In
biology
Biology is the scientific study of life and living organisms. It is a broad natural science that encompasses a wide range of fields and unifying principles that explain the structure, function, growth, History of life, origin, evolution, and ...
, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of
extracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
macromolecule
A macromolecule is a "molecule of high relative molecular mass, the structure of which essentially comprises the multiple repetition of units derived, actually or conceptually, from molecules of low relative molecular mass." Polymers are physi ...
s and minerals, such as
collagen
Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
,
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
s,
glycoprotein
Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...
s and
hydroxyapatite
Hydroxyapatite (International Mineralogical Association, IMA name: hydroxylapatite) (Hap, HAp, or HA) is a naturally occurring mineral form of calcium apatite with the Chemical formula, formula , often written to denote that the Crystal struc ...
that provide structural and
biochemical
Biochemistry, or biological chemistry, is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology, ...
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.
The animal extracellular
matrix
Matrix (: matrices or matrixes) or MATRIX may refer to:
Science and mathematics
* Matrix (mathematics), a rectangular array of numbers, symbols or expressions
* Matrix (logic), part of a formula in prenex normal form
* Matrix (biology), the m ...
includes the interstitial matrix and the
basement membrane
The basement membrane, also known as base membrane, is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between epithelial tis ...
.
Interstitial matrix is present between various animal cells (i.e., in the intercellular spaces). Gels of
polysaccharide
Polysaccharides (), or polycarbohydrates, are the most abundant carbohydrates found in food. They are long-chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. This carbohydrate can react with wat ...
s and fibrous proteins fill the
interstitial space and act as a compression buffer against the stress placed on the ECM.
Basement membranes are sheet-like depositions of ECM on which various
epithelial
Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...
cells rest. Each type of
connective tissue
Connective tissue is one of the four primary types of animal tissue, a group of cells that are similar in structure, along with epithelial tissue, muscle tissue, and nervous tissue. It develops mostly from the mesenchyme, derived from the mesod ...
in animals has a type of ECM:
collagen
Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
fibers and
bone mineral
A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, an ...
comprise the ECM of
bone tissue
A bone is a Stiffness, rigid Organ (biology), organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red blood cell, red and white blood cells, store minerals, provi ...
;
reticular fibers and
ground substance
Ground substance is an amorphous gel-like substance in the extracellular space of animals that contains all components of the extracellular matrix (ECM) except for fibrous materials such as collagen and elastin. Ground substance is active in the d ...
comprise the ECM of
loose connective tissue
Loose connective tissue, also known as areolar tissue, is a cellular connective tissue with thin and relatively sparse collagen fibers. They have a semi-fluid matrix with lesser proportions of fibers. Its ground substance occupies more vol ...
; and
blood plasma
Blood plasma is a light Amber (color), amber-colored liquid component of blood in which blood cells are absent, but which contains Blood protein, proteins and other constituents of whole blood in Suspension (chemistry), suspension. It makes up ...
is the ECM of
blood
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells.
Blood is com ...
.
The plant ECM includes
cell wall
A cell wall is a structural layer that surrounds some Cell type, cell types, found immediately outside the cell membrane. It can be tough, flexible, and sometimes rigid. Primarily, it provides the cell with structural support, shape, protection, ...
components, like cellulose, in addition to more complex signaling molecules. Some single-celled organisms adopt multicellular
biofilms in which the cells are embedded in an ECM composed primarily of
extracellular polymeric substance
Extracellular polymeric substances (EPS) are biopolymer, natural polymers of molecular mass, high molecular weight secreted by microorganisms into their environment. EPS establish the functional and structural integrity of biofilms, and are consid ...
s (EPS).
Structure

Components of the ECM are produced intracellularly by resident cells and secreted into the ECM via
exocytosis.
Once secreted, they then aggregate with the existing matrix. The ECM is composed of an interlocking mesh of fibrous
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s and
glycosaminoglycans (GAGs).
