Extracellular matrix Flashcards
What is diversity in the ECM due to?
variations in relative amounts of macromolecules and the organisation of those macromolecules
each ECM will be adapted to the functional requirements of the particular tissue
What are the functions of the ECM?
functions as adhesive substrate
provides structure
presents growth factors to their receptors
sequesters and stores growth factors
senses and transduces mechanical signals
What are the two main macromolecules that compose the ECM
proeotglycans and fibrous proteins (collagens, elastins, fibronectins and laminin)
What are the function of proteoglycans
to resist compressive forces and loads, highly hydrated to allow rapid diffusion of nutrients, metabolites and hormones between blood and tissue cells
act as a space filler in development
regulate activities of secreted proteins such as proteases and protease inhibitors
What is the structure of proteoglycans
a core protein linked to GAGs
What are GAGs and the 4 main groups
GAGs are unbranched polysaccharide chains composed of repeating disaccharide unites. highly negatively charged because of sulphate or carboxylic groups
hyaluronan, chondroitin + dermatan sulphate, heparan sulphate, keratan sulphate
What are the differences between the left and right side of the dorsal mesentary which will facilitate gut looping
left side = less hyaluronan, epithelial are cuboidal, increased GAGs and basement membrane components
right side = more hyaluronan acting as a space filler, mesenchymal cells are sparsely distributed so cannot communicate or aggregate
What is the function of fibrous proteins in the ECM
strengthen and coordinate organisation of the matrix
What is heparan sulphate needed for
FGF signalling and early specification of germ layers. needed for the FGF4 and FGF8 ligands
What is syndecan-1
a family of 4 transmembrane proteoglycans which bind HS chains and other proteins
allows communication between extracellular and inside the cell
What is the function of syndecan-2
sequesters growth factors through GAG sidechains (HS/CS)
may increase the affinity for GF binding to their receptors
also specifies L/R asymmetry in heart/gut looping
What does the stiffness of the ECM lead to
driving different cell differentiation
Which cells will differentiate from the following ECM:
- soft matrices
- stiffer
- rigid
soft matrices = neurogenic
stiffer = myogenic
rigid = osteogenic
What is the repeating amino acid sequence in collagen?
Gly-X-Y
What are the most common collagen types?
Most common collagens types:
Type I: skin, tendon, vascular ligature, organs, bone
Type II: Cartilage
Type III: reticulate (commonly found in type 1)
Type IV: Basal lamina (epithelium-secreted layer of basement membrane)
Type 5: cell surfaces, hair and placenta
What is the function of collagen?
Resist tensile forces in skin for example ae woven in a wickerwork pattern to resist tensile stress in multiple directions
What is Elastin needed for?
Skin, blood vessels lungs that require strength and elasticity
What is Fibronectin?
Guides cell migration in vertebrate embryos
Need to make mesoderm
Essential for cleft formation during initiation of epithelial branching and is accompanied by an adjacent loss of E-cadherins
What happen when Fibronectin is knocked out?
Shortened anterior posterior axis
Abscence of somites
Deficit in mesenchyme
What are integrins?
Large family of heterodimeric glycoprotein receptors
Exist as two non covalently bound alpha and beta subunits
Bind variety’s of ECM molecules e.g collagen, Fibronectin, laminins
What is the function of integrins?
- Attaching cell to ECM
Cell migration in
Transduction signals from ECM to cell
What happens if a mutation occurs in a5 B1 chain?
Cannot bind to Fibronectin- which acts as a cell communicator
What are the types of way cells can communicate between each other?
Tight junction
Cell-cell anchoring junctions
Channel forming junction
Cell-matrix anchoring junctions
- Actin-linked cell matrix junctions
Hemidesmosome
Gap junction
Desmosomes
Adherens junction
Tight junction
What molecule communicate between cells and ECM?
Integrins and sydecans
What are cadherins?
A cell adhesion molecule involved in formation of Adherens junctions
Ca2+ dependent: extracellular domain facilitates cell-cell crosstalk and project out of cells and intracellular domain binds number of signalling and adaptor proteins
Behave as a recpetor and ligand
O from a junction
What are cadherins involved in during development?
• Positing of cells
• Responsible for separation of different tissue layers
• Cell migration
What is the role E-cadherins?
Epithelium
What is N-cadherins involved in ?
Neuralation- expression alters as neural plate forms
What are Desmosomes?
They link Intracellular to the intermediate filaments cytoskeleton form adhesiveness bonds in a network that gives mechanical strength
In epidermis and myocardium and subject to mechanical force
Stick together- hard to pull apart
What are gap junctions?
Channels composed of connexins, which connect cytoplasm to two adjacent cells of small molecule - Ion/water transport
What is a stem cell niche?
Stem cells reside in dynamic specialised micro environment - a niche
Why is it important or proper bonding between stem cells and their niche essential?
To maintain stem cell pool for long term self renewal
How are developmental processes regulated?
Cell-cell interaction
Systemic or exogenous factors
Endogenous factors
Matrix interaction
Shape and polarity
Why is the ECM vital to the stem cell niche?
Why is THE ECM vital to the stem cell niche?
1. Anchorage restricts stem cell in niche- exposure to Paracrine and cell-cell contact signals
2. Anchorage- vital for orienting mitotic spindle to enable stem cells to undergo asymmetric cell division: essential for self renewal and generation of daughter cells destined to undergo differentiation
3. Maintains stem cell properties e.g biomechanics (ECM stiffness) affects cell fate determination
If a stem cell is sitting in a stiff ECM what is it likely to become?
Cartilage for bones
How do Haematopoietic stem cells DEVELOP
They develop during embryogenesis in complex process involving multiple anatomical sites
Once HSC precursors have been specificed from mesoderm they mature into function HSCs and undergo self needing division to generate a pool of HSCs which colonise the bone marrow at birth
What are osteopontins?
One of the main glycoproteins secreted by osteoblasts essential for HSC numbe and function
What happens when osteopontin is knocked out?
Enhance cyclising of HSCs, negatively regulates stem cell pool- acts as a brake
How do HScs adhere to osteopontin?
Bind to a1B1 and a5B1 integrins - restricting expression to endosteal region
Where are intestinal stem cell niches found? How are they formed?
Found in glandular crypts of small and large intestine.
Formed by epithelial invaginations into the ECM by supportive stroma cells
What ECM molecules are in intestinal stem cell niches?
GAGs,
Type VI collagen Fibronectin, integrins, laminin a5
