Skip to main content

Advertisement

SpringerLink
Log in

Extracellular matrix assembly: a multiscale deconstruction

  • Review Article
  • Published:

From Nature Reviews Molecular Cell Biology

View current issue Sign up to alerts

Key Points

  • Different tissues have unique and specialized extracellular matrix (ECM) components and organization, which enables each ECM to carry out tissue-specific roles, including structural support, the transmission of forces and macromolecular filtration. The architecture of the ECM is highly organized, which partly arises from the innate properties of its constituent molecules and their interactions and partly from the activities of the resident cells.

  • The fibrous (collagens and elastin) and glycoprotein (fibronectin, proteoglycans and laminins) macromolecules that constitute the ECM have evolved structures and chemical properties that are particularly suited to their specific biological functions in their respective tissues. Each class of ECM molecule is designed to interact with another class to produce unique physical and signalling properties that support tissue structure, growth and function. Small, modular subunits form homopolymers and heteropolymers that become supramolecular assemblies with highly specialized organization.

  • Collagens are the major proteins of the ECM. The structural hallmark of all collagens is the triple helix, which is a right-handed helix of three polypeptide α-chains (homotrimers and heterotrimers), each of which contains one or more regions that are characterized by the repeating amino acid motif Gly-X-Y, where X and Y can be any amino acid.

  • The assembly of fibrillar collagen involves multiple complex intracellular and extracellular post-translational steps from the translational product to a fibrillar structure that is capable of withstanding tensile forces. The unique mechanical properties of fibrillar collagen are mainly controlled by the collagen structure, which shows the importance of the relationship between three-dimensional protein structure and the resulting ECM function.

  • The primary biological function of proteoglycans derives from the biochemical and hydrodynamic characteristics of the glycosaminoglycan (GAG) components of the molecules, which are long, negatively charged, linear chains of disaccharide repeats that bind water to provide hydration and compressive resistance. Heparan sulphate proteoglycans (HSPGs) are a major part of the basement membrane and chondroitin sulphate proteoglycans (CSPGs) can be found in cartilage and in neural ECMs.

  • The laminin family of large, mosaic glycoproteins are primarily located in basal lamina and some mesenchymal compartments, and they mediate interactions between cells via cell surface receptors (such as integrins and dystroglycan) and other components of the ECM through the modular domains within the laminin molecule. Similarly, many ECM proteins interact with cells through crucial connections with the multidomain protein fibronectin, which is secreted as a large glycoprotein that assembles via cell-mediated processes into fibrillar structures around cells.

  • The production and assembly of the ECM follow different temporal and spatial patterns in various tissues, with load-bearing tissues such as tendons showing highly ordered, fibrillar structures and the continually evolving brain showing a less organized, GAG-rich ECM. Therefore, disruption of the relative abundance of ECM proteins or their interactions with one another has important consequences for the behaviour and the fate of cells within that tissue.

Abstract

The biochemical and biophysical properties of the extracellular matrix (ECM) dictate tissue-specific cell behaviour. The molecules that are associated with the ECM of each tissue, including collagens, proteoglycans, laminins and fibronectin, and the manner in which they are assembled determine the structure and the organization of the resultant ECM. The product is a specific ECM signature that is comprised of unique compositional and topographical features that both reflect and facilitate the functional requirements of the tissue.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1: Collagen structure.
Figure 2: Fibrillar collagen assembly.
Figure 3: Non-collagenous molecules of the ECM.
Figure 4: Basal lamina assembly.
Figure 5: Perineuronal nets.

Similar content being viewed by others

References

  1. Mecham, R. P. Overview of extracellular matrix. Curr. Protoc. Cell Biol. 10, Unit 10.1 (2012).

    PubMed  Google Scholar 

  2. Lu, P., Takai, K., Weaver, V. M. & Werb, Z. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb. Perspect. Biol. 3, a005058 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Rozario, T. & DeSimone, D. W. The extracellular matrix in development and morphogenesis: a dynamic view. Dev. Biol. 341, 126–140 (2010).

    Article  CAS  PubMed  Google Scholar 

  4. Naba, A. et al. The matrisome: in silico definition and in vivo characterization by proteomics of normal and tumor extracellular matrices. Mol. Cell. Proteomics 11, M111.014647 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. Jakeman, L. B., Williams, K. E. & Brautigam, B. In the presence of danger: the extracellular matrix defensive response to central nervous system injury. Neural Regen. Res. 9, 377–384 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Fratzl, P. et al. Fibrillar structure and mechanical properties of collagen. J. Struct. Biol. 122, 119–122 (1998).

    Article  CAS  PubMed  Google Scholar 

  7. Bonnans, C., Chou, J. & Werb, Z. Remodeling the extracellular matrix in development and diseases. Nature Rev. Cell Mol. Biol. http://dx.doi.org/10.1038/nrm3904 (2014).

  8. Humphrey, J. D., Dufresne, E. R. & Schwartz, A. M. Mechanotransduction and extracellular matrix homeostasis. Nature Rev. Cell Mol. Biol. http://dx.doi.org/10.1038/nrm3896 (2014).

  9. Rowe, R. G. & Weiss, S. J. Breaching the basement membrane: who, when and how? Trends Cell Biol. 18, 560–574 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Schaefer, L. & Schaefer, R. M. Proteoglycans: from structural compounds to signaling molecules. Cell Tissue Res. 339, 237–246 (2010). This paper shows the biological structure and functions of the primarily extracellular SLRPs and highlights SLRP-associated genetic diseases and signalling events.