Proteoglycans
Glycosaminoglycans (GAGs) are
carbohydrate
A carbohydrate () is a biomolecule composed of carbon (C), hydrogen (H), and oxygen (O) atoms. The typical hydrogen-to-oxygen atomic ratio is 2:1, analogous to that of water, and is represented by the empirical formula (where ''m'' and ''n'' ...
polymer
A polymer () is a chemical substance, substance or material that consists of very large molecules, or macromolecules, that are constituted by many repeat unit, repeating subunits derived from one or more species of monomers. Due to their br ...
s and mostly attached to extracellular matrix proteins to form
proteoglycan
Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a serine (Ser) residue to w ...
s (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
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...
within the ECM.
Described below are the different types of proteoglycan found within the extracellular matrix.
Heparan sulfate
Heparan sulfate
Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs in a proteoglycan (HSPG, i.e. Heparan Sulfate ProteoGlycan) in which two or three HS chains are attached in close proximity to cell surface or extracellular ma ...
(HS) is a linear
polysaccharide
Polysaccharides (), or polycarbohydrates, are the most abundant carbohydrates found in food. They are long-chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. This carbohydrate can react with wat ...
found in all animal tissues. It occurs as a
proteoglycan
Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a serine (Ser) residue to w ...
(PG) in which two or three HS chains are attached in close proximity to cell surface or ECM proteins. It is in this form that HS binds to a variety of protein
ligand
In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
s and regulates a wide variety of biological activities, including
developmental processes,
angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...
,
blood coagulation
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of coagulatio ...
, and tumour
metastasis
Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
.
In the extracellular matrix, especially
basement membrane
The basement membrane, also known as base membrane, is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between epithelial tis ...
s, the
multi-domain proteins
perlecan,
agrin, and
collagen XVIII are the main proteins to which heparan sulfate is attached.
Chondroitin sulfate
Chondroitin sulfate
Chondroitin sulfate is a sulfated glycosaminoglycan (GAG) composed of a chain of alternating sugars (N-Acetylgalactosamine, N-acetylgalactosamine and glucuronic acid). It is usually found attached to proteins as part of a proteoglycan. A chondroit ...
s contribute to the tensile strength of cartilage,
tendon
A tendon or sinew is a tough band of fibrous connective tissue, dense fibrous connective tissue that connects skeletal muscle, muscle to bone. It sends the mechanical forces of muscle contraction to the skeletal system, while withstanding tensi ...
s,
ligament
A ligament is a type of fibrous connective tissue in the body that connects bones to other bones. It also connects flight feathers to bones, in dinosaurs and birds. All 30,000 species of amniotes (land animals with internal bones) have liga ...
s, and walls of the
aorta
The aorta ( ; : aortas or aortae) is the main and largest artery in the human body, originating from the Ventricle (heart), left ventricle of the heart, branching upwards immediately after, and extending down to the abdomen, where it splits at ...
. They have also been known to affect
neuroplasticity
Neuroplasticity, also known as neural plasticity or just plasticity, is the ability of neural networks in the brain to change through neurogenesis, growth and reorganization. Neuroplasticity refers to the brain's ability to reorganize and rewir ...
.
Keratan sulfate
Keratan sulfates have a variable sulfate content and, unlike many other GAGs, do not contain
uronic acid. They are present in the
cornea
The cornea is the transparency (optics), transparent front part of the eyeball which covers the Iris (anatomy), iris, pupil, and Anterior chamber of eyeball, anterior chamber. Along with the anterior chamber and Lens (anatomy), lens, the cornea ...
, cartilage,
bone
A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...
s, and the
horns of
animal
Animals are multicellular, eukaryotic organisms in the Biology, biological Kingdom (biology), kingdom Animalia (). With few exceptions, animals heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, ...
s.
Non-proteoglycan polysaccharide
Hyaluronic acid
Hyaluronic acid
Hyaluronic acid (; abbreviated HA; conjugate base hyaluronate), also called hyaluronan, is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is unique among glycosaminog ...
(or "hyaluronan") is a
polysaccharide
Polysaccharides (), or polycarbohydrates, are the most abundant carbohydrates found in food. They are long-chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. This carbohydrate can react with wat ...
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
Turgor pressure is the force within the cell that pushes the plasma membrane against the cell wall.
