Mechanotaxis

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Mechanotaxis refers to the directed movement of cell motility via mechanical cues (e.g., fluidic shear stress, substrate stiffness gradients, etc.). [1] [2] [3] In response to fluidic shear stress, for example, cells have been shown to migrate in the direction of the fluid flow. [1] [4] Mechanotaxis is critical in many normal biological processes in animals, such as gastrulation, [5] inflammation, [6] and repair in response to a wound, [7] as well as in mechanisms of diseases such as tumor metastasis. [7]

Contents

A subset of mechanotaxis - termed durotaxis - refers specifically to cell migration guided by gradients in substrate rigidity (i.e. stiffness). [2] [8] The observation that certain cell types seeded on a substrate rigidity gradient migrate up the gradient (i.e. in the direction of increasing substrate stiffness) was first reported by Lo et al. [9] The primary method for creating rigidity gradients for cells (e.g., in biomaterials) consists of altering the degree of cross-linking in polymers to adjust substrate stiffness. [10] [11] Alternative substrate rigidity gradients include micropost array gradients, where the stiffness of individual microposts is increased in a single, designed direction. [8]

History/background

There are multiple ways in which a cell's migration pattern can be influenced, including mechanotaxis, chemotaxis, which is cell movement following a molecular gradient, and haptotaxis, which is cell movement following an adhesion gradient. The first subset of mechanotaxis to be experimentally observed was durotaxis, detailing how contact with a substrate could cause a change in a cell's migration pattern, [12] but more recently researchers have also examined how contact with a neighboring cell could cause changes in a cell's migration pattern. Researchers began investigating mechanotaxis of endothelial cells in blood vessels and wound repair in the 1990s and early 2000s. [13] The early 2000s and 2010s also saw more interest in mechanotaxis in the biomedical engineering community as a potential method of cell manipulation. [14]

Factors/pathways

Cells can detect and react to mechanical stimuli in a variety of ways. One method is through the interaction of E-cadherin presented on the cell membrane. As these receptors interact and are pulled or pushed, tension can be created, leading to a change in the conformation of alpha-catenin bound to B-catenin on the intracellular portion of E-cadherin. This causes the recruitment of vinculin and leads to a change in actin conformation and in the orientation of the cell. Another signaling pathway important in a cell's response to mechanical stimuli is the Wnt planar cell polarity (PCP) pathway. This noncanonical pathway involves the activation of Rho and Rac families of GTPases, which are essential in reorganizing the cytoskeleton in preparation for cell migration. [15] [16] When cells collide, localized signaling of the PCP pathway leads to a change in the polarity of the cell, redirecting the cell in a different direction. [17]

Different cellular receptors are important in cellular mechanotransduction involved in contact with a substrate such as the extracellular matrix (ECM). For example, many cell types express a5b1 integrin on their membranes, which can bind to a major ECM component called fibronectin. This leads to an accumulation of integrins in the area of contact with the ECM, attaching the ECM to the cytoskeleton of the cell and allowing for migration to occur along the ECM through tension at the points of attachment (called focal adhesions, FA) [18] and subsequently the dismantling of FAs as the cell moves along. [13] For this reason, the elasticity of the ECM or another binding substrate is very important. The tension created by a cell pulling against a stiff substrate needs to reach a certain threshold to allow for mechanotaxis to occur. [14]

Mechanotaxis in development

Cell migration is essential in early embryonic development, as a defining characteristic of this phase is the folding and reorganization of the embryo that occurs during and after gastrulation. Without cell migration, complex structures involving multiple cell types that make up complex organisms – like tissues, organs, limbs, etc. – would not develop correctly. There are multiple factors that influence cells to move during development –– but the factors that influence mechanotaxis in development often involve interactions between cells or between a cell and a substrate such as a yolk or membrane.