    Article  CAS  PubMed  Google Scholar 

  11. Myllyharju, J. & Kivirikko, K. I. Collagens, modifying enzymes and their mutations in humans, flies and worms. Trends Genet. 20, 33–43 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Ricard-Blum, S. & Ruggiero, F. The collagen superfamily: from the extracellular matrix to the cell membrane. Pathol. Biol. (Paris). 53, 430–442 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Brodsky, B. & Persikov, A. V. Molecular structure of the collagen triple helix. Adv. Protein Chem. 70, 301–339 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Ricard-Blum, S. The collagen family. Cold Spring Harb. Perspect. Biol. 3, a004978 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hulmes, D. J. S. in Collagen Struct. Mech. (ed. Fratzl, P.) 15–47 (Springer, 2008). This is a comprehensive review of intracellular and extracellular collagen biosynthesis and collagen fibril assembly.

    Google Scholar 

  16. Hulmes, D. J. S. Building collagen molecules, fibrils, and suprafibrillar structures. J. Struct. Biol. 137, 2–10 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Myllyharju, J. Intracellular post-translational modifications of collagens. Top Curr. Chem. 247, 115–147 (2005).

    Article  CAS  Google Scholar 

  18. Bella, J., Eaton, M., Brodsky, B. & Berman, H. M. Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution. Science 266, 75–81 (1994).

    Article  CAS  PubMed  Google Scholar 

  19. Persikov, A. V., Ramshaw, J. A. M., Kirkpatrick, A. & Brodsky, B. Electrostatic interactions involving lysine make major contributions to collagen triple-helix stability. Biochemistry 44, 1414–1422 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Bourhis, J.-M. et al. Structural basis of fibrillar collagen trimerization and related genetic disorders. Nature Struct. Mol. Biol. 19, 1031–1036 (2012). This paper elucidates the crystal structure of the procollagen C propeptide to reveal an exquisite structural mechanism of α-chain selectivity during intracellular trimerization.

    Article  CAS  Google Scholar 

  21. McLaughlin, S. H. & Bulleid, N. J. Molecular recognition in procollagen chain assembly. Matrix Biol. 16, 369–377 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Lees, J. F., Tasab, M. & Bulleid, N. J. Identification of the molecular recognition sequence which determines the type-specific assembly of procollagen. EMBO J. 16, 908–916 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Boudko, S. P., Engel, J. & Bächinger, H. P. The crucial role of trimerization domains in collagen folding. Int. J. Biochem. Cell Biol. 44, 21–32 (2012).

    Article  CAS  PubMed  Google Scholar 

  24. Ellgaard, L. & Ruddock, L. W. The human protein disulphide isomerase family: substrate interactions and functional properties. EMBO Rep. 6, 28–32 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wess, T. J. Collagen fibril form and function. Adv. Protein Chem. 70, 341–374 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Shoulders, M. D. & Raines, R. T. Collagen structure and stability. Annu. Rev. Biochem. 78, 929–958 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Trelstad, R. L. & Hayashi, K. Tendon collagen fibrillogenesis: intracellular subassemblies and cell surface changes associated with fibril growth. Dev. Biol. 71, 228–242 (1979).

    Article  CAS  PubMed  Google Scholar 

  28. Birk, D. E. & Trelstad, R. L. Extracellular compartments in tendon morphogenesis: collagen fibril, bundle, and macroaggregate formation. J. Cell Biol. 103, 231–240 (1986).

    Article  CAS  PubMed  Google Scholar 

  29. Birk, D. E., Zycband, E. I., Winkelmann, D. A. & Trelstad, R. L. Collagen fibrillogenesis in situ: fibril segments are intermediates in matrix assembly. Proc. Natl Acad. Sci. USA 86, 4549–4553 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Canty, E. G. et al. Coalignment of plasma membrane channels and protrusions (fibripositors) specifies the parallelism of tendon. J. Cell Biol. 165, 553–563 (2004). This paper shows how embryonic fibroblasts produce an ECM that is rich in elongated, parallel, collagen fibrils, through the initiation of collagen fibrillogenesis by targeting collagen fibril-containing Golgi-to-plasma membrane carriers (GPCs) to plasma membrane protrusions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Starborg, T. et al. Using transmission electron microscopy and 3View to determine collagen fibril size and three-dimensional organization. Nature Protoc. 8, 1433–1448 (2013).

    Article  CAS  Google Scholar 

  32. Kalson, N. S. et al. Nonmuscle myosin II powered transport of newly formed collagen fibrils at the plasma membrane. Proc. Natl Acad. Sci. USA 110, E4743–E4752 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Porter, S., Clark, I. M., Kevorkian, L. & Edwards, D. R. The ADAMTS metalloproteinases. Biochem. J. 386, 15–27 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hopkins, D. R., Keles, S. & Greenspan, D. S. The bone morphogenetic protein 1/tolloid-like metalloproteinases. Matrix Biol. 26, 508–523 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Seidah, N. G. & Prat, A. Precursor convertases in the secretory pathway, cytosol and extracellular milieu. Essays Biochem. 38, 79–94 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Pappano, W. N., Steiglitz, B. M., Scott, I. C., Keene, D. R. & Greenspan, D. S. Use of BMP1/TLL1 doubly homozygous null mice and proteomics to identify and validate in vivo substrates of bone morphogenetic protein 1/tolloid-like metalloproteinases. Mol. Cell. Biol. 23, 4428–4438 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kadler, K. E., Holmes, D. F., Trotter, J. A. & Chapman, J. A. Collagen fibril formation. Biochem. J. 316, 1–11 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wenstrup, R. J. et al. Type V collagen controls the initiation of collagen fibril assembly. J. Biol. Chem. 279, 53331–53337 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Chapman, J. A. The staining pattern of collagen fibrils. I. An analysis of electron micrographs. Connect. Tissue Res. 2, 137–150 (1974).

