Regeneration and Repair Flashcards
How can regeneration be defined?
As the proliferation of dead or damaged cells by functional, differentiated cells or tissues in which normal structure is restored.
What are differentiated cells derived from?
Stem cells
What is repair a response to?
An injury involving both regeneration and scar formation (fibrosis)
What does repair lead to?
Permanent alternation in normal structure
How much can stem cells proliferate?
Potentially limitless
What happens to daughter stem cells?
They either remain as a stem cell, or differentiate into a specialised cell type
What is the importance of some daughter stem cells remaining as stem cells?
To maintain the stem cell pool
What happens to stem cells in early life?
They develop into many different cell types
What can stem cells be said to be?
An ‘internal repair system’
What is the purpose of the internal repair system produced by stem cells?
To replace or damaged cell tissues
What is the potential therapeutic utility of stem cells?
In degenerative disease
What does unipotent mean?
Only able to produce one type of differentiated cell
What does multipotent mean?
Able to produce several types of differentiated cells
What does totipotent mean?
Able to produce any cell type
What cells are totipotent?
Embryonic stem cells
Give two examples of where stem cells are found in a mature human?
Bases of crypts
Hematopoietic ontogeny
What happens to stem cells in the bases of crypts?
They produce new cells at the bottom, which then move up and undergo apoptosis, meaning the crypts are constantly regenerating
What happens in haematopoietic ontogeny?
Multipotent stem cells in the bone marrow can produce cells within their lineage
Clinically, what is haemtopoietic ontogeny good for?
Therapeutics
How can haemopoietic ontogeny be useful therapeutically?
It can be used to reconstitute bone marrow is it has been depleted.
Bone marrow can be removed from one patient and infused into another
Is the propensity to regenerate the same among all cell types?
No, it varies
What happens to labile cells?
They are continuously dividing
What is the purpose of the continual division of labile cells?
They are replacing cells that have been destroyed by apoptosis
Give two examples of cells that are labile
Epithelial
Haemopoietic
What is the normal state for labile cells
Cell division (G1-M-G2)
What do labile cells usually display?
Rapid proliferation
What state are stable cells usually in?
The resting state (G0) - they have not get entered the cell cycle
Can stable cells undergo division?
Yes, if appropriately stimulated
Give 3 example of stable cells
Hepatocytes
Osteoblasts
Fibroblasts
What is the speed of regeneration for stable cells?
Usually quite low, but depends on the stimuli exposed to
What state are permanent cells in?
G0
Are permanent cells capable of dividing?
No
Give 2 examples of permanent cells?
Neurones
Cardiac myocytes
When are permanent cells produced?
During embryonic development
Give an example of a response of a permanent cell?
Compensatory hyperplasia
What happens in compensatory hyperplasia?
Not producing new cells, but existing cells get bigger
Where does compensatory hyperplasia occur?
In the liver
What is each phase dependant on in the cell cycle?
Activation and completion of the previous stage
What is advantage of each stage of the cell cycle being dependant on completion of the previous stage?
Helps prevent reduplication of abnormalities such as mutations
Where are there checkpoints in the cell cycle?
Between G1 and S
Between G2 and M
What is the purpose of the checkpoint between G1 and S?
The integrity of DNA is monitored before it’s replicated
What is the purpose of the checkpoint between G2 and M?
DNA is checked after it’s replicated to ensure its safe to continue
What happens in alcoholic cirrhosis of the liver?
The ability of division is shown, as you get scarring that forms fibrous bands that surround nodules that contain numerous dividing hepatocytes. This gives the nodular nature of a cirrhotic liver.
What is the problem with studying the factors that control regeneration?
They are complex and poorly understood
Give two factors that control regeneration?
Growth factors
Contact between basement membrane and adjacent cells
What do growth factors do?
Help drive proliferation in the stem cell population
What do growth factors function as?
Ligands binding to specific receptors
What happens when a growth factor binds to its specific receptor?
