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]

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

edit

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

edit

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

edit

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

edit

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

edit

References

edit
  1. ^ a b Li, S. (March 19, 2002). "The role of the dynamics of focal adhesion kinase in the mechanotaxis of endothelial cells". Proceedings of the National Academy of Sciences. 99 (6): 3546–3551. Bibcode:2002PNAS...99.3546L. doi:10.1073/pnas.052018099. PMC 122560. PMID 11891289.
  2. ^ a b 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.
  3. ^ Mak, M.; Spill, F.; Kamm, R. D.; Zaman, M. H. (2015). "Single-Cell Migration in Complex Microenvironments: Mechanics and Signaling Dynamics". Journal of Biomechanical Engineering. 138 (2): 0210041–0210048. doi:10.1115/1.4032188. PMC 4844084. PMID 26639083.
  4. ^ Hsu, Steve; Thakar, Rahul; Liepmann, Dorian; Li, Song (11 November 2005). "Effects of shear stress on endothelial cell haptotaxis on micropatterned surfaces". Biochemical and Biophysical Research Communications. 337 (1): 401–409. doi:10.1016/j.bbrc.2005.08.272. PMID 16188239.
  5. ^ Juliano, R L; Haskill, S (1993-02-01). "Signal transduction from the extracellular matrix". Journal of Cell Biology. 120 (3): 577–585. doi:10.1083/jcb.120.3.577. ISSN 0021-9525. PMC 2119550. PMID 8381117.
  6. ^ Huse, Morgan (2017). "Mechanical forces in the immune system". Nature Reviews Immunology. 17 (11): 679–690. doi:10.1038/nri.2017.74. ISSN 1474-1733. PMC 6312705. PMID 28757604.
  7. ^ a b 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. ^ a b 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.
  10. ^ Gray, Darren S.; Tien, Joe; Chen, Christopher S. (1 September 2003). "Repositioning of cells by mechanotaxis on surfaces with micropatterned Young's modulus". Journal of Biomedical Materials Research. 66A (3): 605–614. CiteSeerX 10.1.1.646.1614. doi:10.1002/jbm.a.10585. PMID 12918044.
  11. ^ Wong, Joyce Y.; Velasco, Alan; Rajagopalan, Padmavathy; Pham, Quynh (1 March 2003). "Directed Movement of Vascular Smooth Muscle Cells on Gradient-Compliant Hydrogels". Langmuir. 19 (5): 1908–1913. doi:10.1021/la026403p.
  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. ^ a b c d 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. ^ a b 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.
  15. ^ Corda, G.; Sala, A. (2017). "Non-canonical WNT/PCP signalling in cancer: Fzd6 takes centre stage". Oncogenesis. 6 (7): e364. doi:10.1038/oncsis.2017.69. ISSN 2157-9024. PMC 5541719. PMID 28737757.
  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, vol. 839, New York, NY: Springer New York, pp. 119–131, doi:10.1007/978-1-61779-510-7_10, ISBN 978-1-61779-509-1, PMC 4414490, PMID 22218897
  17. ^ a b 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.
  23. ^ Schumacher, Linus (2019), La Porta, Caterina A. M.; Zapperi, Stefano (eds.), "Collective Cell Migration in Development", Cell Migrations: Causes and Functions, Advances in Experimental Medicine and Biology, vol. 1146, Cham: Springer International Publishing, pp. 105–116, doi:10.1007/978-3-030-17593-1_7, ISBN 978-3-030-17592-4, PMID 31612456, S2CID 204702312, retrieved 2022-12-13
  24. ^ Boutillon, Arthur; Escot, Sophie; Elouin, Amélie; Jahn, Diego; González-Tirado, Sebastián; Starruß, Jörn; Brusch, Lutz; David, Nicolas B. (2022-06-20). "Guidance by followers ensures long-range coordination of cell migration through α-catenin mechanoperception". Developmental Cell. 57 (12): 1529–1544.e5. doi:10.1016/j.devcel.2022.05.001. ISSN 1534-5807. PMID 35613615.
  25. ^ Critchley, David R (2000). "Focal adhesions – the cytoskeletal connection". Current Opinion in Cell Biology. 12 (1): 133–139. doi:10.1016/S0955-0674(99)00067-8. PMID 10679361.