    Article  CAS  PubMed  Google Scholar 

  40. Olsen, B. R. Electron microscope studies on collagen. I. Native collagen fibrils. Z. Zellforsch. Mikrosk. Anat. 59, 184–198 (1963).

    Article  CAS  PubMed  Google Scholar 

  41. Petruska, J. A. & Hodge, A. J. A subunit model for the tropocollagen macromolecule. Proc. Natl Acad. Sci. USA 51, 871–876 (1964).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hulmes, D. J. & Miller, A. Quasi-hexagonal molecular packing in collagen fibrils. Nature 282, 878–880 (1979).

    Article  CAS  PubMed  Google Scholar 

  43. Hulmes, D. J., Wess, T. J., Prockop, D. J. & Fratzl, P. Radial packing, order, and disorder in collagen fibrils. Biophys. J. 68, 1661–1670 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Orgel, J. P. R. O., Irving, T. C., Miller, A. & Wess, T. J. Microfibrillar structure of type I collagen in situ. Proc. Natl Acad. Sci. USA 103, 9001–9005 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Schmitt, F. O., Hall, C. E. & Jakus, M. A. Electron microscope investigations of the structure of collagen. J. Cell. Comp. Physiol. 20, 11–33 (1942).

    Article  CAS  Google Scholar 

  46. Bruckner, P. Suprastructures of extracellular matrices: paradigms of functions controlled by aggregates rather than molecules. Cell Tissue Res. 339, 7–18 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Ameye, L. & Young, M. F. Mice deficient in small leucine-rich proteoglycans: novel in vivo models for osteoporosis, osteoarthritis, Ehlers–Danlos syndrome, muscular dystrophy, and corneal diseases. Glycobiology 12, 107R–116R (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Kalamajski, S. & Oldberg, A. The role of small leucine-rich proteoglycans in collagen fibrillogenesis. Matrix Biol. 29, 248–253 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Molnar, J. et al. Structural and functional diversity of lysyl oxidase and the LOX-like proteins. Biochim. Biophys. Acta 1647, 220–224 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Eyre, D. R., Weis, M. A. & Wu, J.-J. Advances in collagen cross-link analysis. Methods 45, 65–74 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Eyre, D. R. & Glimcher, M. J. Collagen cross-linking. Isolation of cross-linked peptides from collagen of chicken bone. Biochem. J. 135, 393–403 (1973).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lucero, H. A. & Kagan, H. M. Lysyl oxidase: an oxidative enzyme and effector of cell function. Cell. Mol. Life Sci. 63, 2304–2316 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Rucker, R. B. & Murray, J. Cross-linking amino acids in collagen and elastin. Am. J. Clin. Nutr. 31, 1221–1236 (1978).

    Article  CAS  PubMed  Google Scholar 

  54. Orgel, J. P., Wess, T. J. & Miller, A. The in situ conformation and axial location of the intermolecular cross-linked non-helical telopeptides of type I collagen. Structure 8, 137–142 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. O'Leary, L. E. R., Fallas, J. A., Bakota, E. L., Kang, M. K. & Hartgerink, J. D. Multi-hierarchical self-assembly of a collagen mimetic peptide from triple helix to nanofibre and hydrogel. Nature Chem. 3, 821–828 (2011).

    Article  CAS  Google Scholar 

  56. Bandtlow, C. E. & Zimmermann, D. R. Proteoglycans in the developing brain: new conceptual insights for old proteins. Physiol. Rev. 80, 1267–1290 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Knudson, C. B. & Knudson, W. Cartilage proteoglycans. Semin. Cell Dev. Biol. 12, 69–78 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Cui, H., Freeman, C., Jacobson, G. A. & Small, D. H. Proteoglycans in the central nervous system: role in development, neural repair, and Alzheimer's disease. IUBMB Life 65, 108–120 (2013).

    Article  CAS  PubMed  Google Scholar 

  59. Schwartz, N. B. & Domowicz, M. Proteoglycans in brain development. Glycoconj. J. 21, 329–341 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. Zhang, L. (ed.) Glycosaminoglycans in Development, Health and Disease (Academic, 2010).

    Google Scholar 

  61. Deepa, S. S. et al. Composition of perineuronal net extracellular matrix in rat brain: a different disaccharide composition for the net-associated proteoglycans. J. Biol. Chem. 281, 17789–17800 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Simon Davis, D. A. & Parish, C. R. Heparan sulfate: a ubiquitous glycosaminoglycan with multiple roles in immunity. Front. Immunol. 4, 470 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bishop, J. R., Schuksz, M. & Esko, J. D. Heparan sulphate proteoglycans fine-tune mammalian physiology. Nature 446, 1030–1037 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Esko, J. D., Kimata, K. & Lindahl, U. in Essentials of Glycobiology. 2nd edn Ch. 16 (Cold Spring Harbor, 2009).

    Google Scholar 

  65. Wade, A., McKinney, A. & Phillips, J. J. Matrix regulators in neural stem cell functions. Biochim. Biophys. Acta http://dx.doi.org/10.1016/j.bbagen.2014.01.017 (2014).

  66. Johnson, K. G. et al. Axonal heparan sulfate proteoglycans regulate the distribution and efficiency of the repellent slit during midline axon guidance. Curr. Biol. 14, 499–504 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Häcker, U., Nybakken, K. & Perrimon, N. Heparan sulphate proteoglycans: the sweet side of development. Nature Rev. Mol. Cell. Biol. 6, 530–541 (2005).

