Extracellular matrix

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Extracellular matrix
Latin matrix extracellularis
MeSH Extracellular+matrix
Code TH H2.00.03.0.02001

In biology, the extracellular matrix (ECM) is a collection of extracellular molecules secreted by cells that provides structural and biochemical support to the surrounding cells.[1] 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.[2]

The animal extracellular matrix includes the interstitial matrix and the basement membrane.[3][page needed] Interstitial matrix is present between various animal cells (i.e., in the intercellular spaces). Gels of polysaccharides and fibrous proteins fill the interstitial space and act as a compression buffer against the stress placed on the ECM.[4][page needed] Basement membranes are sheet-like depositions of ECM on which various epithelial cells rest.

The plant ECM includes cell wall components, like cellulose, in addition to more complex signaling molecules.[5] Some single-celled organisms adopt multicelluar biofilms in which the cells are embedded in an ECM composed primarily of extracellular polymeric substances (EPS).[6]

Role and importance[edit]

Due to its diverse nature and composition, the ECM can serve many functions, such as providing support, segregating tissues from one another, and regulating intercellular communication. The extracellular matrix regulates a cell's dynamic behavior. In addition, it sequesters a wide range of cellular growth factors and acts as a local store for them.[3][page needed] Changes in physiological conditions can trigger protease activities that cause local release of such stores. This allows the rapid and local growth factor-mediated activation of cellular functions without de novo synthesis.

Formation of the extracellular matrix is essential for processes like growth, wound healing, and fibrosis. An understanding of ECM structure and composition also helps in comprehending the complex dynamics of tumor invasion and metastasis in cancer biology as metastasis often involves the destruction of extracellular matrix by enzymes such as serine proteases, threonine proteases, and matrix metalloproteinases.[3][pages needed][7]

Molecular components[edit]

Components of the ECM are produced intracellularly by resident cells and secreted into the ECM via exocytosis.[8][page needed] Once secreted, they then aggregate with the existing matrix. The ECM is composed of an interlocking mesh of fibrous proteins and glycosaminoglycans (GAGs).

Proteoglycans[edit]

GAGs are carbohydrate polymers and are usually attached to extracellular matrix proteins to form proteoglycans (hyaluronic acid is a notable exception, see below). Proteoglycans have a net negative charge that attracts positively charged sodium ions (Na+), which attracts water molecules via osmosis, keeping the ECM and resident cells hydrated. Proteoglycans may also help to trap and store growth factors within the ECM.

Described below are the different types of proteoglycan found within the extracellular matrix.

Heparan sulfate[edit]

Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan (PG) in which two or three HS chains are attached in close proximity to cell surface or ECM proteins.[9][10] It is in this form that HS binds to a variety of protein ligands and regulates a wide variety of biological activities, including developmental processes, angiogenesis, blood coagulation, and tumour metastasis.

In the extracellular matrix, especially basement membranes, the multi-domain proteins perlecan, agrin, and collagen XVIII are the main proteins to which heparan sulfate is attached.

Chondroitin sulfate[edit]

Chondroitin sulfates contribute to the tensile strength of cartilage, tendons, ligaments, and walls of the aorta. They have also been known to affect neuroplasticity.[11]

Keratan sulfate[edit]

Keratan sulfates have a variable sulfate content and, unlike many other GAGs, do not contain uronic acid. They are present in the cornea, cartilage, bones, and the horns of animals.

Non-proteoglycan polysaccharide[edit]

Hyaluronic acid[edit]

Hyaluronic acid (or "hyaluronan") is a polysaccharide consisting of alternating residues of D-glucuronic acid and N-acetylglucosamine, and unlike other GAGs, is not found as a proteoglycan. Hyaluronic acid in the extracellular space confers upon tissues the ability to resist compression by providing a counteracting turgor (swelling) force by absorbing significant amounts of water. Hyaluronic acid is thus found in abundance in the ECM of load-bearing joints. It is also a chief component of the interstitial gel. Hyaluronic acid is found on the inner surface of the cell membrane and is translocated out of the cell during biosynthesis.[12]

