Regeneration and Repair Flashcards
(213 cards)
1
Q
How can regeneration be defined?
A
As the proliferation of dead or damaged cells by functional, differentiated cells or tissues in which normal structure is restored.
2
Q
What are differentiated cells derived from?
A
Stem cells
3
Q
What is repair a response to?
A
An injury involving both regeneration and scar formation (fibrosis)
4
Q
What does repair lead to?
A
Permanent alternation in normal structure
5
Q
How much can stem cells proliferate?
A
Potentially limitless
6
Q
What happens to daughter stem cells?
A
They either remain as a stem cell, or differentiate into a specialised cell type
7
Q
What is the importance of some daughter stem cells remaining as stem cells?
A
To maintain the stem cell pool
8
Q
What happens to stem cells in early life?
A
They develop into many different cell types
9
Q
What can stem cells be said to be?
A
An ‘internal repair system’
10
Q
What is the purpose of the internal repair system produced by stem cells?
A
To replace or damaged cell tissues
11
Q
What is the potential therapeutic utility of stem cells?
A
In degenerative disease
12
Q
What does unipotent mean?
A
Only able to produce one type of differentiated cell
13
Q
What does multipotent mean?
A
Able to produce several types of differentiated cells
14
Q
What does totipotent mean?
A
Able to produce any cell type
15
Q
What cells are totipotent?
A
Embryonic stem cells
16
Q
Give two examples of where stem cells are found in a mature human?
A
Bases of crypts
Hematopoietic ontogeny
17
Q
What happens to stem cells in the bases of crypts?
A
They produce new cells at the bottom, which then move up and undergo apoptosis, meaning the crypts are constantly regenerating
18
Q
What happens in haematopoietic ontogeny?
A
Multipotent stem cells in the bone marrow can produce cells within their lineage
19
Q
Clinically, what is haemtopoietic ontogeny good for?
A
Therapeutics
20
Q
How can haemopoietic ontogeny be useful therapeutically?
A
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
21
Q
Is the propensity to regenerate the same among all cell types?
A
No, it varies
22
Q
What happens to labile cells?
A
They are continuously dividing
23
Q
What is the purpose of the continual division of labile cells?
A
They are replacing cells that have been destroyed by apoptosis
24
Q
Give two examples of cells that are labile
A
Epithelial
Haemopoietic
25
What is the normal state for labile cells
Cell division (G1-M-G2)
26
What do labile cells usually display?
Rapid proliferation
27
What state are stable cells usually in?
The resting state (G0) - they have not get entered the cell cycle
28
Can stable cells undergo division?
Yes, if appropriately stimulated
29
Give 3 example of stable cells
Hepatocytes
Osteoblasts
Fibroblasts
30
What is the speed of regeneration for stable cells?
Usually quite low, but depends on the stimuli exposed to
31
What state are permanent cells in?
G0
32
Are permanent cells capable of dividing?
No
33
Give 2 examples of permanent cells?
Neurones
Cardiac myocytes
34
When are permanent cells produced?
During embryonic development
35
Give an example of a response of a permanent cell?
Compensatory hyperplasia
36
What happens in compensatory hyperplasia?
Not producing new cells, but existing cells get bigger
37
Where does compensatory hyperplasia occur?
In the liver
38
What is each phase dependant on in the cell cycle?
Activation and completion of the previous stage
39
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
40
Where are there checkpoints in the cell cycle?
Between G1 and S
Between G2 and M
41
What is the purpose of the checkpoint between G1 and S?
The integrity of DNA is monitored before it’s replicated
42
What is the purpose of the checkpoint between G2 and M?
DNA is checked after it’s replicated to ensure its safe to continue
43
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.
44
What is the problem with studying the factors that control regeneration?
They are complex and poorly understood
45
Give two factors that control regeneration?
Growth factors
Contact between basement membrane and adjacent cells
46
What do growth factors do?
Help drive proliferation in the stem cell population
47
What do growth factors function as?
Ligands binding to specific receptors
48
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
49
What is the process of growth factors controlling the cell cycle known as?
Receptor mediated signal transduction
50
Give two types of molecules that growth factors can be?
Proteins
Hormones
51
Give two examples of protein growth factors
EGF (epidermal growth factor)
PDGF (platelet derived growth factor)
52
What does EGF do?
Mitogenic for keratinocytes and fibroblasts, and so stimulates the formation of granulation tissue
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What is EGF produced by?