    Article  CAS  Google Scholar 

  68. Maeda, N., Ishii, M., Nishimura, K. & Kamimura, K. Functions of chondroitin sulfate and heparan sulfate in the developing brain. Neurochem. Res. 36, 1228–1240 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Yamaguchi, Y. Lecticans: organizers of the brain extracellular matrix. Cell. Mol. Life Sci. 57, 276–289 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Lundell, A. et al. Structural basis for interactions between tenascins and lectican C-type lectin domains: evidence for a crosslinking role for tenascins. Structure 12, 1495–1506 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Dellett, M., Hu, W., Papadaki, V. & Ohnuma, S. Small leucine rich proteoglycan family regulates multiple signalling pathways in neural development and maintenance. Dev. Growth Differ. 54, 327–340 (2012).

    Article  CAS  PubMed  Google Scholar 

  72. McEwan, P. A., Scott, P. G., Bishop, P. N. & Bella, J. Structural correlations in the family of small leucine-rich repeat proteins and proteoglycans. J. Struct. Biol. 155, 294–305 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Schaefer, L. & Iozzo, R. V. Biological functions of the small leucine-rich proteoglycans: from genetics to signal transduction. J. Biol. Chem. 283, 21305–21309 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Chen, S. & Birk, D. E. The regulatory roles of small leucine-rich proteoglycans in extracellular matrix assembly. FEBS J. 280, 2120–2137 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Oohira, A., Matsui, F., Tokita, Y., Yamauchi, S. & Aono, S. Molecular interactions of neural chondroitin sulfate proteoglycans in the brain development. Arch. Biochem. Biophys. 374, 24–34 (2000).

    Article  CAS  PubMed  Google Scholar 

  76. Timpl, R. & Brown, J. C. The laminins. Matrix Biol. 14, 275–281 (1994).

    Article  CAS  PubMed  Google Scholar 

  77. Aumailley, M. et al. A simplified laminin nomenclature. Matrix Biol. 24, 326–332 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Miner, J. H. & Yurchenco, P. D. Laminin functions in tissue morphogenesis. Annu. Rev. Cell Dev. Biol. 20, 255–284 (2004). This paper discusses how different laminin proteins affect invertebrate and vertebrate tissue morphogenesis through the induction and the maintenance of cell polarity, the establishment of barriers between tissue compartments and the protection of adherent cells from anoikis.

    Article  CAS  PubMed  Google Scholar 

  79. Mercurio, A. M. & Shaw, L. M. Laminin binding proteins. Bioessays 13, 469–473 (1991).

    Article  CAS  PubMed  Google Scholar 

  80. Yurchenco, P. D., Smirnov, S. & Mathus, T. Analysis of basement membrane self-assembly and cellular interactions with native and recombinant glycoproteins. Methods Cell Biol. 69, 111–144 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Schwarzbauer, J. E. & DeSimone, D. W. Fibronectins, their fibrillogenesis, and in vivo functions. Cold Spring Harb. Perspect. Biol. 3, a005041 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Singh, P., Carraher, C. & Schwarzbauer, J. E. Assembly of fibronectin extracellular matrix. Annu. Rev. Cell Dev. Biol. 26, 397–419 (2010). This is an excellent review highlighting the major steps, molecular interactions and cellular mechanisms involved in assembling fibronectin into a fibrillar matrix.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Hynes, R. O. in Guidebook to the Extracellular Matrix, Anchor and Adhesion Proteins. 2nd edn (eds Kreis, T. & Vale, R.) 422–425 (Oxford University Press, 1999).

    Google Scholar 

  84. García, A. J., Schwarzbauer, J. E. & Boettiger, D. Distinct activation states of α5β1 integrin show differential binding to RGD and synergy domains of fibronectin. Biochemistry 41, 9063–9069 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Ilic´, D. et al. FAK promotes organization of fibronectin matrix and fibrillar adhesions. J. Cell Sci. 117, 177–187 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Hay, E. D. Extracellular matrix alters epithelial differentiation. Curr. Opin. Cell Biol. 5, 1029–1035 (1993).

    Article  CAS  PubMed  Google Scholar 

  87. Birk, D. E., Zycband, E. I., Woodruff, S., Winkelmann, D. A. & Trelstad, R. L. Collagen fibrillogenesis in situ: fibril segments become long fibrils as the developing tendon matures. Dev. Dyn. 208, 291–298 (1997).

    Article  CAS  PubMed  Google Scholar 

  88. Zhang, G. et al. Development of tendon structure and function: regulation of collagen fibrillogenesis. J. Musculoskelet. Neuronal Interact. 5, 5–21 (2005).

    CAS  PubMed  Google Scholar 

  89. Wang, J. H.-C. Mechanobiology of tendon. J. Biomech. 39, 1563–1582 (2006).

    Article  PubMed  Google Scholar 

  90. Kannus, P. Structure of the tendon connective tissue. Scand. J. Med. Sci. Sports 10, 312–320 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Tresoldi, I. et al. Tendon's ultrastructure. Muscles. Ligaments Tendons J. 3, 2–6 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Mienaltowski, M. J. & Birk, D. E. Structure, physiology, and biochemistry of collagens. Adv. Exp. Med. Biol. 802, 5–29 (2014).

    Article  CAS  PubMed  Google Scholar 

  93. Craig, A. S., Birtles, M. J., Conway, J. F. & Parry, D. A. An estimate of the mean length of collagen fibrils in rat tail-tendon as a function of age. Connect. Tissue Res. 19, 51–62 (1989).

