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The Extracellular

Matrix (ECM)
Ika Murti Harini – Histology FK Unsoed
What is extracellular matrix ?
 Cells of multicellular organisms
congregate to form structural
and functional associations,
known as tissues
 all tissues are composed of
cells and an extracellular
matrix (ECM)
“Half of the secrets of the
cell are outside the cell.”
Dr. Mina Bissell
Oct. 17, 2007
Erlanger Auditorium
 the noncellular component
present within all tissues and
organs
 provides essential physical
scaffolding for the cellular
constituents
 initiates crucial biochemical
and biomechanical cues that
are required for tissue
morphogenesis, differentiation
and homeostasis
 Some tissues, such as epithelium, form sheets of cells with only a scant
amount of ECM.
 At the opposite extreme is connective tissue, composed mostly of ECM with a
limited number of cells scattered throughout the matrix.
 Cells maintain their associations with the ECM by forming specialized
junctions that hold them to the surrounding macromolecules
 Act as structural support to maintain cell organization and integrity
(epithelial tubes; mucosal lining of gut; skeletal muscle fiber integrity)
 Compartmentalize tissues (pancreas: islets vs. exocrine component;
skin: epidermis vs. dermis)
 Provide hardness to bone and teeth (collagen fibrils become mineralized)
 Present information to adjacent cells:
 Serve as a highway for cell migration during development (neural crest
migration), in normal tissue maintenance (intestinal mucosa), and in
injury or disease (wound healing; cancer)
The extracellular matrix is composed of three
major classes of biomolecules

1. Ground substance : an amorphous gel-like


material composed of glycosaminoglycans
(GAGs), proteoglycans, and glycoproteins
2. Structural proteins/fibers : the collagen, the
fibrillins, and elastin
3. Specialized proteins : the various integrins
and dystroglycans
 negatively charged, long, rod-like chains of repeating disaccharides that have the
capability of binding large quantities of water
 One of the two repeating disaccharides is always an amino sugar (N-
acetylglucosamine or N-acetylgalactosamine); the other typically is a uronic acid
(iduronic or glucuronic)

The repeating disaccharide sequence of a heparan sulfate glycosaminoglycan (GAG) chain


 located primarily on the surface of cells or in the
extracellular matrix but are also found in secretory
vesicles in some types of cells
 long with the high viscosity of GAGs comes low
compressibility, which makes these molecules ideal for a
lubricating fluid in the joints
 their rigidity provides structural integrity to cells and
provides passageways between cells, allowing for cell
migration
 When sulfated GAGs form covalent
bonds with a protein core, they form a
family of macromolecules known as
proteoglycans
 various sizes, ranging from about
50,000 Da (decorin and betaglycan) to
as many as 3 million Da (aggrecan)
 Many proteoglycans, especially
aggrecan, a macromolecule found in
cartilage and connective tissue proper,
attach to hyaluronic acid
 resist compression and retard the rapid movement of microorganisms and metastatic
cells
 facilitate normal cellular locomotion by permitting migrating cells to move into the
space that these hydrated macromolecules occupied
 in association with the basal lamina, they form molecular filters of varying pore sizes
and charge distributions that selectively screen and retard macromolecules as they
pass through them
 possess binding sites for certain signaling molecules, such as transforming growth
factor-β
 have binding sites for several components of the ECM of the cell membrane that
facilitate the attachment of cells to the ECM
 have several domains, at least one of which usually binds to cell surface proteins
called integrins, one to collagen fibers, and one to proteoglycans
 the major types of adhesive glycoproteins : fibronectin, laminin, entactin, tenascin,
chondronectin, and osteonectin
 a large glycoprotein found in all
vertebrates
 important for many cell-matrix
interactions
 extracellular protein that helps cells
attach to the matrix
 guide cell movements in developing
tissues, by serving as tracks along
which cells can migrate or as repellents
that keep cells out of forbidden area
Fibronectin is a dimer composed of two very large subunits joined
by disulfide bonds at one end
• a very large glycoprotein (950,000 Da)
• composed of three large polypeptide
chains, A, B1, and B2
• The location of laminin is almost
strictly limited to the basal lamina
• has binding sites for heparan sulfate,
type IV collagen, entactin, and the cell
membrane
 collagen
 elastic : elastin, fibrillin
 the most abundant proteins
 These 44 genes generate proteins
that combine in a variety of ways to
create over 28 different types of
collagen fibrils
 Types I, II and III collagens are the
most abundant and all three types
form fibrils of similar structure
 Collagens are predominantly
synthesized by fibroblasts
 epithelial cells are also responsible Figure 19-63 A fibroblast surrounded by collagen fibrils in the connective
for the synthesis of some of the tissue of embryonic chick skin
ECM collagen
The intracellular and extracellular events in the formation of a collagen fibril
 Many vertebrate tissues, such as skin,
blood vessels, and lungs, need to be both
strong and elastic in order to function
 A network of elastic fibers gives the
required resilience so that they can recoil
after transient stretch
 The main component of elastic fibers is
elastin
 Elastin is the dominant extracellular
matrix protein in arteries, comprising 50%
of the dry weight of the largest artery (the
aorta)
Elastic fibers

