Extracellular Matrix (ECM)
Introduction
The Extracellular Matrix (ECM) is a vital protein network that constitutes a significant proportion of any
tissue and is far more than a simple "space filler" around cells. Cell interactions with the ECM are critical
for development, healing, and the maintenance of normal tissue architecture. The ECM is also constantly
being remodeled, with its synthesis and degradation accompanying processes like morphogenesis, tissue
regeneration and repair, chronic fibrosis, and even tumor invasion and metastasis.
Functions of the Extracellular Matrix
The ECM performs several crucial functions:
Mechanical Support
Provides mechanical support for cell anchorage
Facilitates cell migration
Maintains cell polarity
Regulation of Cell Proliferation
Regulates cell proliferation by binding and displaying growth factors
Signals via cellular integrin family receptors
Serves as a depot for latent growth factors that can be activated within sites of injury or
inflammation
Scaffolding for Tissue Renewal
Provides essential scaffolding for tissue renewal
The integrity of the basement membrane or stromal scaffolds of parenchymal cells is critical for
organized tissue regeneration
Disruption of the ECM can prevent effective tissue regeneration and repair
Foundation for Tissue Microenvironments
The basement membrane acts as a boundary between epithelium and underlying connective tissue
In organs like the kidney, forms part of the crucial filtration apparatus
Establishes specific tissue microenvironments
Forms of the Extracellular Matrix
The ECM exists in two basic forms:
1. Interstitial Matrix
Location
Occupies spaces between stromal cells within connective tissue
Found between parenchymal epithelium and underlying supportive vascular and smooth muscle
structures in certain organs
Synthesis
Primarily synthesized by mesenchymal cells, such as fibroblasts
Structure
Forms a three-dimensional, relatively amorphous, semi-fluid gel
In some tissues (e.g., gastrointestinal tract, urinary bladder), the fluid within the matrix helps cushion
tissue compression associated with bodily functions like peristalsis
Major Constituents
Fibrillar and nonfibrillar collagens
Fibronectin
Elastin
Proteoglycans
Hyaluronate
2. Basement Membrane
Location
Interstitial matrix becomes highly organized around:
Epithelial cells
Endothelial cells
Smooth muscle cells
Forms specialized surfaces essential for cell growth
Synthesis
Basement membrane components are synthesized by both:
The overlying epithelium
The underlying mesenchymal cells
Structure
Forms a flat lamellar mesh
Despite being called a "membrane," it is quite porous
Major Constituents
Nonfibrillar type IV collagen
Laminin
Components of the Extracellular Matrix
ECM components are broadly classified into three families:
1. Fibrous Structural Proteins
These confer tensile strength and elastic recoil to tissues.
Collagens
Basic Structure
Composed of three separate polypeptide chains braided into a ropelike triple helix
About 30 identified collagen types, some unique to specific cells and tissues
Fibrillar Collagens (Types I, II, III, and V)
Form linear fibrils stabilized by interchain hydrogen bonding
Major components of connective tissue in:
Bone
Tendon
Cartilage
Blood vessels
Skin
Healing wounds and scars
Tensile strength: Comes from lateral cross-linking of triple helices via covalent bonds following lysine
hydroxylation
Enzyme dependency: Lysyl hydroxylase is dependent on vitamin C
Clinical Significance of Vitamin C
Vitamin C deficiency leads to:
Skeletal deformities
Poor wound healing
Easy bleeding
Genetic defects in collagen or lysyl hydroxylase mutations cause:
Osteogenesis imperfecta
Ehlers-Danlos syndrome
Nonfibrillar Collagens
Type IV collagen: Contributes to planar basement membranes
Type IX collagen: A FACIT (fibril-associated collagen with interrupted triple helices) in cartilage
Regulates fibril diameters and interactions
Type VII collagen: Provides anchoring fibrils for stratified squamous epithelium
Mutations lead to blistering skin diseases
Elastin
Function
Confers the ability for tissues to elastically recoil and return to baseline structure after physical stress
Crucial in tissues that accommodate recurrent pulsatile flow:
Cardiac valves
Large blood vessels
Uterus
Skin
Ligaments
Structure
Elastic fibers consist of a central core of elastin associated with a mesh-like network of fibrillin
glycoprotein
Clinical Relevance
Marfan syndrome: Defects in fibrillin synthesis lead to:
Skeletal abnormalities
Weakened aortic walls
Fibrillin also controls the availability of free TGF-β, contributing to Marfan syndrome pathogenesis
2. Water-Hydrated Gels
These permit compressive resistance and lubrication.