    Article  CAS  PubMed  Google Scholar 

  94. Tozer, S. & Duprez, D. Tendon and ligament: development, repair and disease. Birth Defects Res. C. Embryo Today 75, 226–236 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Richardson, S. H. et al. Tendon development requires regulation of cell condensation and cell shape via cadherin-11-mediated cell-cell junctions. Mol. Cell. Biol. 27, 6218–6228 (2007). This paper describes how the precise regulation of cell shape via cell–cell junctions and the coaxial alignment of plasma membrane channels in longitudinally stacked cells drives tendon formation in the developing limb.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Sasaki, N. & Odajima, S. Elongation mechanism of collagen fibrils and force-strain relations of tendon at each level of structural hierarchy. J. Biomech. 29, 1131–1136 (1996).

    Article  CAS  PubMed  Google Scholar 

  97. Graham, H. K., Holmes, D. F., Watson, R. B. & Kadler, K. E. Identification of collagen fibril fusion during vertebrate tendon morphogenesis. The process relies on unipolar fibrils and is regulated by collagen-proteoglycan interaction. J. Mol. Biol. 295, 891–902 (2000).

    Article  CAS  PubMed  Google Scholar 

  98. Paulsson, M. Basement membrane proteins: structure, assembly, and cellular interactions. Crit. Rev. Biochem. Mol. Biol. 27, 93–127 (1992).

    Article  CAS  PubMed  Google Scholar 

  99. Martin Rupert, G. R. T. Laminin and other basement membrane components. Annu. Rev. Cell Biol. 3, 57–85 (1987).

    Article  Google Scholar 

  100. Kalluri, R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nature Rev. Cancer 3, 422–433 (2003). This is an excellent review highlighting the constituents, structure and assembly of the basement membrane, with emphasis on angiogenesis and vascular basement membranes.

    Article  CAS  Google Scholar 

  101. Yurchenco, P. D. Basement membranes: cell scaffoldings and signaling platforms. Cold Spring Harb. Perspect. Biol. 3, a004911 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Yurchenco, P. D. & Schittny, J. C. Molecular architecture of basement membranes. FASEB J. 4, 1577–1590 (1990).

    Article  CAS  PubMed  Google Scholar 

  103. Sanes, J. R. The basement membrane/basal lamina of skeletal muscle. J. Biol. Chem. 278, 12601–12604 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Yurchenco, P. D. & Patton, B. L. Developmental and pathogenic mechanisms of basement membrane assembly. Curr. Pharm. Des. 15, 1277–1294 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Takagi, J., Yang, Y., Liu, J.-H., Wang, J.-H. & Springer, T. A. Complex between nidogen and laminin fragments reveals a paradigmatic β-propeller interface. Nature 424, 969–974 (2003).

    Article  CAS  PubMed  Google Scholar 

  106. Pöschl, E. et al. Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development. Development 131, 1619–1628 (2004).

    Article  CAS  PubMed  Google Scholar 

  107. Iozzo, R. V., Zoeller, J. J. & Nyström, A. Basement membrane proteoglycans: modulators Par Excellence of cancer growth and angiogenesis. Mol. Cells 27, 503–513 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Costello, I., Biondi, C. A., Taylor, J. M., Bikoff, E. K. & Robertson, E. J. Smad4-dependent pathways control basement membrane deposition and endodermal cell migration at early stages of mouse development. BMC Dev. Biol. 9, 54 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Wiradjaja, F., DiTommaso, T. & Smyth, I. Basement membranes in development and disease. Birth Defects Res. C. Embryo Today 90, 8–31 (2010).

    Article  CAS  PubMed  Google Scholar 

  110. Paralkar, V. M., Vukicevic, S. & Reddi, A. H. Transforming growth factor-β type 1 binds to collagen IV of basement membrane matrix: Implications for development. Dev. Biol. 143, 303–308 (1991).

    Article  CAS  PubMed  Google Scholar 

  111. Streuli, C. H. Control of mammary epithelial differentiation: basement membrane induces tissue-specific gene expression in the absence of cell–cell interaction and morphological polarity. J. Cell Biol. 115, 1383–1395 (1991).

    Article  CAS  PubMed  Google Scholar 

  112. Camelo, A., Dunmore, R., Sleeman, M. A. & Clarke, D. L. The epithelium in idiopathic pulmonary fibrosis: breaking the barrier. Front. Pharmacol. 4, 173 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Torricelli, A. A. M., Singh, V., Santhiago, M. R. & Wilson, S. E. The corneal epithelial basement membrane: structure, function, and disease. Invest. Ophthalmol. Vis. Sci. 54, 6390–6400 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Brownell, A. G. & Slavkin, H. C. Role of basal lamina in tissue interactions. Ren. Physiol. 3, 193–204 (1980).

    CAS  PubMed  Google Scholar 

  115. Lau, L. W., Cua, R., Keough, M. B., Haylock-Jacobs, S. & Yong, V. W. Pathophysiology of the brain extracellular matrix: a new target for remyelination. Nature Rev. Neurosci. 14, 722–729 (2013). This paper shows the organization of the brain ECM, emphasizing the pathophysiological roles of CSPGs after neural injury.

    Article  CAS  Google Scholar 

  116. Plantman, S. Proregenerative properties of ECM molecules. Biomed. Res. Int. 2013, 981695 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Ruoslahti, E. Brain extracellular matrix. Glycobiology 6, 489–492 (1996).

    Article  CAS  PubMed  Google Scholar 

  118. Barros, C. S., Franco, S. J. & Müller, U. Extracellular matrix: functions in the nervous system. Cold Spring Harb. Perspect. Biol. 3, a005108 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Chiquet-Ehrismann, R. & Tucker, R. P. Tenascins and the importance of adhesion modulation. Cold Spring Harb. Perspect. Biol. 3, a004960 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Dityatev, A. Remodeling of extracellular matrix and epileptogenesis. Epilepsia 51 (Suppl. 3), 61–65 (2010).