They deliver extracellular signals to their target cells to stimulate the transduction of genes that control the cell cycle and progression
What is the process of growth factors controlling the cell cycle known as?
Receptor mediated signal transduction
Give two types of molecules that growth factors can be?
Proteins
Hormones
Give two examples of protein growth factors
EGF (epidermal growth factor)
PDGF (platelet derived growth factor)
What does EGF do?
Mitogenic for keratinocytes and fibroblasts, and so stimulates the formation of granulation tissue
What is EGF produced by?
Keratinocytes and macrophages, and other inflammatory cells attracted to the area of damage
What does PDGF do?
Causes the migration and proliferation of lots of cells that help with inflammation and healing of skin wounds
Where is PDGF stored?
Platelet granules
When does PDGF get released?
When platelets become activated
Give 3 examples of hormones that can act as growth factors
Oestrogen
Testosterone
Growth hormone
What kinds of hormones can growth factors be?
Autocrine
Paracrine
Endocrine
What does an autocrine hormone do?
Acts on the cell that produced it
What do paracrine hormones do?
Acts on the cells adjacent to the one that produced it that have the appropriate receptor
What do endocrine hormones do?
Travel in the blood and act on cells far away from the original site of production
How does contact between basement membranes and adjacent cells control regeneration?
There is signalling through adhesion molecules, which inhibits proliferation in intact tissue
What is the control of regeneration by contact between the basement membrane and adjacent cells known as?
Contact inhibition
Where are regenerative control mechanisms deranged?
Cancer
What is fibrous repair?
The replacement of functional tissue by scar tissue
When do fibrous repair and scarring occur?
When there is necrosis of permanent cells, or when there is a necrosis of labile or stable cells which leads to the collagen framework being destroyed
Why does a destruction in collagen framework lead to scarring?
Because you get deposition of collagen to replace the framework
What are the key components of fibrous repair?
Cell migration and inflammation
Angiogenesis
Extracellular matrix production and remodelling
Why is cell migration important in fibrous repair?
Need to get cells there so they can exert their effects
What are the cell types in fibrous repair?
Inflammatory cells
Endothelial cells
Fibroblasts and myofibroblasts
What inflammatory cells are involved in fibrous repair?
Neutrophils
Macrophages
Lymphocytes
What is the purpose of neutrophils and macrophages in fibrous repair?
Phagocytosis of debris
What is the purpose of lymphocytes and macrophages in fibrous repair?
Chemical mediators
What do chemical mediators do?
Attract other cells
What is the purpose of the endothelial cells in fibrous repair?
Angiogenesis
What is the purpose of (myo)fibroblasts in fibrous repair?
Extracellular matrix production
Wound contraction
What is angiogenesis known as in utero?
Vasculogenesis
Why is the development of a blood supply vital for wound healing?
It provides access for inflammatory cells and fibroblasts
Allows delivery of oxygen and nutrients
What is angiogenesis initiated by?
Proangiogenic growth factors
Give an example of a proangiogenic growth factor
VEGF
What happens to pre-exisiting vessels in angiogenesis?
They sprout new vessels
What are the stages of angiogenesis
- Vasodilation of pre-exisiting vessels in response to nitric oxide
- Endothelial proteolysis of basement membrane
- Migration of endothelial cells via chemotaxis towards the angiogenic stimulus of VEGF
- Endothelial proliferation
- Endothelial maturation and tubular regeneration
- Recruitment of periendothelial cells
What is the importance of endothelial maturation and tubular regeneration?
So can form a tubular structure that blood can flow through
What do periendothelial cells do?
Make the outer layers of vessels
What do periendothelial cells consist of?
Pericytes and vascular smooth muscle cells
Where is the angiogenic mechanism exploited?
In malignant cells, so they can have a blood supply and continue to grow
What do both tissue repair and regeneration depend on?
The activity of soluble factors and interaction between cells and components of the extracellular matrix
Where is the extracellular matrix found?
