Extracellular matrix Flashcards
Learning outcomes
- Connect previous lectures on cytoskeleton, epithelium and connective tissue
- Identify that vitamin C is essential in collagen biosynthesis and the consequences of vitamin C deficiency
- Illustrate how integrin molecules link the extracellular matrix to the cytoskeleton
- Identify the role of hemi-desmosomes in epithelial cell function
Relevance of ECM and Cell Adhesion in Medicine
Scurvy- vitamin C deficiency causes reduced collagen turnover, skin spots, bleeding gums, loss of teeth
Metastatic Breast Cancer- epithelial cells detatch from basal lamina, degrade ECM and migrate to other tissues such as bone
Marfan’s Syndrome- ECM faulty fibrillin, heart malfunction due to defective CT
How do cells organise themselves in an organism?
-cells form tissuessuch as nervous, muscle, epithelial and connective tissue
-cells are held in place in a tissue by the connections with the extracellular matrix
-tissues are also strengthened by cell-cell connections
(desmosomes/hemidesmosomes)
What is the ECM?
- the extracellular matrix is defined as the “material” in between cells that gives eachtissue it’s structure and strength
- this “material” is called connective tissue (fibres, fibroblasts and ground substance)
- the amount of connective tissue and the molecular make-up differs between tissues
What cells make collagen?
- most connective tissues such as skin, tendons, epithelial sheets, ECM/collagen is produced by cells called fibroblasts
- in bone, ECM/collagen is produced by osteoblasts-other components of bone ECM such as hydroxyapatite crystals also produced by osteoblasts
How are collagen triplets linked?
-Lysyl hydroxylase-adds OH to some lysines. Requires Iron and Vitamin C
Prolyl hydroxylase-adds OH to some prolines. Requires Iron and Vitamin C.
-lysyl hydroxylases work inside the cell to form bonds between 3 collagen molecules to cross link the triple helix (needs Fe 2+and Vitamin C as cofactors):
poor vitamin C leads to insufficient cross linkages, scurvy
(triple helices formed inside cell, secreted and form collagen fibrils outside cell)
What is the name of the precursor form of collagen?
Procollagen- procollagen peptidases required to remove ‘caps’ to allow strong cross linkages
What happens if p.c peptidases don’t work properly?
Defective collagen fibril/ fibre assembly in skin and other tissues
Ehlers- Danlos syndrome, hypermobile joints
Example of ECM in action in the body
Heart valves are made of elastin ( stretch to valves)
Collagen gives strength
Proteoglycans ensure valves arent too stiff, and to withstand pressure of blood flow
What is Epidermolysis Bullosa and what is its relevance to the ECM?
It affects epithelial cells that can’t form strong intermediate filament networks, may blister and come off
ECM protein mutation, like collagen, can lead to dystrophic EB
Junctional EB- mutation to laminin J. protein (mutations in collagen 17A1, or in laminin genes LAMB3)
What role do fibroblasts play in scar formation?
Migrate to wound site and on skin, will repair tissue and form a scar.
In oral mucosa there is low scar formation
Fibrosis is pathogenic scar formation, overscarring and damaging tissue
What is Alport Syndrome?
- hereditary nephritis causing end stage renal disease, hearing loss and sometimes vision(cataracts)
- caused by mutations in genes for type IV collagen crucial for basement membranes in the kidney, inner ear and eye
- classic symptom is haematuria (blood in the urine)
How do cells degrade ECM?
- enzymes exist in the ECM that can degrade collagen and other ECM molecules
- examples of these enzymes are Matrix Metalloproteinases-degradation of ECM critical for macrophage invasion of tissue during infection-normal ECM degradation essential for healthy tissue growth and repair
- diseases such as cancer (metastasis) and arthritis involve matrix proteases
Uses of collagen in treatment
Diabetic ulcers- apply collagen immediately after debridement of wound.
How do cells attach to the ECM?
cells attach poorly to bare collagen, so an adaptor molecule called Fibronectin is needed
- cells bind Fibronectin via transmembrane receptors called Integrins
- the Integrins attach to the actin cytoskeleton and thus give the cell its tensile strength
What is the role of integrin?
Intergrin function is critical to normal tissue homeostasis
- they form and break atttachments as a cell moves through a tissue
- about 24 integrins in mammalian cells, and they form dimers to carry out their function
What happens if there are mutations in integrin?
- Leukocyte integrin- WBC can’t invade tissues/organs on infection, more severe infectious due to the immunocompromise
- Platelet integrin- clotting ability is compromised
How do ECM molecules perform a compression resistance function?
- Collagen and related molecules provide tensile strength to tissues-other gel-like molecules act as “shock absorbers” that resist compression and fill space
- Proteins with sugar groups attached-proteoglycanse.g. hyaluronancontain sugar groups called glycosaminoglycans (GAGs)
What is a glycoprotein?
Protein with covalently linked carbohydrate moieties eg some cell surface proteins (blood group antigens)
What is a proteoglycan?
X.cell proteins linked to complex -vely charged carbohydrates (GAGs)
Sugar is predominant
They form huge macromolecular complexes in tissues
Give examples of varying levels of GAGs in tissue
GAGs very hydrophilic, attract water and form gels (ground substance)
Bone/tendons- lots of collagen/ hydroxyapatite crystals, very little GAGs (no room)
Cartilage- mix of collagen and GAGs, tough materials that can withstand huge pressures
Eye vitreous- mostly GAGs and water (small amount of collagen)
What is the difference between lamin and laminin?
Lamin- nuclear intermediate filament protein inside cell
Laminin- extracellular matrix protein found outside cell in basal lamina, point at which epithelial cell bases connect
What are the 2 faces of epithelial sheets?
the apical and the basal/basolateral surface-apical side is exposed to air/fluid such as GIT-basal side is the “bottom” of the cell and is attached to the basal lamina -basal lamina is a specialised ECM made up of type IV collagen and laminin -laminin connects the basal lamina to integrins in the epithelial cells-keeps the cells anchored
-laminin plays a similar role to fibronectin in connective tissue
What is the role of hemidesmosomes?
Hemidesmosomes anchor the keratin filaments to the basal lamina-integrins link the cell to the basal lamina via the keratin filaments-critical to have the epithelial cellsconnected to the basal lamina-defective hemidesmosomes canlead to blistering diseases