    Article  CAS  PubMed  Google Scholar 

  121. Lajtha, A. & Banik, N. Handbook of Neurochemistry and Molecular Neurobiology: Neural Protein Metabolism and Function. Vol. 3 (Springer, 2007).

    Book  Google Scholar 

  122. Howell, M. D. & Gottschall, P. E. Lectican proteoglycans, their cleaving metalloproteinases, and plasticity in the central nervous system extracellular microenvironment. Neuroscience 217, 6–18 (2012).

    Article  CAS  PubMed  Google Scholar 

  123. Carulli, D., Rhodes, K. E. & Fawcett, J. W. Upregulation of aggrecan, link protein 1, and hyaluronan synthases during formation of perineuronal nets in the rat cerebellum. J. Comp. Neurol. 501, 83–94 (2007).

    Article  CAS  PubMed  Google Scholar 

  124. Frischknecht, R. & Gundelfinger, E. D. The brain's extracellular matrix and its role in synaptic plasticity. Adv. Exp. Med. Biol. 970, 153–171 (2012).

    Article  CAS  PubMed  Google Scholar 

  125. Kwok, J. C. F., Dick, G., Wang, D. & Fawcett, J. W. Extracellular matrix and perineuronal nets in CNS repair. Dev. Neurobiol. 71, 1073–1089 (2011).

    Article  CAS  PubMed  Google Scholar 

  126. Wang, D. & Fawcett, J. The perineuronal net and the control of CNS plasticity. Cell Tissue Res. 349, 147–160 (2012).

    Article  PubMed  Google Scholar 

  127. Romberg, C. et al. Depletion of perineuronal nets enhances recognition memory and long-term depression in the perirhinal cortex. J. Neurosci. 33, 7057–7065 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Grimpe, B. & Silver, J. The extracellular matrix in axon regeneration. Prog. Brain Res. 137, 333–349 (2002).

    Article  CAS  PubMed  Google Scholar 

  129. Fitch, M. T. & Silver, J. Glial cell extracellular matrix: boundaries for axon growth in development and regeneration. Cell Tissue Res. 290, 379–384 (1997).

    Article  CAS  PubMed  Google Scholar 

  130. Ishii, M. & Maeda, N. Oversulfated chondroitin sulfate plays critical roles in the neuronal migration in the cerebral cortex. J. Biol. Chem. 283, 32610–32620 (2008).

    Article  CAS  PubMed  Google Scholar 

  131. Sharma, K., Selzer, M. E. & Li, S. Scar-mediated inhibition and CSPG receptors in the CNS. Exp. Neurol. 237, 370–378 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Bartus, K., James, N. D., Bosch, K. D. & Bradbury, E. J. Chondroitin sulphate proteoglycans: key modulators of spinal cord and brain plasticity. Exp. Neurol. 235, 5–17 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Li, A.-H., Liu, P. P., Villarreal, F. J. & Garcia, R. A. Dynamic changes in myocardial matrix and relevance to disease: translational perspectives. Circ. Res. 114, 916–927 (2014).

    Article  CAS  PubMed  Google Scholar 

  134. Page-McCaw, A., Ewald, A. J. & Werb, Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nature Rev. Mol. Cell Biol. 8, 221–233 (2007).

    Article  CAS  Google Scholar 

  135. Fan, D., Takawale, A., Lee, J. & Kassiri, Z. Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease. Fibrogen. Tissue Repair 5, 15 (2012).

    Article  CAS  Google Scholar 

  136. Nickla, H., Klug, W. S. & Cummings, M. R. Concepts of Genetics. (Prentice Hall, 1997).

    Google Scholar 

  137. Jäälinoja, J., Ylöstalo, J., Beckett, W., Hulmes, D. J. S. & Ala-Kokko, L. Trimerization of collagen IX α-chains does not require the presence of the COL1 and NC1 domains. Biochem. J. 409, 545–554 (2008).

    Article  CAS  PubMed  Google Scholar 

  138. Liu, Y., Ramanath, H. S. & Wang, D.-A. Tendon tissue engineering using scaffold enhancing strategies. Trends Biotechnol. 26, 201–209 (2008).

    Article  CAS  PubMed  Google Scholar 

  139. Edwards, I. J. Proteoglycans in prostate cancer. Nature Rev. Urol. 9, 196–206 (2012).

    Article  CAS  Google Scholar 

  140. Rudd, T. R. et al. A key biological signalling system promises new routes to intervention in medically important processes. Diamond Science [online], (2014).

  141. Marinkovich, M. P. Tumour microenvironment: laminin 332 in squamous-cell carcinoma. Nature Rev. Cancer 7, 370–380 (2007).

    Article  CAS  Google Scholar 

  142. Bezakova, G. & Ruegg, M. A. New insights into the roles of agrin. Nature Rev. Mol. Cell. Biol. 4, 295–308 (2003).

    Article  CAS  Google Scholar 

  143. Meier, T. & Wallace, B. G. Formation of the neuromuscular junction: molecules and mechanisms. Bioessays 20, 819–829 (1998).

    Article  CAS  PubMed  Google Scholar 

  144. McMahan, U. J. et al. Agrin isoforms and their role in synaptogenesis. Curr. Opin. Cell Biol. 4, 869–874 (1992).

    Article  CAS  PubMed  Google Scholar 

  145. Fisher, L. W., Torchia, D. A., Fohr, B., Young, M. F. & Fedarko, N. S. Flexible structures of SIBLING proteins, bone sialoprotein, and osteopontin. Biochem. Biophys. Res. Commun. 280, 460–465 (2001).

