The Extracellular Matrix
(ECM)
Sashwati Roy, PhD
Associate Professor
Department of Surgery
Learning Objectives
Describe
Determine
Describe
At the end of this module,
you will learn to:
• the composition of the extracellular
matrix and its function.
• the role and significance of insoluble
and soluble components of ECM
• the clinical implication of ECM in
tissue repair
Extracellular matrix (ECM)
• Network of proteins and carbohydrates
that binds cells together
• Supports and surrounds cells
• Regulates cells activities
• Lattice for cell movement
Cells surrounded by spaces filled with
extracellular matrix
(Molecular Biology of the Cell. 4th edition.
Alberts B, Johnson A, Lewis J, et al.
New York: Garland Science; 2002)
ECM key functions
• Mechanical support
• Embryonic
development
• Pathways for cellular
migration
• Wound healing
• Management of growth
factors
Class of macromolecules that form the ECM
Insoluble
components
• (fibrous
proteins:
Collagen,
Elastic fibers,
Fibronectin,
Laminin
Soluble
components• polysaccharide
chains Proteoglycans,
Hyaluronan,
Adhesive
glycoproteins
INSOLUBLE COMPONENTS
1.Collagen
2.Elastic fibers
3.Fibronectin
4.Laminin
Collagen
Collagen is
strong,
resisting
tensile forces
(in
abundance in
the Achilles
heel)
Major
insoluble
fibrous
protein of the
extracellular
matrix and
connective
tissue
Most
abundant
protein in
animals
Made by
fibroblasts
and some
epithelial
cells
Collagen –structure
Crystal Structure of The Collagen Triple
Helix Model Pro- Pro-Gly103 04
Crystal structure of the collagen triple helix
model [(Pro-Pro-Gly)10]3. Protein Sci.
2002 February; 11(2): 262–270.
Types of collagen
Fibrillar
• Forms
structures
such as
tendon or
cartilage
Connecting
Sheet
forming
• Supports and
organizes
fibrous
collagen
Transmembrane
Fibrillar Collagen
Fibrillar collagen
are components
of the well-known
striated fibrils
The fibrillar
collagen family
includes types IIII, V and XI
Sheet forming collagen
Polymerizes into
sheets
Forms basal
membranes –
collagen IV
Collagen VIII –
Descemet’s
membrane of
cornea
Connecting collagens
Link fibrillar and
sheet forming
collagens to into
networks and
connect them to
other structures
Collagen VI –
short helices
interspersed with
globular domains
Align collagen I
into parallel
structures
Role of Collagen in Wound healing
(Collagen is a key component of a healing wound)
• Collagens serve as a structural support
• Recent evidences indicate that collagen
and collagen-derived fragments control
many cellular functions, including cell
shape and differentiation, migration, and
synthesis of proteins
Collagen-based Wound Dressings
•
•
•
•
are a number of different collagen dressings available.
are purified in order to render it non-antigenic.
can vary in concentration and type.
may contain ingredients, that can enhance absorbency,
flexibility, and comfort, and help maintain a moist wound
environment.
• are meant to enhance the wound management aspects of
the dressings.
Collagenbased wound
dressings
By: David Brett, Wounds, 2009
Collagen Degradation
MMP-1
• Proteinase resistant
triple helix
• Cleaved by
collagenase (MMP-1)
Matrix Metalloproteinases
J. Cell. Mol. Med. Vol 9, No 2, 2005 pp. 267-285
"Tissue" Proteinases
• Epidermis
– collagenase (MMP-1)
– stromelysin-1,2 (MMP-3,10)
– plasminogen activator (urokinase type)
• Mesenchyme
–
–
–
–
–
collagenase (MMP-1)
stromelysin 1 (MMP-3)
72kDa gelatinase (MMP-2)
92kDa gelatinase (MMP-9)
plasminogen activator (uPA)
MMP Biology
• MMPs secreted as zymogens
• Complex activation pathways
• Counteraction by Tissue Inhibitors
of Metalloproteinases (TIMPs)
Cell-associated MMPs and their target substrates that modulate
cell motility.
MMP Activation in Epithelial Repair
• Injury exposes epithelia to a new ECM
environment - collagen I/fibrin/fibronectin
• Migration on to these substrates requires
– Regprogramming of matrix receptors (integrins)
– Loss of intercellular contacts
– Activation of MMP pathways
Granulocyte Proteinases
• Serine proteinases
– elastase
– cathepsin G
– proteinase 3
– azurocidin
– neutrophil collagenase (MMP-8)
Macrophage proteinases
– collagenase (MMP-1)
– metalloelastase (MMP-12)
Modulators of Proteinase Activity
•
•
•
•
•
•
Serpins
Maspins
TIMP's
SLPI
a-2 macroglobulin
PAI-1
Insoluble components
1.Collagen
2.Elastic fibers
3.Fibronectin
4.Laminin
Elastic fibers
A network of elastic fibers in the extracellular matrix of the tissue
gives it the required resilience so that they can recoil after
transient stretch
Elastic fibers. These scanning electron micrographs show (A) a lowpower 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.
