lecture 10 Flashcards
(7 cards)
Describe cell signalling
Cell = basic unit of life
Organised hierarchically in tissues and organ systems
Cells control and are controlled by other cells both directly (cell:cell contact) and indirectly/remotely via soluble chemical messages:
Short and long range
Over time & distance
Cell signalling regulates development, growth & repair
Can we exploit this to control cell behaviour for TERM?
It is the interactions between cells which regulate our bodies, and these interactions take place through signalling of cells. These can occur through the whole body (endocrine and hormonal systems), cells interacting with themselves (autocrine signalling) and cells interacting with different types of cells (paracrine signalling).Cell signalling regulates everything from development through to repair, so it is hardly surprising that we want to exploit this for tissue engineering and regenerative medicine.
Describe how Natural signals that regulate cell behaviour
Growth factors & mitogens – regulate cell growth (size) & proliferation
Steroid & nuclear receptor ligands (eg: retinoids, oestrogen, PPAR ligands) - regulate lineage & differentiation
Cytokines = immunomodulatory agents (eg interleukins, interferons)
chemokines – chemotaxis (eg IL-8)
Peptide hormones (eg growth hormone, vasopressin, insulin, leptin, neuropeptides) have systemic effects
e.g. If we wanted to programme an iPSC cells down a particular pathway, we may use steroid and nuclear receptor ligands to regulate which lineage they are differentiated down.Cytokines and peptide hormones aren’t really used in tissue engineering - really just growth factors and mitogens, and steroid and nuclear receptor ligands which are used. Out of these it is mainly growth factors which are employed
What are growth factors?
Low molecular weight cell-signalling peptides/proteins or glycoproteins
Bind to high-affinity receptors on the surface of target cellsleading to the activation of intracellular signal transduction pathways
May stimulate many different cell types or be specific to a particular cell type (receptor expression)
Highly context-specific - promote multiple effects on growth, survival, proliferation, migration & differentiation.
Normal roles in
Fetal development & growth
Tissue maintenance (homeostasis)
Wound repair
But - major role in diseases – including cancer
Growth factors bind to receptors on cell surface leading to the activation of intracellular signal transduction pathways, usually through some sort of phosphorylation cascade.Growth factors are sometimes referred to as pleiotropic because in different circumstances they can have different effects - if we want to use a growth factor to manipulate a particular behaviour, how do we harness this?If cells are inappropriately stimulated by growth factors, or cancer cells are residing in the target tissue, then this may promote cancer development.
What is Platelet-derived growth factor (PDGF)?
Complex: 4 genes produce 5 isoforms (PDGFAA, PDGFBB, PDGFAB); plus 2 receptors
role in development, proliferation, migration & angiogenesis.
linked to atherosclerosis, fibrosis and malignant diseases.
PDGF = potent stimulator of fibroblast growth
attracts fibroblasts into the wound site and triggers proliferation
without PDGF cultured fibroblasts remain viable and metabolically active, but do not grow or divide (mitotically-quiescent)
The most common isoforms of PDGF are AA, BB and AB, and these are formed from dimers of PDGF.PDGF attracts fibroblasts into a wound site, stimulating proliferation. For example, it’s used in dental implants - PDGF is packed into the dental implant and it will promote fibroblast growth and repair.Figure shows scratch-wound assay that the wound is not repaired when PDGF is not present.
What is Epidermal growth factor (EGF) family?
Family of ligands that activate EGFR
EGF, TGFα, amphiregulin, HB-EGF, betacellulin, epiregulin
Target epithelial cells
Many have autocrine/juxtacrine role
Promote re-epithelialisation after wounding
Role in development, differentiation, migration
But also cancer….
Many different ligands produced by cells bind to the EGF receptor.EGFs primarily regulate epithelial cell growth, are often autocrine or juxtacrine (made by epithelial cells to stimulate epithelial cells) and are very important in epithelial wound repair, but also play a role in epithelial cancers.
Growth factor delivery – systemic?
Short half-lives after IV injection
PDGF half-life = <2 mins
bFGF half-life = 3 mins
VEGF half-life = 50 mins
Toxicity at high systemic levels
Relatively large size & slow tissue penetration
But may diffuse away to cause effects in other tissues
eg growth of tumours following delivery of angiogenic factors
Can just inject growth factors into the body, but the problem with this is that these growth factors have very short half-lives - not wanted in circulation by the body. There are a number of other problems associated with this approach.
Growth factor delivery – Controlled Delivery?
Polymer materials for growth factor delivery:
Controlled
Sustained
Localised
Polymer delivery vehicles
Physical entrapment of growth factor within matrix/hydrogel
Encapsulation of growth factor within microparticles/nanoparticles
Immobilisation of growth factors
GF protected from degradation until released
Can incorporate growth factors into different polymer materials, allowing controlled, sustained and localised growth factor delivery. This is done through a number of different polymer delivery vehicles.