Hyaluronic acid acts as an environmental cue that regulates cell behavior during embryonic development, healing processes, inflammation, and tumor development. It interacts with a specific transmembrane receptor, CD44.[13]

Fibers[edit]

Collagen[edit]

Collagens are the most abundant protein in the ECM. In fact, collagen is the most abundant protein in the human body[14][15] and accounts for 90% of bone matrix protein content.[16] Collagens are present in the ECM as fibrillar proteins and give structural support to resident cells. Collagen is exocytosed in precursor form (procollagen), which is then cleaved by procollagen proteases to allow extracellular assembly. Disorders such as Ehlers Danlos Syndrome, osteogenesis imperfecta, and epidermolysis bullosa are linked with genetic defects in collagen-encoding genes.[8] The collagen can be divided into several families according to the types of structure they form:

  1. Fibrillar (Type I, II, III, V, XI)
  2. Facit (Type IX, XII, XIV)
  3. Short chain (Type VIII, X)
  4. Basement membrane (Type IV)
  5. Other (Type VI, VII, XIII)

Elastin[edit]

Elastins, in contrast to collagens, give elasticity to tissues, allowing them to stretch when needed and then return to their original state. This is useful in blood vessels, the lungs, in skin, and the ligamentum nuchae, and these tissues contain high amounts of elastins. Elastins are synthesized by fibroblasts and smooth muscle cells. Elastins are highly insoluble, and tropoelastins are secreted inside a chaperone molecule, which releases the precursor molecule upon contact with a fiber of mature elastin. Tropoelastins are then deaminated to become incorporated into the elastin strand. Disorders such as cutis laxa and Williams syndrome are associated with deficient or absent elastin fibers in the ECM.[8]

Other[edit]

Fibronectin[edit]

Fibronectins are glycoproteins that connect cells with collagen fibers in the ECM, allowing cells to move through the ECM. Fibronectins bind collagen and cell-surface integrins, causing a reorganization of the cell's cytoskeleton and facilitating cell movement. Fibronectins are secreted by cells in an unfolded, inactive form. Binding to integrins unfolds fibronectin molecules, allowing them to form dimers so that they can function properly. Fibronectins also help at the site of tissue injury by binding to platelets during blood clotting and facilitating cell movement to the affected area during wound healing.[8]

Laminin[edit]

Laminins are proteins found in the basal laminae of virtually all animals. Rather than forming collagen-like fibers, laminins form networks of web-like structures that resist tensile forces in the basal lamina. They also assist in cell adhesion. Laminins bind other ECM components such as collagens, nidogens, and entactins.[8]

Cell adhesion to the ECM[edit]

Many cells bind to components of the extracellular matrix. Cell adhesion can occur in two ways; by focal adhesions, connecting the ECM to actin filaments of the cell, and hemidesmosomes, connecting the ECM to intermediate filaments such as keratin. This cell-to-ECM adhesion is regulated by specific cell-surface cellular adhesion molecules (CAM) known as integrins. Integrins are cell-surface proteins that bind cells to ECM structures, such as fibronectin and laminin, and also to integrin proteins on the surface of other cells.

Fibronectins bind to ECM macromolecules and facilitate their binding to transmembrane integrins. The attachment of fibronectin to the extracellular domain initiates intracellular signalling pathways as well as association with the cellular cytoskeleton via a set of adaptor molecules such as actin.[4]

Cell types involved in ECM formation[edit]

There are many cell types that contribute to the development of the various types of extracellular matrix found in plethora of tissue types. The local components of ECM determine the properties of the connective tissue.

Fibroblasts are the most common cell type in connective tissue ECM, in which they synthesize, maintain, and provide a structural framework; fibroblasts secrete the precursor components of the ECM, including the ground substance. Chondrocytes are found in cartilage and produce the cartilagenous matrix. Osteoblasts are responsible for bone formation.