Keratinocytes and macrophages, and other inflammatory cells attracted to the area of damage
54
What does PDGF do?
Causes the migration and proliferation of lots of cells that help with inflammation and healing of skin wounds
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Where is PDGF stored?
Platelet granules
56
When does PDGF get released?
When platelets become activated
57
Give 3 examples of hormones that can act as growth factors
Oestrogen
Testosterone
Growth hormone
58
What kinds of hormones can growth factors be?
Autocrine
Paracrine
Endocrine
59
What does an autocrine hormone do?
Acts on the cell that produced it
60
What do paracrine hormones do?
Acts on the cells adjacent to the one that produced it that have the appropriate receptor
61
What do endocrine hormones do?
Travel in the blood and act on cells far away from the original site of production
62
How does contact between basement membranes and adjacent cells control regeneration?
There is signalling through adhesion molecules, which inhibits proliferation in intact tissue
63
What is the control of regeneration by contact between the basement membrane and adjacent cells known as?
Contact inhibition
64
Where are regenerative control mechanisms deranged?
Cancer
65
What is fibrous repair?
The replacement of functional tissue by scar tissue
66
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
67
Why does a destruction in collagen framework lead to scarring?
Because you get deposition of collagen to replace the framework
68
What are the key components of fibrous repair?
Cell migration and inflammation
Angiogenesis
Extracellular matrix production and remodelling
69
Why is cell migration important in fibrous repair?
Need to get cells there so they can exert their effects
70
What are the cell types in fibrous repair?
Inflammatory cells
Endothelial cells
Fibroblasts and myofibroblasts
71
What inflammatory cells are involved in fibrous repair?
Neutrophils
Macrophages
Lymphocytes
72
What is the purpose of neutrophils and macrophages in fibrous repair?
Phagocytosis of debris
73
What is the purpose of lymphocytes and macrophages in fibrous repair?
Chemical mediators
74
What do chemical mediators do?
Attract other cells
75
What is the purpose of the endothelial cells in fibrous repair?
Angiogenesis
76
What is the purpose of (myo)fibroblasts in fibrous repair?
Extracellular matrix production
Wound contraction
77
What is angiogenesis known as in utero?
Vasculogenesis
78
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
79
What is angiogenesis initiated by?
Proangiogenic growth factors
80
Give an example of a proangiogenic growth factor
VEGF
81
What happens to pre-exisiting vessels in angiogenesis?
They sprout new vessels
82
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
83
What is the importance of endothelial maturation and tubular regeneration?
So can form a tubular structure that blood can flow through
84
What do periendothelial cells do?
Make the outer layers of vessels
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What do periendothelial cells consist of?
Pericytes and vascular smooth muscle cells
86
Where is the angiogenic mechanism exploited?
In malignant cells, so they can have a blood supply and continue to grow
87
What do both tissue repair and regeneration depend on?
The activity of soluble factors and interaction between cells and components of the extracellular matrix
88
Where is the extracellular matrix found?
It fills spaces between tissues
89
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
90
Where does the extracellular matrix help maintain polarity?
The skin- keeps basal cells in the bottom and keratin layer on top
91
What is the importance of the separation of tissue compartments?
Maintains tissue microenvironment
Contains separate areas
92
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
93
What is the importance of collagen?
Provides extracellular framework
94
What is collagen composed of?
Triple helices of various polypeptide alpha chains
95
What are the fibrillar collagens?
Type I-III
96
Give two places fibrillar collagen is found
Dermis
Bone
97
What are fibrillar collagens composed of?
Uninterrupted triple helices
98
What are the amorphous collagens?
IV-VI
99
Where are amorphous collagens found?
Basement membrane
100
What does amorphous collagen form?
Sheets
101
How is collagen remodelled?
By specific collagenases
102
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
103
Give 4 defects of collagen synthesis
Vitamin C deficiency
Erlers-Danlos syndomes
Osteogenesis imperfecta
Alport
104
What is vitamin C deficiency known as?
Scurvy
105
What happens in scurvy?
Inadequate vit C dependant hydroxylation of α chains
106
What does inadequate vitamin C hydroxylation lead to?
Defective helix formation
107
What is the result of defective helix formation?
Lacks strength
Vulnerable to enzymatic degradation
108
Where does scurvy particularly affect?
