In biology, the extracellular matrix is a collection of extracellular molecules secreted
by cells that provides structural and biochemical support to the 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 includes the interstitial matrix and the basement membrane.
Interstitial matrix is present between various animal cells.
Gels of polysaccharides 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 cells rest.
The plant ECM includes cell wall components, like cellulose, in addition to more complex
signaling molecules.
Some single-celled organisms adopt multicelluar biofilms in which the cells are embedded in
an ECM composed primarily of extracellular polymeric substances.
Role and importance 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.
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.
Molecular components 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 proteins and glycosaminoglycans.
Proteoglycans GAGs are carbohydrate polymers and are usually
attached to extracellular matrix proteins to form proteoglycans.
Proteoglycans have a net negative charge that attracts positively charged sodium ions, 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 Heparan sulfate is a linear polysaccharide
found in all animal tissues.
It occurs as a proteoglycan 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 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 Chondroitin sulfates contribute to the tensile
strength of cartilage, tendons, ligaments, and walls of the aorta.
They have also been known to affect neuroplasticity.
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, cartilage, bones, and the horns of animals.
Non-proteoglycan polysaccharide Hyaluronic acid
Hyaluronic acid 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 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, and tumor development.
It interacts with a specific transmembrane receptor, CD44.
Fibers Collagen
Collagens are the most abundant protein in the ECM.
In fact, collagen is the most abundant protein in the human body and 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, 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.
The collagen can be divided into several families according to the types of structure they form:
Fibrillar Facit
Short chain Basement membrane
Other Elastin
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.
Other Fibronectin
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.
Laminin 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.
Cell adhesion to the ECM 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
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.
Cell types involved in ECM formation 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 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 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.
Medical applications
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.
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.
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.
Not all ECM devices come from the bladder.
Extracellular matrix coming from pig small intestine submucosa are being used to repair
"atrial septal defects", "patent foramen ovale" and inguinal hernia.
After one year 95% of the collagen ECM in these patches is replaced by 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.
References
Further reading ANAT3231 Lecture 08 Extracellular Matrix - Lecture
about extracellular matrix from UNSW Cell Biology website.
Extracellular matrix: review of its roles in acute and chronic wounds
Usage of Extracellular Matrix from pigs to regrow human extremities
"The Extracellular Matrix of Animals", from Chapter 19 of The Molecular Biology of the
Cell, 4th edition, Alberts et al. Biology, John W. Kimball.
An online Biology textbook. [1], The man who grew a finger, By Matthew
Price, BBC news Sound Medicine - Heart Tissue Regeneration
- July 19 interview discussing ECM and its uses in cardiac tissue repair [broken link].
Growing Body Parts - A December 2009 report by 60 Minutes