Extracellular matrix in plants[edit]

Plant cells are tessellated to form tissues. The cell wall is the relatively rigid structure surrounding the plant cell. The cell wall provides lateral strength to resist osmotic turgor pressure, but it is flexible enough to allow cell growth when needed; it also serves as a medium for intercellular communication. The cell wall comprises multiple laminate layers of cellulose microfibrils embedded in a matrix of glycoproteins, including hemicellulose, pectin, and extensin. The components of the glycoprotein matrix help cell walls of adjacent plant cells to bind to each other. The selective permeability of the cell wall is chiefly governed by pectins in the glycoprotein matrix. Plasmodesmata (singular: plasmodesma) are pores that traverse the cell walls of adjacent plant cells. These channels are tightly regulated and selectively allow molecules of specific sizes to pass between cells.[12]

Medical applications[edit]

Extracellular matrix cells have been found to cause regrowth and healing of tissue. In human fetuses, for example, the extracellular matrix works with stem cells to grow and regrow all parts of the human body, and fetuses can regrow anything that gets damaged in the womb. Scientists have long believed that the matrix stops functioning after full development. It has been used in the past to help horses heal torn ligaments, but it is being researched further as a device for tissue regeneration in humans.[17]

In terms of injury repair and tissue engineering, the extracellular matrix serves two main purposes. First, it prevents the immune system from triggering from the injury and responding with inflammation and scar tissue. Next, it facilitates the surrounding cells to repair the tissue instead of forming scar tissue.[17]

For medical applications, the cells required are usually extracted from pig bladders, an easily accessible and relatively unused source. It is currently being used regularly to treat ulcers by closing the hole in the tissue that lines the stomach, but further research is currently being done by many universities as well as the U.S. Government for wounded soldier applications. As of early 2007, testing was being carried out on a military base in Texas. Scientists are using a powdered form on Iraq War veterans whose hands were damaged in the war.[18]

Not all ECM devices come from the bladder. Extracellular matrix coming from pig small intestine submucosa are being used to repair "atrial septal defects" (ASD), "patent foramen ovale" (PFO) and inguinal hernia. After one year 95% of the collagen ECM in these patches is replaced by the normal soft tissue of the heart.[19]

Extracellular matrix proteins are commonly used in cell culture systems to maintain stem and precursor cells in an undifferentiated state during cell culture and function to induce differentiation of epithelial, endothelial and smooth muscle cells in vitro. Extracellular matrix proteins can also be used to support 3D cell culture in vitro for modelling tumor development.[20]

A class of biomaterials derived from processing human or animal tissues to retain portions of the extracellular matrix are called ECM Biomaterial.

References[edit]