Contact inhibition of locomotion is involved in the migration of many cell types, including neural crest (NC) cells in vertebrates which give rise to cells of the peripheral nervous system (PNS), facial cartilage, and other non-neural cells throughout the body. NC cells are very mobile, with actin-rich protrusions at the leading edge of each cell in the direction of travel. When an NC cell collides with another NC cell, activation of the Wnt planar cell polarity (PCP) signaling pathway occurs at the point of cell contact, causing localized activation of the downstream effector RhoA. This activation is likely caused by interactions between cadherins on the cell surfaces, [19] and leads to the retraction of the cell protrusions and a change in the cell's polarity, causing the NC cell to change direction. [17] Interestingly, this contact inhibition of locomotion among NC cells is coupled with chemical coattraction between NC cells, which allows the cells to keep in motion for efficient migration as well as to stay together, [20] respectively, leading to collective migration. Cells are most often influenced by surrounding cells towards collective migration in development, [21] [22] [23] such as polster cells which are the first to internalize at the start of gastrulation in zebrafish. [24] Unlike neural crest cells, these cells don't exhibit contact inhibition of locomotion or coattraction, but instead migrate collectively due to E-cadherin interactions between leading cells and following cells. The following polster cells are polarized and migrate towards the animal pole of the embryo for unknown reasons, reaching their actin-rich protrusions towards the leading cells and inducing interactions between E-cadherin proteins located on following cell protrusion membranes and leading cell membranes. The interactions between E-cadherins create tension, which causes internal a-catenin (bridging extracellular E-cadherin with intracellular actin) to be stretched into an open configuration, leading to the recruitment of vinculin and eventually the orientation of actin towards the same direction of migration as the following cells. Without these E-cadherin interactions, leading cells will exhibit non-directional migration.

Mechanotaxis in wound healing

In wound healing, fluid shear stress plays a large role in the mechanotaxis of endothelial cells to the wound site. The inner lining of blood vessels is composed of these endothelial cells, which means that these cells are continuously experiencing fluid shear stress from blood rushing through the vessels. This mechanical stress on the apical side of the endothelial cells leads to integrin signaling, which involves the recruitment of focal adhesion kinase (FAK), Shc, and Crk, [25] and will lead to changes in cell-cell and cell-ECM adhesion. These changes involve lamellipodial protrusions and focal adhesion (FA) formation at the front of the cell, as well as the dismantling of FAs at the rear of the cell, and cause endothelial cells to move in the direction of the flow. [13] Constant laminar flow has been found to improve cell migration in wounds and increases the rate of wound closure. [13]

See also

Related Research Articles

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<span class="mw-page-title-main">Pseudopodia</span> False leg found on slime molds, archaea, protozoans, leukocytes and certain bacteria

A pseudopod or pseudopodium is a temporary arm-like projection of a eukaryotic cell membrane that is emerged in the direction of movement. Filled with cytoplasm, pseudopodia primarily consist of actin filaments and may also contain microtubules and intermediate filaments. Pseudopods are used for motility and ingestion. They are often found in amoebas.

<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.

<span class="mw-page-title-main">Cell adhesion</span> Process of cell attachment

Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indirect interaction, where cells attach to surrounding extracellular matrix, a gel-like structure containing molecules released by cells into spaces between them. Cells adhesion occurs from the interactions between cell-adhesion molecules (CAMs), transmembrane proteins located on the cell surface. Cell adhesion links cells in different ways and can be involved in signal transduction for cells to detect and respond to changes in the surroundings. Other cellular processes regulated by cell adhesion include cell migration and tissue development in multicellular organisms. Alterations in cell adhesion can disrupt important cellular processes and lead to a variety of diseases, including cancer and arthritis. Cell adhesion is also essential for infectious organisms, such as bacteria or viruses, to cause diseases.

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.

Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each other and to their surroundings. CAMs are crucial components in maintaining tissue structure and function. In fully developed animals, these molecules play an integral role in generating force and movement and consequently ensuring that organs are able to execute their functions normally. In addition to serving as "molecular glue", CAMs play important roles in the cellular mechanisms of growth, contact inhibition, and apoptosis. Aberrant expression of CAMs may result in a wide range of pathologies, ranging from frostbite to cancer.

