Durotaxis
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]
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
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
- it is the latter two fibers that are most influential in defining the mechanical properties of the ECM.Collagen is the fibrous
Measuring rigidity
In biological research, the rigidity (or stiffness) is commonly measured using
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:
- Bovine articular cartilage - 950 kPa [19]
- Mouse skeletal muscle - 12 kPa [20]
- Guinea pig lung - 5-6 kPa [21]
- Human fibrotic liver - 1.6 kPa, healthy human liver 640 Pa [22]
- Swine brain - 260-490 Pa [23]
Synthesizing varying rigidity
Matrices of varying stiffness are commonly engineered for experimental and therapeutic purposes (e.g. collagen matrices for wound healing
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
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
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
Liver fibrosis
Atherosclerosis
The pathology of
Mathematical models
Several mathematical models have been used to describe durotaxis, including:
- One 2-dimensional model based on the Langevin equation, modified to include the local mechanical properties of the matrix.[46]
- One model based on the description of durotaxis as an elastic stability phenomenon where the cytoskeleton is modeled as a planar system of prestressed elastic line elements that represent actin stress fibers.[47]
- A model where stiffen mediated persistence has the form of Fokker-Planck equation.[48]
- A model where stiffen mediated persistence affect durotaxis.[49]
See also
References
- ^ PMID 23260139.
- PMID 6706005.
- S2CID 4235755.
- PMID 9191042.
- PMID 9889119.
- PMID 7684161.
- PMID 7867709.
- PMID 10508649.
- PMID 9019403.
- PMID 9391082.
- ^ PMID 10866943.
- PMID 16923388.
- ^ PMID 28566691.
- ISBN 978-0-8153-3218-3.
- ^ PMID 24981707.
- S2CID 13744966.
- S2CID 37542025.
- PMID 9391122.
- PMID 15364962.
- S2CID 5263222.
- PMID 12049960.
- PMID 10940395.
- PMID 14623403.
- S2CID 135688441.
- PMID 19170223.
- PMID 22833566.
- PMID 21107430.
- PMID 9818165.
- PMID 21967638.
- S2CID 40665081.
- PMID 17461730.
- ^ PMID 29070586.
- PMID 17827246.
- PMID 24581230.
- PMID 19332889.
- PMID 19951899.
- PMID 21822285.
- S2CID 5169384.
- PMID 15690074.
- S2CID 201357.
- PMC 4137103.
- PMID 17933075.
- PMID 19720019.
- PMID 20648629.
- S2CID 25123237.
- PMID 18308324.
- PMID 29347081.
- PMID 28256894.
External links
Media related to Durotaxis at Wikimedia Commons- Renken, Elena (28 March 2022). "Cells Blaze Their Own Trails to Navigate Through the Body". Quanta Magazine.