  1. ^ Michel, Gurvan; Thierry Tonon; Delphine Scornet; J. Mark Cock; Bernard Kloareg (October 2010). "The cell wall polysaccharide metabolism of the brown alga Ectocarpus siliculosus. Insights into the evolution of extracellular matrix polysaccharides in Eukaryotes". New Phytologist 188 (1): 82–97. doi:10.1111/j.1469-8137.2010.03374.x. 
  2. ^ Abedin, Monika; Nicole King (December 2010). "Diverse evolutionary paths to cell adhesion". Trends in Cell Biology 20 (12): 734–742. doi:10.1016/j.tcb.2010.08.002. PMC 2991404. 
  3. ^ a b c Kumar; Abbas; Fausto. Robbins and Cotran: Pathologic Basis of Disease (7th ed.). Philadelphia: Elsevier. ISBN 0-7216-0187-1. 
  4. ^ a b Alberts B, Bray D, Hopin K, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2004). "Tissues and Cancer". Essential cell biology. New York and London: Garland Science. ISBN 0-8153-3481-8. 
  5. ^ Brownlee, Colin (October 2002). "Role of the extracellular matrix in cell-cell signalling: paracrine paradigms". Current Option in Plant Biology 5 (5): 396–401. doi:10.1016/S1369-5266(02)00286-8. 
  6. ^ Kostakioti, Maria (2013). "Bacterial Biofilms: Development, Dispersal, and Therapeutic Strategies in the Dawn of the Postantibiotic Era". Cold Spring Harbor Perspectives in Medicine. 
  7. ^ Liotta LA, Tryggvason K, Garbisa S, Hart I, Foltz CM, Shafie S (1980). "Metastatic potential correlates with enzymatic degradation of basement membrane collagen". Nature 284 (5751): 67–68. doi:10.1038/284067a0. PMID 6243750. Closed access
  8. ^ a b c d e Plopper G (2007). The extracellular matrix and cell adhesion, in Cells (eds Lewin B, Cassimeris L, Lingappa V, Plopper G). Sudbury, MA: Jones and Bartlett. ISBN 0-7637-3905-7. 
  9. ^ Gallagher, J.T., Lyon, M. (2000). "Molecular structure of Heparan Sulfate and interactions with growth factors and morphogens". In Iozzo, M, V. Proteoglycans: structure, biology and molecular interactions. Marcel Dekker Inc. New York, New York. pp. 27–59. ISBN 9780824703349. 
  10. ^ Iozzo, R. V. (1998). "Matrix proteoglycans: from molecular design to cellular function". Annu. Rev. Biochem. 67: 609–652. doi:10.1146/annurev.biochem.67.1.609. PMID 9759499. Closed access
  11. ^ Hensch TK (2005). "Critical period mechanisms in developing visual cortex". Curr. Top. Dev. Biol. 69: 215–237. doi:10.1016/S0070-2153(05)69008-4. PMID 16243601. Closed access
  12. ^ a b Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J. "Integrating Cells Into Tissues". Molecular Cell Biology (5th ed.). New York: WH Freeman and Company. pp. 197–234. 
  13. ^ Peach RJ, Hollenbaugh D, Stamenkovic I, Aruffo A (July 1993). "Identification of hyaluronic acid binding sites in the extracellular domain of CD44". J. Cell Biol. 122 (1): 257–264. doi:10.1083/jcb.122.1.257. PMC 2119597. PMID 8314845. open access publication - free to read
  14. ^ Di Lullo GA, Sweeney SM, Korkko J, Ala-Kokko L, San Antonio JD (2002). "Mapping the ligand-binding sites and disease-associated mutations on the most abundant protein in the human, type I collagen". J. Biol. Chem. 277 (6): 4223–4231. doi:10.1074/jbc.M110709200. PMID 11704682. open access publication - free to read
  15. ^ Karsenty G, Park RW (1995). "Regulation of type I collagen genes expression". Int. Rev. Immunol. 12 (2–4): 177–185. doi:10.3109/08830189509056711. PMID 7650420. Closed access
  16. ^ Kern B, Shen J, Starbuck M, Karsenty G (2001). "Cbfa1 contributes to the osteoblast-specific expression of type I collagen genes". J. Biol. Chem. 276 (10): 7101–7107. doi:10.1074/jbc.M006215200. PMID 11106645. open access publication - free to read
  17. ^ a b 'Pixie dust' helps man grow new finger
  18. ^ HowStuffWorks, Humans Can Regrow Fingers? In 2009, the St. Francis Heart Center announced the use of the extracellular matrix technology in repair surgery.
  19. ^ "First Ever Implantation of Bioabsorbable Biostar Device at DHZB". DHZB NEWS. December 2007. Retrieved 2008-08-05. "The almost transparent collagen matrix consists of medically purified pig intestine, which is broken down by the scavenger cells (macrophages) of the immune system. After about 1 year the collagen has been almost completely (90-95%) replaced by normal body tissue: only the tiny metal framework remains. An entirely absorbable implant is currently under development." 
  20. ^ Kleinman, H.K.; L. Luckenbill-Edds1, F.W. Cannon, G.C. Sephel (October 1987). "Use of extracellularmatrix components for cell culture". Analytical Biochemistry 186 (1): 1–13. doi:10.1016/0003-2697(87)90538-0. Retrieved 2012-05-14. 

Further reading[edit]