    Article  CAS  PubMed  Google Scholar 

  146. Bellahcène, A., Castronovo, V., Ogbureke, K. U. E., Fisher, L. W. & Fedarko, N. S. Small integrin-binding ligand N-linked glycoproteins (SIBLINGs): multifunctional proteins in cancer. Nature Rev. Cancer 8, 212–226 (2008).

    Article  CAS  Google Scholar 

  147. Ogata, Y. Bone sialoprotein and its transcriptional regulatory mechanism. J. Periodontal Res. 43, 127–135 (2008).

    Article  CAS  PubMed  Google Scholar 

  148. Deák, F., Wagener, R., Kiss, I. & Paulsson, M. The matrilins: a novel family of oligomeric extracellular matrix proteins. Matrix Biol. 18, 55–64 (1999).

    Article  PubMed  Google Scholar 

  149. Klatt, A. R., Becker, A.-K. A., Neacsu, C. D., Paulsson, M. & Wagener, R. The matrilins: modulators of extracellular matrix assembly. Int. J. Biochem. Cell Biol. 43, 320–330 (2011).

    Article  CAS  PubMed  Google Scholar 

  150. Wagener, R. et al. The matrilins — adaptor proteins in the extracellular matrix. FEBS Lett. 579, 3323–3329 (2005).

    Article  CAS  PubMed  Google Scholar 

  151. Chen, Q., Johnson, D. M., Haudenschild, D. R. & Goetinck, P. F. Cartilage matrix protein: expression patterns in chicken, mouse, and human. Ann. NY Acad. Sci. 785, 238–240 (1996).

    Article  CAS  PubMed  Google Scholar 

  152. Mithieux, S. M. & Weiss, A. S. Elastin. Adv. Protein Chem. 70, 437–461 (2005).

    Article  CAS  PubMed  Google Scholar 

  153. Halper, J. & Kjaer, M. Basic components of connective tissues and extracellular matrix: elastin, fibrillin, fibulins, fibrinogen, fibronectin, laminin, tenascins and thrombospondins. Adv. Exp. Med. Biol. 802, 31–47 (2014).

    Article  CAS  PubMed  Google Scholar 

  154. Pepe, A., Bochicchio, B. & Tamburro, A. M. Supramolecular organization of elastin and elastin-related nanostructured biopolymers. Nanomed. 2, 203–218 (2007).

    Article  CAS  Google Scholar 

  155. Wagenseil, J. E. & Mecham, R. P. New insights into elastic fiber assembly. Birth Defects Res. C. Embryo Today 81, 229–240 (2007).

    Article  CAS  PubMed  Google Scholar 

  156. Weisel, J. W. Fibrinogen and fibrin. Adv. Protein Chem. 70, 247–299 (2005).

    Article  CAS  PubMed  Google Scholar 

  157. Mosesson, M. W., Siebenlist, K. R. & Meh, D. A. The structure and biological features of fibrinogen and fibrin. Ann. NY Acad. Sci. 936, 11–30 (2001).

    Article  CAS  PubMed  Google Scholar 

  158. Ramirez, F., Sakai, L. Y., Dietz, H. C. & Rifkin, D. B. Fibrillin microfibrils: multipurpose extracellular networks in organismal physiology. Physiol. Genom. 19, 151–154 (2004).

    Article  CAS  Google Scholar 

  159. Kielty, C. M. et al. Fibrillin: from microfibril assembly to biomechanical function. Phil. Trans. R. Soc. 357, 207–217 (2002).

    Article  CAS  Google Scholar 

  160. Timpl, R., Sasaki, T., Kostka, G. & Chu, M.-L. Fibulins: a versatile family of extracellular matrix proteins. Nature Rev. Mol. Cell. Biol. 4, 479–489 (2003).

    Article  CAS  Google Scholar 

  161. De Vega, S., Iwamoto, T. & Yamada, Y. Fibulins: multiple roles in matrix structures and tissue functions. Cell. Mol. Life Sci. 66, 1890–1902 (2009).

    Article  CAS  PubMed  Google Scholar 

  162. Cirulli, V. & Yebra, M. Netrins: beyond the brain. Nature Rev. Mol. Cell Biol. 8, 296–306 (2007).

    Article  CAS  Google Scholar 

  163. Lai Wing Sun, K., Correia, J. P. & Kennedy, T. E. Netrins: versatile extracellular cues with diverse functions. Development 138, 2153–2169 (2011).

    Article  CAS  PubMed  Google Scholar 

  164. Bradshaw, A. D. Diverse biological functions of the SPARC family of proteins. Int. J. Biochem. Cell Biol. 44, 480–488 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Brekken, R. A. & Sage, E. H. SPARC, a matricellular protein: at the crossroads of cell-matrix communication. Matrix Biol. 19, 816–827 (2001).

    Article  CAS  PubMed  Google Scholar 

  166. Giachelli, C. M. & Steitz, S. Osteopontin: a versatile regulator of inflammation and biomineralization. Matrix Biol. 19, 615–622 (2000).

    Article  CAS  PubMed  Google Scholar 

  167. Hunter, G. K. Role of osteopontin in modulation of hydroxyapatite formation. Calcif. Tissue Int. 93, 348–354 (2013).

    Article  CAS  PubMed  Google Scholar 

  168. Fatemi, S. H. Reelin glycoprotein: structure, biology and roles in health and disease. Mol. Psychiatry 10, 251–257 (2005).

