Regeneration and Repair Flashcards Preview

ESA 2- Mechanisms of Disease > Regeneration and Repair > Flashcards

Flashcards in Regeneration and Repair Deck (213):
1

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.

2

What are differentiated cells derived from?

Stem cells

3

What is repair a response to?

An injury involving both regeneration and scar formation (fibrosis)

4

What does repair lead to?

Permanent alternation in normal structure

5

How much can stem cells proliferate?

Potentially limitless

6

What happens to daughter stem cells?

They either remain as a stem cell, or differentiate into a specialised cell type

7

What is the importance of some daughter stem cells remaining as stem cells?

To maintain the stem cell pool

8

What happens to stem cells in early life?

They develop into many different cell types

9

What can stem cells be said to be?

An ‘internal repair system’

10

What is the purpose of the internal repair system produced by stem cells?

To replace or damaged cell tissues

11

What is the potential therapeutic utility of stem cells?

In degenerative disease

12

What does unipotent mean?

Only able to produce one type of differentiated cell

13

What does multipotent mean?

Able to produce several types of differentiated cells

14

What does totipotent mean?

Able to produce any cell type

15

What cells are totipotent?

Embryonic stem cells

16

Give two examples of where stem cells are found in a mature human?

Bases of crypts 
Hematopoietic ontogeny

17

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

18

What happens in haematopoietic ontogeny?

Multipotent stem cells in the bone marrow can produce cells within their lineage

19

Clinically, what is haemtopoietic ontogeny good for?

Therapeutics

20

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

21

Is the propensity to regenerate the same among all cell types?

No, it varies

22

What happens to labile cells?

They are continuously dividing

23

What is the purpose of the continual division of labile cells?

They are replacing cells that have been destroyed by apoptosis

24

Give two examples of cells that are labile

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

53

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

55

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

85

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