Collagen supporting blood vessels
109
What is the result of scurvy affecting collagen affecting blood vessels?
Haemorrhage
110
What does scurvy lead to in infants?
Skeletal changes
111
What is Erlers-Danlos syndrome?
A genetic defect in synthesis or structure of fibrillar collagen
112
What defect occurs in Erlers-Danlos syndrome?
Defective conversion of procollagen to tropocollagen
113
What are the symptoms of Erlers-Danlos syndrome?
Stretchy skin
Hypermobile joints
114
How many types of osteogenesis imperfecta are there?
4, of varying severity
115
What happens in severe osteogenesis imperfecta?
Children die in utero
116
What causes children to die in utero in osteogenesis imperfecta?
Multiple fractures
Poor development
117
What is Alport syndrome?
Genetic deafness
118
What are the components of the extracellular matrix?
Matrix glycoproteins
Proteoglycans
Elastin
119
What is the purpose of matrix glycoproteins?
Organise and orientate cells
Support cell migration
120
Give 3 examples of matrix glycoproteins
Fibronectin
Laminin
Tenascin
121
What is the purpose of proteoglycans?
Matrix organisation
Cell support
Regulate availability of growth factors
122
Give an example of a proteoglycan
Heparin sulphate proteoglycan
123
What is the purpose of elastin?
Provides tissue elasticity
124
What is the importance of tissue elasticity?
Provides tensile strength and recoil
125
What are the stages of the mechanism of fibrous repair?
#NAME?
126
What happens in the inflammatory cell infiltrate stage of fibrous repair?
Blood clot forms
Acute inflammation around edges
Chronic inflammation occurs
127
How does a blood clot form?
Platelet adhesion and aggregation
128
What is the importance of blood clot formation?
Prevents further bleeding and promotes inflammatory response
129
What is the importance of acute inflammation around the edges in fibrous repair?
Used as a scaffold for migration in, and clears debris
130
What happens to accommodate chronic inflammation?
Macrophages and lymphocytes migrate into clot
131
What happens as the clot is replaced by granulation tissue?
Angiogenesis
(Myo)fibroblasts migrate and differentiate
132
What is the importance of the migration and differentiation of (myo)fibroblasts?
Produce extracellular matrix, which makes glycoproteins
133
How long does the maturation stage of fibrous repair take?
Relatively long
134
What happens in the maturation stage of fibrous repair?
Cell population falls
Collagen increases, matures and remodels
Myofibroblasts contract
Vessels differente and are reduced
135
Why does the cell population fall in maturation?
Because neutrophils predominantly replaced macrophages
136
In what situation are neutrophils not replaced by macrophages in maturation?
If infection present
137
What is the purpose of myofibrillar contraction in maturation?
Reduces volume of defect
138
What is left after maturation
A fibrous scar
139
What is the problem with studying the control of fibrous repair?
Complex and poorly understood
140
How is fibrotic repair controlled?
Inflammatory cells recruited by chemotaxis
Angiogenesis controlled by platelets, ECM and others
Fibrosis controlled by macrophages
141
How is angiogenesis controlled by platelets and ECM?
They produce cytokines in response to hypoxia
142
How do macrophages control macrophages?
They produce various pro-fibrotic cytokines, and cause fibroblast proliferation and ECM production
143
Give 3 examples of pro-fibrotic cytokines
IL1
TNT-α
TGF-ß
144
What is the simplest type of healing?
Healing by primary intention
145
When does healing by primary intention occur?
In clean, uninfected surgical incisions, where two edges can be imposed
146
What usually happens with surgical incisions?
They are sutured to make it easier to heal
147
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
148
What occurs first in healing by primary intention?
The epidermis regenerates
149
What is the process of epidermal regeneration called?
Re-epitheliasation
150
How extensive is the formation of clots and granulation tissue in healing by primary intention?
Minimal
151
What happens once the epidermis has regenerated in healing by primary intention?
The dermis undergoes fibrous repair
152
When are sutures removed from a surgical incision?
Usually after ~10 days
153
How strong is the skin after 10 days?
~10% of normal
154
What happens once granulation tissue has been formed?
There is a transition to scar tissue
155
How long does maturation of a scar occur for?
Up to 2 years
156
What is the advantage of healing by primary intention?
There is minimal contraction and scarring, and the skin has good strength
157
What is the downside of healing by primary intention?
There is a risk of trapping infection
158
What is the result of trapped infection?