    Article  CAS  PubMed  Google Scholar 

  169. Magdaleno, S. M. & Curran, T. Brain development: integrins and the Reelin pathway. Curr. Biol. 11, R1032–R1035 (2001).

    Article  CAS  PubMed  Google Scholar 

  170. Vincent, T. L., Woolfson, D. N. & Adams, J. C. Prediction and analysis of higher-order coiled-coils: insights from proteins of the extracellular matrix, tenascins and thrombospondins. Int. J. Biochem. Cell Biol. 45, 2392–2401 (2013).

    Article  CAS  PubMed  Google Scholar 

  171. Tucker, R. P. & Chiquet-Ehrismann, R. The regulation of tenascin expression by tissue microenvironments. Biochim. Biophys. Acta 1793, 888–892 (2009).

    Article  CAS  PubMed  Google Scholar 

  172. Leavesley, D. I. et al. Vitronectin — master controller or micromanager? IUBMB Life 65, 807–818 (2013).

    CAS  PubMed  Google Scholar 

  173. Preissner, K. T. & Reuning, U. Vitronectin in vascular context: facets of a multitalented matricellular protein. Semin. Thromb. Hemost. 37, 408–424 (2011).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors apologize to all colleagues whose work cannot be cited owing to space limitations. This work was supported by DOD Breast Cancer Research Program (BCRP) grant W81XWH-07-1-0538 (to J.K.M.), US National Science Foundation (NSF) Graduate Research Fellowship (to G.O.), DOD BCRP grants W81XWH-05-1-0330 and W81XWH-13-1-0216 (to V.M.W.), US National Institutes of Health National Cancer Institute (NCI) grants R01 CA138818, U54 CA143836, R01 CA085492 and U01 ES019458 (to V.M.W.), and Susan G. Komen grant KG110560PP (to V.M.W.).

Author information

Authors and Affiliations

  1. Department of Surgery, Center for Bioengineering and Tissue Regeneration, University of California, San Francisco

    Janna K. Mouw, Guanqing Ou & Valerie M. Weaver

  2. University of California San Francisco and University of California Berkeley Joint Graduate Group in Bioengineering, San Francisco, 94143, California, USA

    Guanqing Ou

  3. Department of Anatomy, University of California, San Francisco

    Valerie M. Weaver

  4. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco

    Valerie M. Weaver

  5. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco

    Valerie M. Weaver

  6. UCSF Helen Diller Comprehensive Cancer Center, University of California, San Francisco, 94143, California, USA

    Valerie M. Weaver

Authors
  1. Janna K. Mouw
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guanqing Ou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Valerie M. Weaver
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Valerie M. Weaver.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Topographies

The three-dimensional qualities of surfaces or structures, including contours and relief. In the context of the ECM this includes features such as peaks and valleys, changes in roughness and geometric features.

Morphogenesis

The process of cell movement during embryonic development that controls the size, the shape and the patterning of tissues and organs.

Proteoglycans

(PGs). Glycoproteins that consist of a core protein to which one or more glycosaminoglycan chain is attached.

Glycosaminoglycans

(GAGs). Long, linear, charged polysaccharides that comprise repeating pairs of sugars, of which one is an amino sugar.

Fibrillar collagen

Polymerized, supramolecular collagen that has been organized into fibrils; collagen types I, II and III form fibrils.

Tensile forces

The forces required to exert a certain amount of tension (which is a type of normal stress) on a one-dimensional object. In this context, a pulling force on a cable tending to cause extension of the cable.

Procollagen

A trimeric collagen precursor molecule containing large amino- and carboxy-terminal propeptide domains.

Lysyl oxidase

An enzyme that participates in the formation of collagen polymers by facilitating oxidative deamination of peptidyl lysine residues on collagen monomers.

Pericellular space

The space surrounding a cell.

Fibripositors

(Also known as fibropositors). Plasma membrane protrusions projecting from the cell surface, where procollagen can potentially be processed, assembled and organized by individual cells.

Fibrillogenesis

The development or formation of fibrils, used to refer to collagen- or fibronectin-rich structures.

Small leucine-rich repeat proteoglycans

(SLRPs). A family of proteoglycans that share a common leucine-rich-repeat motif in their conserved carboxy termini; they have been strongly implicated in modulating fibrillar collagen assembly.

FACIT

(Fibril-associated collagens with interrupted triple helices). A type of collagen that does not form fibrils by itself but that is associated with the surface of fibrillar collagen.

Basement membrane

A thin, complex extracellular matrix that separates endothelial and epithelial cells from their subjacent connective tissues. It is composed of various collagens, proteoglycans and adhesive glycoproteins.

Syndecans

One of the two major families of heparin sulphate proteoglycans.

Glypicans

One of the two major families of heparin sulphate proteoglycans.

Epimerization

The formation of stereoisomers.

Integrins

A large family of heterodimeric transmembrane proteins, which are present in the plasma membrane as heterodimers of α- and β-subunits and function as receptors for cell adhesion molecules.

Nidogens

(Also known as entactins). Glycoproteins and key parts of the basement membrane.

Fibrillar adhesions

Cell–matrix connections that are typified by their location near the centre of the cell and their higher length to width ratio compared with focal adhesions at the periphery of cells.

Fascicles

Bundles of fibres.

Reticular lamina

A collagen-rich layer that is often found below the basal lamina that connects the combined basement membrane to the connective tissue.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mouw, J., Ou, G. & Weaver, V. Extracellular matrix assembly: a multiscale deconstruction. Nat Rev Mol Cell Biol 15, 771–785 (2014). https://doi.org/10.1038/nrm3902

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3902

  • Springer Nature Limited

This article is cited by

Search

Navigation