It fills spaces between tissues
What are the functions of the extracellular matrix?
Supports and anchors cells
Helps maintain polarity
Separates tissue compartments
Sequesters growth factors
Allows for communication between cells
Facilitates cell migration
Where does the extracellular matrix help maintain polarity?
The skin- keeps basal cells in the bottom and keratin layer on top
What is the importance of the separation of tissue compartments?
Maintains tissue microenvironment
Contains separate areas
What is the importance of the ability of the extracellular matrix to sequester growth factors?
They can be stored in the extracellular matrix after being secreted, allowing for rapid deployment when they’re needed
What is the importance of collagen?
Provides extracellular framework
What is collagen composed of?
Triple helices of various polypeptide alpha chains
What are the fibrillar collagens?
Type I-III
Give two places fibrillar collagen is found
Dermis
Bone
What are fibrillar collagens composed of?
Uninterrupted triple helices
What are the amorphous collagens?
IV-VI
Where are amorphous collagens found?
Basement membrane
What does amorphous collagen form?
Sheets
How is collagen remodelled?
By specific collagenases
What are the stages in the synthesis of fibrillar collagens?
- Polypeptide α chains synthesis in ER
- Enzymatic modification steps, including vitamin C dependant hydroxylation
- α chains alight and cross, linking to from procollagen triple helix
- Soluble procollagen secreted
- After secretion, procollagen cleaved to give tropocollagen
- Bundles of fibrils form fibres
- Slow remodelling by specific collagenases
Give 4 defects of collagen synthesis
Vitamin C deficiency
Erlers-Danlos syndomes
Osteogenesis imperfecta
Alport
What is vitamin C deficiency known as?
Scurvy
What happens in scurvy?
Inadequate vit C dependant hydroxylation of α chains
What does inadequate vitamin C hydroxylation lead to?
Defective helix formation
What is the result of defective helix formation?
Lacks strength
Vulnerable to enzymatic degradation
Where does scurvy particularly affect?
Collagen supporting blood vessels
What is the result of scurvy affecting collagen affecting blood vessels?
Haemorrhage
What does scurvy lead to in infants?
Skeletal changes
What is Erlers-Danlos syndrome?
A genetic defect in synthesis or structure of fibrillar collagen
What defect occurs in Erlers-Danlos syndrome?
Defective conversion of procollagen to tropocollagen
What are the symptoms of Erlers-Danlos syndrome?
Stretchy skin
Hypermobile joints
How many types of osteogenesis imperfecta are there?
4, of varying severity
What happens in severe osteogenesis imperfecta?
Children die in utero
What causes children to die in utero in osteogenesis imperfecta?
Multiple fractures
Poor development
What is Alport syndrome?
Genetic deafness
What are the components of the extracellular matrix?
Matrix glycoproteins
Proteoglycans
Elastin
What is the purpose of matrix glycoproteins?
Organise and orientate cells
Support cell migration
Give 3 examples of matrix glycoproteins
Fibronectin
Laminin
Tenascin
What is the purpose of proteoglycans?
Matrix organisation
Cell support
Regulate availability of growth factors
Give an example of a proteoglycan
Heparin sulphate proteoglycan
What is the purpose of elastin?
Provides tissue elasticity
What is the importance of tissue elasticity?
Provides tensile strength and recoil
What are the stages of the mechanism of fibrous repair?
NAME?
What happens in the inflammatory cell infiltrate stage of fibrous repair?
Blood clot forms
Acute inflammation around edges
Chronic inflammation occurs
How does a blood clot form?
Platelet adhesion and aggregation
What is the importance of blood clot formation?
Prevents further bleeding and promotes inflammatory response
What is the importance of acute inflammation around the edges in fibrous repair?
Used as a scaffold for migration in, and clears debris
What happens to accommodate chronic inflammation?
Macrophages and lymphocytes migrate into clot
What happens as the clot is replaced by granulation tissue?