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

Catenins are a family of proteins found in complexes with cadherin cell adhesion molecules of animal cells. The first two catenins that were identified became known as α-catenin and β-catenin. α-Catenin can bind to β-catenin and can also bind filamentous actin (F-actin). β-Catenin binds directly to the cytoplasmic tail of classical cadherins. Additional catenins such as γ-catenin and δ-catenin have been identified. The name "catenin" was originally selected because it was suspected that catenins might link cadherins to the cytoskeleton.

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<span class="mw-page-title-main">Fascin</span> Actin bundling protein

Fascin is an actin bundling protein.

α-Catenin Primary protein link between cadherins and the actin cytoskeleton

α-Catenin (alpha-catenin) functions as the primary protein link between cadherins and the actin cytoskeleton. It has been reported that the actin binding proteins vinculin and α-actinin can bind to alpha-catenin. It has been suggested that alpha-catenin does not bind with high affinity to both actin filaments and the E-cadherin-beta-catenin complex at the same time. It has been observed that when α-catenin is not in a molecular complex with β-catenin, it dimerizes and functions to regulate actin filament assembly, possibly by competing with Arp2/3 protein. α-Catenin exhibits significant protein dynamics. However, a protein complex including a cadherin, actin, β-catenin and α-catenin has not been isolated.

<span class="mw-page-title-main">Cadherin-2</span> Protein-coding gene in the species Homo sapiens

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

Cadherin-5, or VE-cadherin, also known as CD144, is a type of cadherin. It is encoded by the human gene CDH5.

p120 catenin Protein-coding gene in the species Homo sapiens

p120 catenin, or simply p120, also called catenin delta-1, is a protein that in humans is encoded by the CTNND1 gene.

<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">Cadherin-1</span> Human protein-coding gene

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<span class="mw-page-title-main">Catenin alpha-1</span> Protein-coding gene in the species Homo sapiens

αE-catenin, also known as Catenin alpha-1 is a protein that in humans is encoded by the CTNNA1 gene. αE-catenin is highly expressed in cardiac muscle and localizes to adherens junctions at intercalated disc structures where it functions to mediate the anchorage of actin filaments to the sarcolemma. αE-catenin also plays a role in tumor metastasis and skin cell function.

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

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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.

<span class="mw-page-title-main">Synaptic stabilization</span> Modifying synaptic strength via cell adhesion molecules

Synaptic stabilization is crucial in the developing and adult nervous systems and is considered a result of the late phase of long-term potentiation (LTP). The mechanism involves strengthening and maintaining active synapses through increased expression of cytoskeletal and extracellular matrix elements and postsynaptic scaffold proteins, while pruning less active ones. For example, cell adhesion molecules (CAMs) play a large role in synaptic maintenance and stabilization. Gerald Edelman discovered CAMs and studied their function during development, which showed CAMs are required for cell migration and the formation of the entire nervous system. In the adult nervous system, CAMs play an integral role in synaptic plasticity relating to learning and memory.