Abscesses in the skin
159
Why does healing by primary intention carry with it a risk of trapping infection?
Because the edges are opposed so tightly, infection cannot escape
160
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
161
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
162
What is the result of the epidermis regenerating from the base up?
It brings up extensive collagen deposition
163
What is the result of the repair process producing more granulation tissue?
Formation of a substantial scar
164
What happens to the scar over time?
It gets smaller because of myofibrillar contraction
165
How does healing of bone fractures compare to repair at other sites?
Similar, but some modification for special environment
166
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
167
What is the purpose of haemotoma formation in bone repair?
Fills fracture gap and surrounds area of injury
168
What happens with the stimulation of osteoclasts and osteoblasts?
Fracture ends of bone start to get remodelled
169
What is the specialised mixture of cells formed in bone repair called?
Callus
170
What is the limitation of the soft callus?
It provides no structural rigidity for weight bearing
171
What is sometimes present when bone is laid down in the irregular woven pattern during fracture repair?
Islands of cartilage
172
How long does it take to start to get bone being laid down after a fracture?
2-3 weeks
173
What is the purpose of the irregular woven bone in fracture repair?
Helps stabilise the fracture site
174
What does the external callus do?
Provides splint-like support
175
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
176
Where may a wound heal faster, and why?
The face, because it’s highly vascularised
177
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
178
How does apposition affect wound healing?
Healing good if skin edges easily opposed
179
How does movement affect wound healing?
Movement can cause skin to become unopposed
180
What can infection lead to?
Suppuration
Gangrene
Systemic infection
181
What affect does infection have on healing?
Delays it
182
What foreign materials can affect wound healing?
Dirt
Glass
Sutures
Necrotic damage
183
What general factors can affect wound healing?
Age
Drugs
General dietary deficiencies
Specific dietary deficiencies
General state of health
General cardiovascular status
184
Give an example of a drug that can affect healing
Steroids
185
How can steroids affect healing?
They have anti-inflammatory effects, and inhibit collagen synthesis, so slow healing
186
How can general state of health affect healing?
Some chronic disease, for example if immunocompromised, more likely to pick up infection
187
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
188
What complications of repair can occur?
Insufficient fibrosis
Excessive fibrosis
Keloid scar
Strictures
Contractures
189
What could insufficient fibrosis be due do?
Inadequate granulation tissue or scar formation
190
What does insufficient fibrosis lead to?
Wound dehiscence hernia
191
What is a wound dehiscence hernia?
Where the wound come apart with its contents bulging out
192
Where do wound dehiscence hernias commonly occur?
In the abdomen, as high abdominal pressure
193
What are the risk factors for wound dehiscence hernias?
Obesity
Elderly
Malnutrition
Steroids
194
What happens in excessive fibrosis?
Excessive deposition of collagen
195
Where does excessive fibrosis usually occur?
In chronic disease, where there is chronic stimulation of the inflammatory process
196
What is the result of excessive fibrosis?
Cosmetic scarring
Keloids
Cirrhosis
Lung fibrosis
197
What does cirrhosis of the liver usually result from?
Alcohol
Hepatatis B
198
What happens in cirrhosis of the liver?
The liver is constantly chronically inflamed, leading to regenerative nodules and cirrotic fibrous bands
199
What happens in lung fibrosis?
Chronic stimulation leads to irritation and therefore a chronic inflammatory response, leading to fibrosis
200
What can cause chronic stimulation in the lungs?
Asbestos
Silicon
201
What does fibrosis in the lungs cause?
Contraction of the lung lobes, leading to problems with breathing
202
What causes a keloid scar?
Excessive formation of components of the repair process, including collagen
203
What are the features of a keloid scar?
Hypertrophic, and outside the edges of injury
204
What are strictures?
Obstruction of tubes and channels
205
What causes strictures?
Excessive contraction
206
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
207
What causes a diverticular stricture?
Chronic inflammation of the diverticulum
208
What is the diverticulum?
Outpouchings of the bowel wall
209
What is a contracture?
Where there is excessive contraction leading to limitation of joint movement
210
When does a contracture occur?
When there is collagen deposition and then contraction, which leads to a decrease in the size of the wound
211
What determines the severity of a contracture?
How much scar tissue is laid down
212
What can happen if a contracture is very exaggerated?
Can compromise movement of the area
213
Where are contractures commonly seen?
After serious burns