Proteoglycans and Hyaluronan
Structure
Proteoglycans composed of long polysaccharides called glycosaminoglycans:
Keratan sulfate
Chondroitin sulfate
Attached to a core protein
Linked to a long hyaluronic acid polymer (hyaluronan)
Resembles bristles on a round brush
Function
Highly negatively charged sulfated sugars attract cations (like sodium)
With cations comes abundant osmotically attracted water
Creates a viscous, gel-like matrix
Provides compressibility to tissues (e.g., joint cartilage for lubrication between bony surfaces)
Role as Growth Factor Reservoirs
Serve as reservoirs for growth factors (e.g., FGF and HGF) secreted into the ECM
Some proteoglycans are integral cell membrane proteins involved in:
Cell proliferation
Migration
Adhesion
Often function by binding and concentrating growth factors and chemokines
Example: Heparan Sulfate Proteoglycans
Can bind fibroblast growth factors (FGFs) in the ECM
Act as a reservoir for inactive factors
Released by proteolysis (e.g., during wound healing)
3. Adhesive Glycoproteins and Adhesion Receptors
These connect ECM elements to one another and to cells.
Fibronectin
Structure
Large (450-kDa), disulfide-linked heterodimer
Exists in tissue and plasma forms
Sources
Synthesized by various cells:
Fibroblasts
Monocytes
Endothelium
Binding Properties
Has specific domains that bind to distinct ECM components:
Collagen
Fibrin
Heparin
Proteoglycans
Also binds to cell integrins
Role in Healing
In healing wounds, tissue and plasma fibronectin provide scaffolding for:
Subsequent ECM deposition
Angiogenesis
Reepithelialization
Laminin
Characteristics
Most abundant glycoprotein in basement membranes
820-kDa cross-shaped heterotrimer
Connections
Connects cells to underlying ECM components:
Type IV collagen
Heparan sulfate
Functions
Mediates cell attachment to the basement membrane
Can modulate:
Cell proliferation
Differentiation
Motility
Integrins
Structure
Large family of transmembrane heterodimeric glycoproteins
Composed of α- and β-subunits
Primary Functions
Act as adhesion receptors
Link cells to ECM constituents (e.g., laminin, fibronectin)
Functionally and structurally connect the intracellular cytoskeleton with the extracellular environment
Additional Roles
Facilitate cell-cell adhesive interactions
On leukocytes: Mediate firm adhesion to and migration across endothelium and epithelium at sites of
inflammation
Play critical role in platelet aggregation
Binding Mechanism
Attach to ECM components via a tripeptide arginine-glycine-aspartic acid (RGD) motif
Signaling Functions
Integrin binding can trigger signaling cascades that regulate:
Cell locomotion
Proliferation
Shape
Differentiation
Components of focal adhesion complexes
Link the ECM to the cytoskeleton
Can generate intracellular signals when cells are subjected to shear stress (e.g., endothelium in the
bloodstream)
Other Cell Adhesion Molecules (CAMs)
Besides integrins, CAMs also include:
Immunoglobulin family members
Cadherins
Selectins
Clinical and Pathological Significance
ECM in Disease
ECM remodeling is involved in:
Morphogenesis
Tissue regeneration and repair
Chronic fibrosis
Tumor invasion and metastasis
Genetic Disorders
Osteogenesis imperfecta: Collagen mutations
Ehlers-Danlos syndrome: Lysyl hydroxylase mutations
Marfan syndrome: Fibrillin defects
Blistering skin diseases: Type VII collagen mutations
Nutritional Deficiencies
Vitamin C deficiency affects collagen cross-linking, leading to:
Scurvy
Poor wound healing
Skeletal abnormalities
These notes provide a comprehensive overview of the extracellular matrix, its components, organization, and
critical roles in tissue structure and function.