Elastic fibers
Elastin
•
•
•
is unusually rich in proline and glycine
is not glycosylated
contains some hydroxy-proline has no
hydroxylysine.
Soluble tropoelastin (the biosynthetic precursor of
elastin)
Elastin
•
The molecules are joined
together by covalent bonds
(red) to generate a crosslinked network.
•
In this model, each elastin
molecule in the network can
expand and contract as a
random coil, so that the
entire assembly can stretch
and recoil like a rubber
band.
Elastin
Rich in
hydrophobic
amino acids
Synthesized
as soluble
tropoelastin
Crosslinked
by lysyl
oxidase
Diseases of connective Tissue
Cutis laxa (CL), or
elastolysis. is a group of rare
connective tissue disorders in
which the skin becomes inelastic
and hangs loosely in folds.
Marfan syndrome. a genetic
disorder of the connective tissue.
The syndrome is carried by the
gene FBN1, which encodes the
connective protein fibrillin-1.
Ehlers–Danlos syndrome
(EDS) is an inherited
connective tissue disorder
caused by a defect in the
synthesis of collagen, specifically
mutations in the COL5A and
COL3A genes.
Insoluble components
1. Collagen
2. Elastic fibers
3. Fibronectin
4. Laminin
Fibronectin
a dimer
composed of two
very large
subunits joined
by disulfide
bonds at one end
Each subunit is
folded into a
series of
functionally
distinct domains
All forms of
fibronectin are
encoded
Fibronectin binds
integrins.
The structure of a fibronectin dimer
Molecular Biology of
the Cell. 4th edition.
Alberts B, Johnson A,
Lewis J, et al.
New York: Garland
Science; 2002)
Fibronectin
secreted
primarily by
fibroblasts
cell adhesion,
growth,
migration, and
differentiation
important for
wound
healing
cancer and
fibrosis
Insoluble components
1. Collagen
2. Elastic fibers
3. Fibronectin
4. Laminin
Laminin
Molecular Biology of the Cell. 4th edition.
Alberts B, Johnson A, Lewis J, et al.
New York: Garland Science; 2002)
Laminin modulation during wound repair
Reduced laminin-322
levels has been
associated with poor
keratinocyte
migration
Hemidesmosomes
bind to laminin in the
basal lamina
During wound
healing, laminin-5 is
expressed by
keratinocytes
The epidermal
growth factor-like
repeats in laminin
are examples of
matrikines.
Soluble components of extracellular
matrix
• polysaccharide chains of the class
called glycosaminoglycans (GAG),
which are usually found covalently
linked to protein in the form of
proteoglycans
Glycosaminoglycan (GAG)
Molecular Biology of the Cell. 4th edition.
Alberts B, Johnson A, Lewis J, et al.
New York: Garland Science; 2002)
Figure. The repeating disaccharide sequence of a dermatan sulfate
glycosaminoglycan (GAG) chain.
Glycosaminoglycan (GAG)
Hyaluronan
chondroitin
sulfate and
dermatan
sulfate
heparan
sulfate
keratan
sulfate
Hyaluronan is a polysaccharide
The relative dimensions
and volumes occupied
by various proteins, a
glycogen granule, and
a single hydrated
molecule of hyaluronan
are shown.
Proteoglycans
Molecular Biology of the Cell. 4th edition.
Alberts B, Johnson A, Lewis J, et al.
New York: Garland Science; 2002)
Examples of proteoglycans
Molecular Biology of the Cell. 4th edition. Alberts B, Johnson A, Lewis J,
et al. New York: Garland Science; 2002)
SUMMARY
•
•
•
•
•
•
•
ECM are network of proteins and carbohydrates that binds cells
together.
ECM is required for mechanical support, embryonic development,
pathways for cellular migration, wound healing and management of
growth factors
ECM is composed of insoluble and soluble macromolecules
Insoluble components involve: collagen, elastic fibers, fibronectin
and laminin
The soluble components involve polysaccharide chains of the class
called glycosaminoglycans (GAG), which are usually found
covalently linked to protein in the form of proteoglycans
The inheritable ECM disorders in human are Marfan syndrome,
Ehlers-Danlos syndrome, venous malformation etc.
Other ECM disorders include cancer, fibrosis, scleroderma etc,
Learning Resources
1. The Molecular and Cellular Biology of Wound
Repair, edited by R.A.F. Clark, Plenum Press,
NY
2. The Extracellular Matrix of Animals.
Molecular Biology of the Cell. 4th edition.
New York: Garland Science; 2002.
Thank you for completing this module.
Questions? Sashwati.Roy@osumc.edu
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