It is also called ''hydrostatic pressure'', and is defined as the pressure in a fluid measured at a certain point within itself when at equilib ...
(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.
Hyaluronic acid acts as an environmental cue that regulates cell behavior during embryonic development, healing processes,
inflammation
Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
, and
tumor
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
development. It interacts with a specific transmembrane receptor,
CD44.
Proteins
Collagen
Collagen
Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
is the most abundant protein in the ECM, and is the most abundant protein in the human body. It accounts for 90% of bone matrix protein content. Collagens are present in the ECM as fibrillar proteins and give structural support to resident cells. Collagen is exocytosed in
precursor form (
procollagen
Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
), which is then cleaved by procollagen
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...
s to allow extracellular assembly. Disorders such as
Ehlers Danlos Syndrome,
osteogenesis imperfecta
Osteogenesis imperfecta (; OI), colloquially known as brittle bone disease, is a group of genetic disorders that all result in bones that bone fracture, break easily. The range of symptoms—on the skeleton as well as on the body's other Or ...
, and
epidermolysis bullosa are linked with
genetic defects in collagen-encoding
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
s.
[ The collagen can be divided into several families according to the types of structure they form:
# Fibrillar (Type I, II, III, V, XI)
# Facit (Type IX, XII, XIV)
# Short chain (Type VIII, X)
# Basement membrane (Type IV)
# Other (Type VI, VII, XIII)
]
Elastin
Elastin
Elastin is a protein encoded by the ''ELN'' gene in humans and several other animals. Elastin is a key component in the extracellular matrix of gnathostomes (jawed vertebrates). It is highly Elasticity (physics), elastic and present in connective ...
s, 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
Blood vessels are the tubular structures of a circulatory system that transport blood throughout many animals’ bodies. Blood vessels transport blood cells, nutrients, and oxygen to most of the tissues of a body. They also take waste an ...
, the lungs
The lungs are the primary organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the backbone on either side of the heart. Their function in the respiratory syste ...
, in skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other animal coverings, such as the arthropod exoskeleton, have different ...
, and the ligamentum nuchae, and these tissues contain high amounts of elastins. Elastins are synthesized by fibroblast
A fibroblast is a type of cell (biology), biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and ...
s and smooth muscle
Smooth muscle is one of the three major types of vertebrate muscle tissue, the others being skeletal and cardiac muscle. It can also be found in invertebrates and is controlled by the autonomic nervous system. It is non- striated, so-called bec ...
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
Williams syndrome (WS), also Williams–Beuren syndrome (WBS), is a genetic disorder that affects many parts of the body. Facial features frequently include a broad forehead, underdeveloped chin, short nose, and full cheeks. Mild to moderate int ...
are associated with deficient or absent elastin fibers in the ECM.[
]
Extracellular vesicles
In 2016, Huleihel et al., reported the presence of DNA, RNA, and Matrix-bound nanovesicles (MBVs) within ECM bioscaffolds. MBVs shape and size were found to be consistent with previously described exosomes. MBVs cargo includes different protein molecules, lipids, DNA, fragments, and miRNAs. Similar to ECM bioscaffolds, MBVs can modify the activation state of macrophages and alter different cellular properties such as; proliferation, migration and cell cycle. MBVs are now believed to be an integral and functional key component of ECM bioscaffolds.
Cell adhesion proteins
Fibronectin
Fibronectin
Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as col ...
s are glycoproteins
Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...
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
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
to facilitate 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 platelet
Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...
s during blood clotting
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a thrombus, blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of co ...
and facilitating cell movement to the affected area during wound healing.[
]
Laminin
Laminin
Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major constituents of the basement membrane, namely the basal lamina (the protein network foundation for most cells and organs). Laminins are vital to bi ...
s are proteins found in the basal lamina
The basal lamina is a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. It is often incorrectly referred to as the basement membrane, though it does constitute a portion of the basement membrane. The b ...
e 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 and nidogens.[
]
Development
There are many cell types that contribute to the development of the various types of extracellular matrix found in the plethora of tissue types. The local components of ECM determine the properties of the connective tissue.