References

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  2. 1 2 LO, C (1 July 2000). "Cell Movement Is Guided by the Rigidity of the Substrate". Biophysical Journal. 79 (1): 144–152. Bibcode:2000BpJ....79..144L. doi:10.1016/S0006-3495(00)76279-5. PMC   1300921 . PMID   10866943.
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  7. 1 2 Jiang, Jianxin; Li, Li; He, Yong; Zhao, Min (2013). "Collective cell migration: Implications for wound healing and cancer invasion". Burns & Trauma. 1 (1): 21–26. doi: 10.4103/2321-3868.113331 . ISSN   2321-3868. PMC   4994501 . PMID   27574618.
  8. 1 2 Sochol, Ryan D.; Higa, Adrienne T.; Janairo, Randall R. R.; Li, Song; Lin, Liwei (1 January 2011). "Unidirectional mechanical cellular stimuli via micropost array gradients". Soft Matter. 7 (10): 4606. Bibcode:2011SMat....7.4606S. doi:10.1039/C1SM05163F.
  9. ↑ Lo, C (1 July 2000). "Cell Movement Is Guided by the Rigidity of the Substrate". Biophysical Journal. 79 (1): 144–152. Bibcode:2000BpJ....79..144L. doi:10.1016/S0006-3495(00)76279-5. PMC   1300921 . PMID   10866943.
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  12. ↑ Lo, Chun-Min; Wang, Hong-Bei; Dembo, Micah; Wang, Yu-li (2000). "Cell Movement Is Guided by the Rigidity of the Substrate". Biophysical Journal. 79 (1): 144–152. Bibcode:2000BpJ....79..144L. doi:10.1016/S0006-3495(00)76279-5. PMC   1300921 . PMID   10866943.
  13. 1 2 3 4 Li, Song; Huang, Ngan F.; Hsu, Steven (2005-12-15). "Mechanotransduction in endothelial cell migration". Journal of Cellular Biochemistry. 96 (6): 1110–1126. doi: 10.1002/jcb.20614 . ISSN   0730-2312. PMID   16167340. S2CID   21176533.
  14. 1 2 Kawano, Takahito; Kidoaki, Satoru (2011-04-01). "Elasticity boundary conditions required for cell mechanotaxis on microelastically-patterned gels". Biomaterials. 32 (11): 2725–2733. doi:10.1016/j.biomaterials.2011.01.009. ISSN   0142-9612. PMID   21276611.
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  16. ↑ Mezzacappa, Courtney; Komiya, Yuko; Habas, Raymond (2012), Turksen, Kursad (ed.), "Activation and Function of Small GTPases Rho, Rac, and Cdc42 During Gastrulation", Planar Cell Polarity, Methods in Molecular Biology, New York, NY: Springer New York, vol. 839, pp. 119–131, doi:10.1007/978-1-61779-510-7_10, ISBN   978-1-61779-509-1, PMC   4414490 , PMID   22218897
  17. 1 2 Carmona-Fontaine, Carlos; Matthews, Helen K.; Kuriyama, Sei; Moreno, Mauricio; Dunn, Graham A.; Parsons, Maddy; Stern, Claudio D.; Mayor, Roberto (2008). "Contact inhibition of locomotion in vivo controls neural crest directional migration". Nature. 456 (7224): 957–961. Bibcode:2008Natur.456..957C. doi:10.1038/nature07441. ISSN   0028-0836. PMC   2635562 . PMID   19078960.
  18. ↑ Choquet, Daniel; Felsenfeld, Dan P.; Sheetz, Michael P. (1997-01-10). "Extracellular Matrix Rigidity Causes Strengthening of Integrin–Cytoskeleton Linkages". Cell. 88 (1): 39–48. doi: 10.1016/S0092-8674(00)81856-5 . ISSN   0092-8674. PMID   9019403. S2CID   14791012.
  19. ↑ Roycroft, Alice; Mayor, Roberto (2016). "Molecular basis of contact inhibition of locomotion". Cellular and Molecular Life Sciences. 73 (6): 1119–1130. doi:10.1007/s00018-015-2090-0. ISSN   1420-682X. PMC   4761371 . PMID   26585026.
  20. ↑ Carmona-Fontaine, Carlos; Theveneau, Eric; Tzekou, Apostolia; Tada, Masazumi; Woods, Mae; Page, Karen M.; Parsons, Maddy; Lambris, John D.; Mayor, Roberto (2011-12-13). "Complement Fragment C3a Controls Mutual Cell Attraction during Collective Cell Migration". Developmental Cell. 21 (6): 1026–1037. doi:10.1016/j.devcel.2011.10.012. ISSN   1534-5807. PMC   3272547 . PMID   22118769.
  21. ↑ Norden, Caren; Lecaudey, Virginie (2019-08-01). "Collective cell migration: general themes and new paradigms". Current Opinion in Genetics & Development. Developmental mechanisms, patterning and evolution. 57: 54–60. doi:10.1016/j.gde.2019.06.013. hdl: 21.11116/0000-0006-7F20-8 . ISSN   0959-437X. PMID   31430686. S2CID   201116217.
  22. ↑ Scarpa, Elena; Mayor, Roberto (2016-01-18). "Collective cell migration in development". Journal of Cell Biology. 212 (2): 143–155. doi:10.1083/jcb.201508047. ISSN   0021-9525. PMC   4738384 . PMID   26783298.
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