Angiogenesis
(Myo)fibroblasts migrate and differentiate
What is the importance of the migration and differentiation of (myo)fibroblasts?
Produce extracellular matrix, which makes glycoproteins
How long does the maturation stage of fibrous repair take?
Relatively long
What happens in the maturation stage of fibrous repair?
Cell population falls
Collagen increases, matures and remodels
Myofibroblasts contract
Vessels differente and are reduced
Why does the cell population fall in maturation?
Because neutrophils predominantly replaced macrophages
In what situation are neutrophils not replaced by macrophages in maturation?
If infection present
What is the purpose of myofibrillar contraction in maturation?
Reduces volume of defect
What is left after maturation
A fibrous scar
What is the problem with studying the control of fibrous repair?
Complex and poorly understood
How is fibrotic repair controlled?
Inflammatory cells recruited by chemotaxis
Angiogenesis controlled by platelets, ECM and others
Fibrosis controlled by macrophages
How is angiogenesis controlled by platelets and ECM?
They produce cytokines in response to hypoxia
How do macrophages control macrophages?
They produce various pro-fibrotic cytokines, and cause fibroblast proliferation and ECM production
Give 3 examples of pro-fibrotic cytokines
IL1
TNT-α
TGF-ß
What is the simplest type of healing?
Healing by primary intention
When does healing by primary intention occur?
In clean, uninfected surgical incisions, where two edges can be imposed
What usually happens with surgical incisions?
They are sutured to make it easier to heal
What is the advantage of incisions?
It causes death to only a limited number of epithelial and connective tissue cells, so very slight disruption to basement membrane continuity
What occurs first in healing by primary intention?
The epidermis regenerates
What is the process of epidermal regeneration called?
Re-epitheliasation
How extensive is the formation of clots and granulation tissue in healing by primary intention?
Minimal
What happens once the epidermis has regenerated in healing by primary intention?
The dermis undergoes fibrous repair
When are sutures removed from a surgical incision?
Usually after ~10 days
How strong is the skin after 10 days?
~10% of normal
What happens once granulation tissue has been formed?
There is a transition to scar tissue
How long does maturation of a scar occur for?
Up to 2 years
What is the advantage of healing by primary intention?
There is minimal contraction and scarring, and the skin has good strength
What is the downside of healing by primary intention?
There is a risk of trapping infection
What is the result of trapped infection?
Abscesses in the skin
Why does healing by primary intention carry with it a risk of trapping infection?
Because the edges are opposed so tightly, infection cannot escape
When does healing by secondary intention occur?
When there is an infarct, ulcer, abscess, or any large wound which causes an extensive loss of cels, including epithelial cells, extracellular matrix, and sometimes extensive damage to basement membrane
How is healing by secondary intention different from by primary intention?
Unopposed wound edges
Large clot dries
Epidermis regenerates from base up
Repair process produces much more granulation tissue
Produces more contraction to reduce volume of defect
Takes longer
What is the result of the epidermis regenerating from the base up?
It brings up extensive collagen deposition
What is the result of the repair process producing more granulation tissue?
Formation of a substantial scar
What happens to the scar over time?
It gets smaller because of myofibrillar contraction
How does healing of bone fractures compare to repair at other sites?
Similar, but some modification for special environment
What are the stages of healing of bone fractures?
- Haemotoma forms from ruptured vessels within marrow cavity and periosteum
- Organising haemotoma provides framework for ingress of macropahges, endothelial cells, fibroblasts and osteblasts
- Growth factors released that stimulate osteoclasts and osteoblasts
- Necrotic tissue removed
- Capillaries develop
- Bone laid down in irregular woven pattern
- Woven bone gradually replaced by more organised lamellar bone
- Lamellar bone gradually remodelled to direction of mechanical stress
What is the purpose of haemotoma formation in bone repair?
Fills fracture gap and surrounds area of injury
What happens with the stimulation of osteoclasts and osteoblasts?
Fracture ends of bone start to get remodelled
What is the specialised mixture of cells formed in bone repair called?