Fibroblast
A fibroblast is a type of cell (biology), biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and ...
s 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
Ground substance is an amorphous gel-like substance in the extracellular space of animals that contains all components of the extracellular matrix (ECM) except for fibrous materials such as collagen and elastin. Ground substance is active in the d ...
. Chondrocytes are found in cartilage
Cartilage is a resilient and smooth type of connective tissue. Semi-transparent and non-porous, it is usually covered by a tough and fibrous membrane called perichondrium. In tetrapods, it covers and protects the ends of long bones at the joints ...
and produce the cartilaginous matrix. Osteoblast
Osteoblasts (from the Greek combining forms for " bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts fu ...
s are responsible for bone formation.
Physiology
Stiffness and elasticity
The ECM can exist in varying degrees of stiffness
Stiffness is the extent to which an object resists deformation in response to an applied force.
The complementary concept is flexibility or pliability: the more flexible an object is, the less stiff it is.
Calculations
The stiffness, k, of a ...
and elasticity, from soft brain tissues to hard bone tissues. The elasticity of the ECM can differ by several orders of magnitude. This property is primarily dependent on collagen
Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
and elastin
Elastin is a protein encoded by the ''ELN'' gene in humans and several other animals. Elastin is a key component in the extracellular matrix of gnathostomes (jawed vertebrates). It is highly Elasticity (physics), elastic and present in connective ...
concentrations,[ and it has recently been shown to play an influential role in regulating numerous cell functions.
Cells can sense the mechanical properties of their environment by applying forces and measuring the resulting backlash.] This plays an important role because it helps regulate many important cellular processes including cellular contraction, cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryogenesis, embryonic development, wound healing and immune system, immune responses all require the orchestrated movemen ...
, cell proliferation
Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation ...
, differentiation and cell death (apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
).
Inhibition of nonmuscle myosin II blocks most of these effects, indicating that they are indeed tied to sensing the mechanical properties of the ECM, which has become a new focus in research during the past decade.
Effect on gene expression
Differing mechanical properties in ECM exert effects on both cell behaviour and gene expression
Gene expression is the process (including its Regulation of gene expression, regulation) by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA, ...
. Although the mechanism by which this is done has not been thoroughly explained, adhesion complexes and the actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ...
-myosin
Myosins () are a Protein family, family of motor proteins (though most often protein complexes) best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are adenosine triphosphate, ATP- ...
cytoskeleton
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
, whose contractile forces are transmitted through transcellular structures are thought to play key roles in the yet to be discovered molecular pathways.
Effect on differentiation
ECM elasticity can direct cellular differentiation
Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellula ...
, the process by which a cell changes from one cell type to another. In particular, naive mesenchymal stem cells
Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells or medicinal signaling cells, are multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage ...
(MSCs) have been shown to specify lineage and commit to phenotypes with extreme sensitivity to tissue-level elasticity. MSCs placed on soft matrices that mimic the brain differentiate into neuron
A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
-like cells, showing similar shape, RNAi profiles, cytoskeletal markers, and transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
levels. Similarly stiffer matrices that mimic muscle are myogenic, and matrices with stiffnesses that mimic collagenous bone are osteogenic.
Durotaxis
Stiffness and elasticity also guide cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryogenesis, embryonic development, wound healing and immune system, immune responses all require the orchestrated movemen ...
, this process is called durotaxis. The term was coined by Lo CM and colleagues when they discovered the tendency of single cells to migrate up rigidity gradients (towards more stiff substrates) and has been extensively studied since. The molecular mechanisms behind durotaxis are thought to exist primarily in the focal adhesion
In cell biology, focal adhesions (also cell–matrix adhesions or FAs) are large macromolecular assemblies through which mechanical force and regulatory signals are transmitted between the extracellular matrix (ECM) and an interacting Cell (biolo ...
, a large protein complex
A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multidomain enzymes, in which multiple active site, catalytic domains are found in a single polypeptide chain.