Figure 1 9-70 Elastic fibers. These


scanning electron micrographs show
(A) a low-power view of a segment of
a dog's aorta and (B) a high-power
view of the dense network of
longitudinally oriented elastic fibers in
the outer layer of the same blood
vessel. All the other components
have been digested away with
enzymes and formic acid. (From
K.S. Haas et al., AnaL Rec.230:86-
96, 1991. With permission from
Wiley-Liss)
Figure 4-9 Light micrograph of elastic
cartilage (×270). Note the presence
of elastic fibers (arrows) in the matrix.
The large chondrocytes of elastic
cartilage occupy spaces known as
lacunae in the proteoglycan-rich
matrix. The large bundles of elastic
fibers are clearly evident, and they
appear to be arranged in a
haphazard fashion. Observe that the
thicker elastic fibers are composed
of fine fibrils. C, chondrocyte; P,
perichondrium
Figure 19-71. Stretching a network of elastin
molecules. The molecules are joined together
by covalent bonds (red) to generate a cross-
linked network. In this model, each elastin
molecule in the network can extend and
contract in a manner resembling a random
coil, so that the entire assembly can stretch
and recoil like a rubber band
 The other major proteins in elastic fibers
 Humans express three fibrillin genes identified as FBN1, FBN2, and FBN3
 FBN1 expression is high in most cell types of mesenchymal origin,
particularly bone
 FBN2 expression is highest in fetal cells and has more restricted expression
in mesenchymal cell types postnatally
 FBN3 is expressed in embryonic and fetal tissues in human
 Specialized layers of extracellular matrix surrounding or
adjacent to all epithelia, endothelia, peripheral nerves, muscle
cells, and fat cells
 composed of the basal lamina and lamina reticularis
 the basal lamina elaborated by epithelial cells
 the lamina reticularis manufactured by cells of the connective
tissue
 Influence cell proliferation, differentiation, and migration
 Maintain cell polarization and organization, as well as tissue
structure
 Act as a filtration barrier in the kidney between the vasculature and
the urinary space
 Separate epithelia from the underlying
stroma/mesenchyme/interstitium, which contains a non-basement
membrane matrix
This section of kidney shows the typical
basement membranes (arrows) of several
tubules and of structures within the single
glomerulus included here. In renal
glomeruli the basement membrane,
besides having a supporting function, has
an important role as a filter. X100.
Picrosirius-hematoxylin (PSH).
An extracellular basal lamina always lies at the interface of
epithelial cells and connective tissue
 manufactured by the epithelium
 composed of the lamina lucida and the lamina densa
 The lamina lucida consists mainly of the extracellular glycoproteins laminin
and entactin
 The lamina densa comprises a meshwork of type IV collagen
 derived from the connective tissue component
 responsible for affixing the lamina densa to the underlying connective tissue
 manufactured by fibroblasts and is composed of type I and type III collagen
 the interface between the basal lamina and the underlying connective tissue,
and its thickness varies with the amount of frictional force on the overlying
epithelium
• transmembrane proteins that are similar to cell membrane receptors in
that they form bonds with ligands
• unlike those of receptors, their cytoplasmic regions are linked to the
cytoskeleton
• their ligands are not signaling molecules but structural members of the
ECM such as collagen, laminin, and fibronectin
• the association between an integrin and its ligand is much weaker than
that between a receptor and its ligand
• Many integrins differ in their ligand specificity, cellular distribution, and
function
• integrins function : transducing biochemical signals into intracellular
events by activating second messenger system cascades
 glycoproteins that are composed of two subunits, a transmembrane β-dystroglycan
and an extracellular α-dystroglycan
 The α-dystroglycan binds to the laminin of the basal lamina but at different sites
than does the integrin molecule
 The intracellular moiety of the β-dystroglycan binds to the actin-binding protein
dystrophin, which, in turn, binds to α-actinin of the cytoskeleton
 Dystroglycans and integrins have significant roles in the assembly of basal laminae
because embryos lacking either or both of these glycoproteins are unable to form
normal basal laminae
Nice to know

 Caused by dominant
Fibrillin-1 (FBN1)
mutations
 Skeletal, ocular, and
cardiovascular defects
 Deficiency of elastin-
associated microfibrils
Nice to know

 Damage to the lung air sacs


(alveoli) that affects breathing
 Macrophages induced to “ingest”
particles in smoke also secrete
proteases that degrade elastic
fibers
 Loss of lung elasticity makes
exhalation difficult
 Increased alveolar size reduces the
surface area for gas exchange
Nice to know

Clinical:
Ranges in severity from mild to perinatal lethal
bone fragility, short stature, bone deformities, teeth
abnormalities, gray-blue sclerae, hearing loss
Biochemical:
reduced and/or abnormal type I collagen
Nice to know

 Liver spots on skin, spongy


gums, bleeding from mucous
membranes, depression,
immobility
 Vitamin C deficiency
 Ascorbate is required for prolyl
hydroxylase and lysyl
hydroxylase activities
 Acquired disease of fibrillar
collagen
Illustration from Man-of-War by Stephen Biesty (Dorling-Kindersley, NY, 1993)