Callus
What is the limitation of the soft callus?
It provides no structural rigidity for weight bearing
What is sometimes present when bone is laid down in the irregular woven pattern during fracture repair?
Islands of cartilage
How long does it take to start to get bone being laid down after a fracture?
2-3 weeks
What is the purpose of the irregular woven bone in fracture repair?
Helps stabilise the fracture site
What does the external callus do?
Provides splint-like support
What local factors influence wound healing?
Type of wound
Location of wound
Size of wound
Apposition
Lack of movement
Blood supply
Infection
Foreign material
Radiation damage
Where may a wound heal faster, and why?
The face, because it’s highly vascularised
How does the size of the wound affect healing?
If its a large wound that causes a lot of damage, there will be lots of granulation tissue, so will be a large scar
How does apposition affect wound healing?
Healing good if skin edges easily opposed
How does movement affect wound healing?
Movement can cause skin to become unopposed
What can infection lead to?
Suppuration
Gangrene
Systemic infection
What affect does infection have on healing?
Delays it
What foreign materials can affect wound healing?
Dirt
Glass
Sutures
Necrotic damage
What general factors can affect wound healing?
Age
Drugs
General dietary deficiencies
Specific dietary deficiencies
General state of health
General cardiovascular status
Give an example of a drug that can affect healing
Steroids
How can steroids affect healing?
They have anti-inflammatory effects, and inhibit collagen synthesis, so slow healing
How can general state of health affect healing?
Some chronic disease, for example if immunocompromised, more likely to pick up infection
How can general cardiovascular status affect healing?
If don’t have good blood supply, or venous supply to take away from area of damage, slow healing
What complications of repair can occur?
Insufficient fibrosis
Excessive fibrosis
Keloid scar
Strictures
Contractures
What could insufficient fibrosis be due do?
Inadequate granulation tissue or scar formation
What does insufficient fibrosis lead to?
Wound dehiscence hernia
What is a wound dehiscence hernia?
Where the wound come apart with its contents bulging out
Where do wound dehiscence hernias commonly occur?
In the abdomen, as high abdominal pressure
What are the risk factors for wound dehiscence hernias?
Obesity
Elderly
Malnutrition
Steroids
What happens in excessive fibrosis?
Excessive deposition of collagen
Where does excessive fibrosis usually occur?
In chronic disease, where there is chronic stimulation of the inflammatory process
What is the result of excessive fibrosis?
Cosmetic scarring
Keloids
Cirrhosis
Lung fibrosis
What does cirrhosis of the liver usually result from?
Alcohol
Hepatatis B
What happens in cirrhosis of the liver?
The liver is constantly chronically inflamed, leading to regenerative nodules and cirrotic fibrous bands
What happens in lung fibrosis?
Chronic stimulation leads to irritation and therefore a chronic inflammatory response, leading to fibrosis
What can cause chronic stimulation in the lungs?
Asbestos
Silicon
What does fibrosis in the lungs cause?
Contraction of the lung lobes, leading to problems with breathing
What causes a keloid scar?
Excessive formation of components of the repair process, including collagen
What are the features of a keloid scar?
Hypertrophic, and outside the edges of injury
What are strictures?
Obstruction of tubes and channels
What causes strictures?
Excessive contraction
What happens if getting constant acid reflex from the stomach to the lower oesophagus?
It can lead to inflammation, fibrosis and consequent stricture formation, which can lead to difficulty swallowing
What causes a diverticular stricture?
Chronic inflammation of the diverticulum
What is the diverticulum?
Outpouchings of the bowel wall
What is a contracture?
Where there is excessive contraction leading to limitation of joint movement
When does a contracture occur?
When there is collagen deposition and then contraction, which leads to a decrease in the size of the wound
What determines the severity of a contracture?
How much scar tissue is laid down
What can happen if a contracture is very exaggerated?
Can compromise movement of the area
Where are contractures commonly seen?
After serious burns