...
that acts as the primary site of contact between the cell and the ECM. This complex contains many proteins that are essential to durotaxis including structural anchoring proteins (integrins
Integrins are transmembrane receptors that help cell–cell and cell– extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
) and signaling proteins (adhesion kinase ( FAK), talin, vinculin, paxillin, α-actinin, GTPases etc.) which cause changes in cell shape and actomyosin contractility. These changes are thought to cause cytoskeletal
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all Cell (biology), cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane ...
rearrangements in order to facilitate directional migration
Migration, migratory, or migrate may refer to: Human migration
* Human migration, physical movement by humans from one region to another
** International migration, when peoples cross state boundaries and stay in the host state for some minimum le ...
.
Function
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 factor
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for ...
s and acts as a local store for them. Changes in physiological conditions can trigger protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...
activities that cause local release of such stores. This allows the rapid 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
Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue.
In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier again ...
, and fibrosis. An understanding of ECM structure and composition also helps in comprehending the complex dynamics of tumor
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
invasion and metastasis
Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
in cancer biology as metastasis often involves the destruction of extracellular matrix by enzymes such as serine protease
Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site.
They are found ubiquitously in both eukaryotes and prokaryotes. Serin ...
s, threonine proteases, and matrix metalloproteinases.
The stiffness
Stiffness is the extent to which an object resists deformation in response to an applied force.
The complementary concept is flexibility or pliability: the more flexible an object is, the less stiff it is.
Calculations
The stiffness, k, of a ...
and elasticity of the ECM has important implications in cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryogenesis, embryonic development, wound healing and immune system, immune responses all require the orchestrated movemen ...
, gene expression, and differentiation. Cells actively sense ECM rigidity and migrate preferentially towards stiffer surfaces in a phenomenon called durotaxis. They also detect elasticity and adjust their gene expression accordingly, which has increasingly become a subject of research because of its impact on differentiation and cancer progression.
In the brain, hyaluronan
Hyaluronic acid (; abbreviated HA; conjugate acid, conjugate base hyaluronate), also called hyaluronan, is an anion#Anions and cations, anionic, Sulfation, nonsulfated glycosaminoglycan distributed widely throughout connective tissue, connective ...
serves as the primary component of the extracellular matrix, contributing to both structural integrity and signaling functions. High-molecular-weight hyaluronan forms a diffusional barrier that regulates local extracellular diffusion. When the ECM undergoes degradation, hyaluronan fragments are released into the extracellular space, where they act as pro-inflammatory molecules, influencing immune cell responses, including those of microglia
Microglia are a type of glia, glial cell located throughout the brain and spinal cord of the central nervous system (CNS). Microglia account for about around 5–10% of cells found within the brain. As the resident macrophage cells, they act as t ...
.
Cell adhesion
Many cells bind to components of the extracellular matrix. Cell adhesion can occur in two ways; by focal adhesions, connecting the ECM to actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ...
filaments of the cell, and hemidesmosomes, connecting the ECM to intermediate filaments such as keratin
Keratin () is one of a family of structural fibrous proteins also known as ''scleroproteins''. It is the key structural material making up Scale (anatomy), scales, hair, Nail (anatomy), nails, feathers, horn (anatomy), horns, claws, Hoof, hoove ...
. This cell-to-ECM adhesion is regulated by specific cell-surface cellular adhesion molecules (CAM) known as integrins
Integrins are transmembrane receptors that help cell–cell and cell– extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
. 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
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ...
.[
]
Clinical significance
Extracellular matrix has been found to cause regrowth and healing of tissue. Although the mechanism of action by which extracellular matrix promotes constructive remodeling of tissue is still unknown, researchers now believe that Matrix-bound nanovesicles (MBVs) are a key player in the healing process. 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.['Pixie dust' helps man grow new finger](_blank)
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In terms of injury repair and tissue engineering
Tissue engineering is a biomedical engineering discipline that uses a combination of cells, engineering, materials methods, and suitable biochemical and physicochemical factors to restore, maintain, improve, or replace different types of biolo ...
, 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.
For medical applications, the required ECM is 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.
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
An inguinal hernia or groin hernia is a hernia (protrusion) of abdominal cavity contents through the inguinal canal. Symptoms, which may include pain or discomfort especially with or following coughing, exercise, or bowel movements, are absen ...
