of cell–substratum contact and, in lymphocytes, at cell–cell contacts. Discovered in 1983 by Keith Burridge and colleagues, talin is a ubiquitous cytosolic protein that is found in high concentrations in focal adhesions. It is capable of linking integrins to the actin cytoskeleton either directly or indirectly by interacting with vinculin and α-actinin.

<span class="mw-page-title-main">MMP2</span> Protein-coding gene in the species Homo sapiens

72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an enzyme that in humans is encoded by the MMP2 gene. The MMP2 gene is located on chromosome 16 at position 12.2.

<span class="mw-page-title-main">PTK2</span> Protein-coding gene in humans

PTK2 protein tyrosine kinase 2 (PTK2), also known as focal adhesion kinase (FAK), is a protein that, in humans, is encoded by the PTK2 gene. PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion and spreading processes. It has been shown that when FAK was blocked, breast cancer cells became less metastatic due to decreased mobility.

<span class="mw-page-title-main">MMP7</span> Protein-coding gene in humans

Matrilysin also known as matrix metalloproteinase-7 (MMP-7), pump-1 protease (PUMP-1), or uterine metalloproteinase is an enzyme in humans that is encoded by the MMP7 gene. The enzyme has also been known as matrin, putative metalloproteinase-1, matrix metalloproteinase pump 1, PUMP-1 proteinase, PUMP, metalloproteinase pump-1, putative metalloproteinase, MMP). Human MMP-7 has a molecular weight around 30 kDa.

<span class="mw-page-title-main">Stress fiber</span> Contractile actin bundles found in non-muscle cells

Stress fibers are contractile actin bundles found in non-muscle cells. They are composed of actin (microfilaments) and non-muscle myosin II (NMMII), and also contain various crosslinking proteins, such as α-actinin, to form a highly regulated actomyosin structure within non-muscle cells. Stress fibers have been shown to play an important role in cellular contractility, providing force for a number of functions such as cell adhesion, migration and morphogenesis.

<span class="mw-page-title-main">Dermatopontin</span> Protein-coding gene in the species Homo sapiens

Dermatopontin also known as tyrosine-rich acidic matrix protein (TRAMP) is a protein that in humans is encoded by the DPT gene. Dermatopontin is a 22-kDa protein of the noncollagenous extracellular matrix (ECM) estimated to comprise 12 mg/kg of wet dermis weight. To date, homologues have been identified in five different mammals and 12 different invertebrates with multiple functions. In vertebrates, the primary function of dermatopontin is a structural component of the ECM, cell adhesion, modulation of TGF-β activity and cellular quiescence). It also has pathological involvement in heart attacks and decreased expression in leiomyoma and fibrosis. In invertebrate, dermatopontin homologue plays a role in hemagglutination, cell-cell aggregation, and expression during parasite infection.

Mechanobiology is an emerging field of science at the interface of biology, engineering, chemistry and physics. It focuses on how physical forces and changes in the mechanical properties of cells and tissues contribute to development, cell differentiation, physiology, and disease. Mechanical forces are experienced and may be interpreted to give biological responses in cells. The movement of joints, compressive loads on the cartilage and bone during exercise, and shear pressure on the blood vessel during blood circulation are all examples of mechanical forces in human tissues. A major challenge in the field is understanding mechanotransduction—the molecular mechanisms by which cells sense and respond to mechanical signals. While medicine has typically looked for the genetic and biochemical basis of disease, advances in mechanobiology suggest that changes in cell mechanics, extracellular matrix structure, or mechanotransduction may contribute to the development of many diseases, including atherosclerosis, fibrosis, asthma, osteoporosis, heart failure, and cancer. There is also a strong mechanical basis for many generalized medical disabilities, such as lower back pain, foot and postural injury, deformity, and irritable bowel syndrome.

<span class="mw-page-title-main">Role of cell adhesions in neural development</span>

Cellular adhesions can be defined as proteins or protein aggregates that form mechanical and chemical linkages between the intracellular and extracellular space. Adhesions serve several critical processes including cell migration, signal transduction, tissue development and repair. Due to this functionality, adhesions and adhesion molecules have been a topic of study within the scientific community. Specifically, it has been found that adhesions are involved in tissue development, plasticity, and memory formation within the central nervous system (CNS), and may prove vital in the generation of CNS-specific therapeutics.

Traction force microscopy (TFM) is an experimental method for determining the tractions on the surface of a biological cell by obtaining measurements of the surrounding displacement field within an in vitro extracellular matrix (ECM).

Cell mechanics is a sub-field of biophysics that focuses on the mechanical properties and behavior of living cells and how it relates to cell function. It encompasses aspects of cell biophysics, biomechanics, soft matter physics and rheology, mechanobiology and cell biology.

Contact guidance refers to a phenomenon for which the orientation of cells and stress fibers is influenced by geometrical patterns such as nano/microgrooves on substrates, or collagen fibers in gels and soft tissues. This phenomenon was discovered in 1912, and the terminology was introduced in 1945, but it is with the development of tissue engineering that researchers drew increasing attention on this topic, seeing the potential of contact guidance in influencing the morphology and organization of cells. Nevertheless, the biological processes underlying contact guidance are still unclear.

Collective cell migration describes the movements of group of cells and the emergence of collective behavior from cell-environment interactions and cell-cell communication. Collective cell migration is an essential process in the lives of multicellular organisms, e.g. embryonic development, wound healing and cancer spreading (metastasis). Cells can migrate as a cohesive group or have transient cell-cell adhesion sites. They can also migrate in different modes like sheets, strands, tubes, and clusters. While single-cell migration has been extensively studied, collective cell migration is a relatively new field with applications in preventing birth defects or dysfunction of embryos. It may improve cancer treatment by enabling doctors to prevent tumors from spreading and forming new tumors.

Physical oncology (PO) is defined as the study of the role of mechanical signals in a cancerous tumor. The mechanical signals can be forces, pressures. If we generalize we will speak of "stress field" and "stress tensor".

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