Extracellular matrix

Describe ECM

• Extracellular matrix

• Non-cellular component present within all tissues and organs

• Network of macromolecules that occupy extra-cellular space

• Proteins, proteoglycans (carbohydrates) and minerals

• Secreted by cells

• Forms large percentage of connective tissue

• Constituents and organisation vary between different tissues

• Synthesised by fibroblasts, myofibroblasts and smooth muscle cells

Functions of ECM

• Strength, support and protection

• Stores and presents growth factors

• Acts as a scaffold for tissue repair

• Important in cell adhesion and migration

• ECM acts as a signal which influences cell function

  • E.g. growth and survival

• Establishes a tissue microenvironment

Examples of ECM

• Basement membrane (basal lamina)

  • Epithelia, endothelia, muscle, fat, nerves

• Elastic tissues

  • Skin, lung, large blood vessels

• Stromal or interstitial matrix

• Bone, tooth and cartilage

• Tendons and ligaments

ECM molecules

• Collagens

• Elastic fibres

  • Fibrillin and elastin

• Proteoglycans

• Glycosaminoglycanas

  • Hyaluronan

• Adhesive glycoproteins

  • Lamina and fibronectin

Structural proteins:

• Collagen

• Elastin

Adhesion proteins:

• Fibronectin

• Fibrilin

• Laminin

• Tenascin

• Vitronectin

• Osteonectin

Glycosaminoglycans and proteoglycans:

• PGs = protein core + GAG

• Protein cores

  • Biglycan

  • Agrecan

  • Versican

  • Neurocan

• GAG

  • Heparin sulphat

  • Kondroitin 4-sulphate

  • Kondroitin 6-sulphate

  • Deparan sulphat

  • Hyaluronan

Describe collagen

• Main structural protein of extracellular space

• Type I - skin, tendon, bone

• Type II - cartilage, vitreous humour

• Type III - skin, muscle

• Type IV - basal lamina (mesh work)

• Types V to XII - less abundant

• Made by fibroblasts in epithelial cells

Describe elastic fibres

• Allows tissues to resume their shape after stretching

  • E.g. artery, lung, skin, bladder

• Elastic fibres are crosslinked arrays of tropelastin

• Synthesised by muscle cells and fibroblasts

• UV damage weaken elastic fibers

Describe proteoglycans

• Protein backbone polysaccharide side chains

• Large branching aggregates retaining H20

• Glycosaminoglycans (GAGs):

  • Chondroitin sulphate- hyaline cartilage

  • Heparin sulphate- basement membrane

  • Keratin sulphate- cornea

  • Hyaluronic acid- skin, polysaccharide only

Describe proteoglycans

• Can be small or large

  • E.g. decorin (small) or aggrecan (large)

• Binds to proteins

  • Can regulate their activities

  • E.g. decorin to collagen

• Cell surface proteoglycans

  • E.g. syndecan

• Act as co-receptors

Describe glycosaminoglycans (GAGs)

E.g. Hyaluronan (hyaluronic acid, hyaluronate)

• Major component of proteoglycans

• Extremely long, negatively charged polysaccharide

• Resists compression

• Swollen gel creates turgor pressure

• Forms viscous, hydrated gels

• Large number of an ionic residues on surface bind water

• Hyaluronan keeps cells apart of one another

• Facilitates cell migration

• Surrounds migrating and proliferating cells

• Inhibits cell-cell adhesion

Describe adhesive glycoproteins

• Attach to cell matrixes that contain fibrous collagen

• Facilitate migration and cellular differentiation

E.g. Fribronectin

• Large denier of two nearby identical particles

• Soluble form in plasma

• Several regions which bind to other proteins

• Arg-gly-asp (RGD) mediates cellular binding through integrins

E.g. Laminin

• Trimeric (cross) structure

• Binding sites for cells and other proteins

• Major components of basal lamina (one layer of basement membrane)

• Cell differentiation, adhesion and migration

• Mutation causes junctional epidermolysis bullnose (skin blisters and tears with minimal trauma) and nephrotic syndrome (kidney disorder- large amount of protein in urine causing fluid retention)

Describe basement membrane

• Specialised ECM

• Cell attachment

• Separates cells e.g. epithelium and connective tissue

• Cells on BM can divide i.e. to signal

• Role in filtration in kidney

Interactions with ECM

• Cells interact with ECM through specific membrane bound receptors (integrins)

• Specific dimer pairings determine ligand binding

• Mediates cellular effects

• Bidirectional signalling molecules

Mineralised ECM

• Contains calcium hydroxyapatite

• Provides mechanical stiffness

• E.g. bone (65%), dentine (70%), enamel (96%)

Modifications of ECM

• Cells can modify ECM surrounding them

• Proteolytic enzymes e.g. matrix metalloproteinses can create a path for cell migration

• Create products which can have biological activity

• Releases and activates growth factors

• Altered expression in wound healing and disease e.g. cancer

Describe MMPs

• Collagenases, gelatinises and stromelysins

• MMP-1: collagenase-1, cuts triple helical collagens

• MMP-9: gelatinase-B, cuts e.g. type IV collagen and laminins

• MT-MMPs: membrane bound enzymes

• Regulate amount of ECM

  • Degradation and remodelling

• Cell migration, wound healing, angiogenesis

• Activate other MMPs

• Release or activate growth factors and other bioacive molecules

ECM mechanics

• ECM can be different stiffnesses and elasticity dependent on composition

• Affects cell behaviour and gene expression

• Integrins can act as mechanosensors

• Stiffness changes in disease

  • Fibrosis and cancer (how cells are organised and broken down)

ECM and integrins in cancer

• ECM and integrin expression is changed in cancer

• Normal cell-cell and cell-ECM interactions are disrupted

• Integrin signalling influences cell growth, anoikis (programmed cell death), cell migration and invasion

• Targeting ECM and integrins in anti-cancer therapy and imaging

Tumour metastasis

• Proliferation of cancer to a new part of body

• Growth

• Decrease cell-cell contact

• BM breakdown

• Stromal invasion

• Endothelium BM breakdown

• Attach and invade stroma

• Re-grow with angiogenesis

MMPs in disease

• Extensive matrix degradation in disease

  • E.g. periodontitis, rheumatoid arthritis

• Tumour cell invasion and metastasis

  • E.g. carcinoma breaks basement membrane and invades surrounding stroma

• MMP inhibitors tested for therapeutic use