. After one year, 95% of the collagen ECM in these patches has been replaced by the body with the normal soft tissue of the heart.
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.
A class of biomaterials derived from processing human or animal tissues to retain portions of the extracellular matrix are called ECM Biomaterial.
In plants
Plant
Plants are the eukaryotes that form the Kingdom (biology), kingdom Plantae; they are predominantly Photosynthesis, photosynthetic. This means that they obtain their energy from sunlight, using chloroplasts derived from endosymbiosis with c ...
cells are tessellated to form tissues. The cell wall
A cell wall is a structural layer that surrounds some Cell type, cell types, found immediately outside the cell membrane. It can be tough, flexible, and sometimes rigid. Primarily, it provides the cell with structural support, shape, protection, ...
is the relatively rigid structure surrounding the plant cell
Plant cells are the cells present in Viridiplantae, green plants, photosynthetic eukaryotes of the kingdom Plantae. Their distinctive features include primary cell walls containing cellulose, hemicelluloses and pectin, the presence of plastids ...
. The cell wall provides lateral strength to resist osmotic turgor pressure
Turgor pressure is the force within the cell that pushes the plasma membrane against the cell wall.
It is also called ''hydrostatic pressure'', and is defined as the pressure in a fluid measured at a certain point within itself when at equilibri ...
, 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
Cellulose is an organic compound with the chemical formula, formula , a polysaccharide consisting of a linear chain of several hundred to many thousands of glycosidic bond, β(1→4) linked glucose, D-glucose units. Cellulose is an important s ...
microfibrils embedded in a matrix
Matrix (: matrices or matrixes) or MATRIX may refer to:
Science and mathematics
* Matrix (mathematics), a rectangular array of numbers, symbols or expressions
* Matrix (logic), part of a formula in prenex normal form
* Matrix (biology), the m ...
of glycoproteins
Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...
, including hemicellulose
A hemicellulose (also known as polyose) is one of a number of heteropolymers (matrix polysaccharides), such as arabinoxylans, present along with cellulose in almost all embryophyte, terrestrial plant cell walls. Cellulose is crystalline, strong, an ...
, pectin
Pectin ( ': "congealed" and "curdled") is a heteropolysaccharide, a structural polymer contained in the primary lamella, in the middle lamella, and in the cell walls of terrestrial plants. The principal chemical component of pectin is galact ...
, and extensin. The components of the glycoprotein matrix help cell walls of adjacent plant cells to bind to each other. The selective permeability
Semipermeable membrane is a type of synthetic or biologic, polymeric membrane that allows certain molecules or ions to pass through it by osmosis. The rate of passage depends on the pressure, concentration, and temperature of the molecules o ...
of the cell wall is chiefly governed by pectins in the glycoprotein matrix. Plasmodesmata
Plasmodesmata (singular: plasmodesma) are microscopic channels which traverse the cell walls of plant cells and some algal cells, enabling transport and communication between them. Plasmodesmata evolved independently in several lineages, and spe ...
(''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.[
]
In Pluriformea and Filozoa
The extracellular matrix functionality of animals (Metazoa) developed in the common ancestor of the Pluriformea and Filozoa, after the Ichthyosporea diverged.
History
The importance of the extracellular matrix has long been recognized (Lewis, 1922), but the usage of the term is more recent (Gospodarowicz et al., 1979).
See also
* Anoikis
* Interstitium
* Perineuronal net
Perineuronal nets (PNNs) are specialized extracellular matrix structures responsible for synaptic stabilization in the adult brain. PNNs are found around certain neuron cell bodies and proximal neurites in the central nervous system. PNNs play ...
* Temporal feedback
References
Further reading
Extracellular matrix: review of its roles in acute and chronic wounds
* ttps://web.archive.org/web/20110719215952/http://soundmedicine.iu.edu/segment.php4?seg=2108 Sound Medicine - Heart Tissue Regeneration- July 19 interview discussing ECM and its uses in cardiac tissue repair (requires MP3 playback).
{{DEFAULTSORT:Extracellular Matrix
Matrices (biology)
Tissues (biology)