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NancyMEDSCI203 > Lecture 10: Regeneration, Rpair And Fibrosis > Flashcards

Lecture 10: Regeneration, Rpair And Fibrosis Flashcards

0
Q

What is regeneration?

A

The replacement of lost cells by new cells of the SAME KIND

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1
Q

Healing can occur via which two ways?

A

Regeneration

Repair

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2
Q

Which kind of wounds can be fully healed by regeneration alone?

A

Wounds in which the epithelial lining ONLY is damaged.

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3
Q

Give an example of wounds in which the epithelial lining is the only thing that is damaged

A
  1. Abrasions of the skin

2. loss of intestinal villi which depend on epithelial cells for their shape.

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4
Q

The capacity of a tissue to regenerate arises largely from which type of cells?

A

Stem cells

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5
Q

How frequent are populations of stem cells in adult tissue?

A

Low frequency. < 10^-4 in bone marrow

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6
Q

What are stem cells?

A

Undifferentiated cells with the capacity to generate one, several or all differentiated cell types

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7
Q

What is the name given to a stem cell that has the capacity to generate only one differentiated cell type?

A

Unipotent stem cells

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8
Q

What is the name given to stem cells which have the capacity to generate several differentiated cell types?

A

Multipotent stem cells

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9
Q

What is the name given to stem cells which have the capacity to generate all differentiated cell types?

A

Pluripotent stem cells

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10
Q

What are stem cells like in their usual state?

A

They are usually quiescent (non-dividing)

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11
Q

Despite being normally quiescent, stem cells have indefinite what?

A

Proliferative potential

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12
Q

At what rate do stem cells divide?

A

At a rate that is dictated by tissue demand

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13
Q

What are stem cell progeny?

A

Transit amplifying cells

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14
Q

What kind of division do transit amplifying cells do?

A

Vigorous but transient division

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15
Q

Which two types of division can stem cells undergo?

A
  1. Asymmetrical cell division

2. Symmetrical cell division

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16
Q

What sort of cells are generated from asymmetrical division

A

One replacement stem cell

One differentiating stem cell

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17
Q

What sort of cells are generated in symmetrical division?

A

Identical daughter cells

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18
Q

Divisions with reduced probabilities of generating stem cells (I.e. too much asymmetrical divisions) lead to what?

A

Tissue degeneraton

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19
Q

Divisions with increased probabilities of generating stem cells (I.e. more symmetrical divisions) may lead to what?

A

Tumours

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20
Q

Which type of division is generated by a “big emergency”

A

Symmetrical division

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21
Q

What are the main cells that populate our tissues?

A

Differentiated cells

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22
Q

List the three types of states, tissues may be in

A

Mitotically active all the time,

Normally quiescent,

Terminally differentiated

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23
Q

What do mitotically active tissues do?

A

Regenerate readily after injury

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24
Q

What are some examples of mitotically active tissues?

A

Bone marrow haematopoietic cells
Skin
Gut
Respiratory and genitourinary epithelium

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25
Q

How is regeneration in colon crypts stimulated?

A

Via an lipopolisaccharide > macrophage > toll like receptor-4 > cyclooxyenase-2 > Prostaglandin E-2

pathway

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26
Q

What are normally quiescent tissues like?

A

Generally non- dividing but they can be induced into regenerative cell division by injury

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27
Q

What are some examples of normally quiescent tissues?

A

Endocrine glands

Liver

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28
Q

What happens when less than 70% of liver is lost?

A

Division of mature hepatocytes and stromal cells rapidly replace tissue

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29
Q

What other cells also contribute to tissue replacement when 70% of liver is lost?

A

Hepatic stem cells (via oval cells)

Mesenchymal stem cells

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30
Q

What do division of mature hepatocytes respond to?

A

Kupffer cell derived tumour necrosis factor, interleukin-6, hepatocyte growth factor, and transforming growth factor-α

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31
Q

What happens to terminally differentiated tissues?

A

They cannot re-enter the cell cycle and are not replaced

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32
Q

Give some examples of terminally differentiated tissues

A

Some neurons, cardiac myocytes

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33
Q

Which transcription factors may be used to reprogrammed differentiated cells?

A

Oct4, Sox2, Klf4, Myc

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34
Q

What are these differentiated cells reprogrammed into?

A

Induced pluripotent stem cells (iPS)

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35
Q

What does repair follow?

A

Loss of both functional (parenchymal) and connective (stromal) components of tissues

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36
Q

What does repair involve

A

The temporary formation of granulation tissue

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37
Q

The tissue cannot be what?

A

Reconstituted as ‘new’

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38
Q

What is the wound replaced by?

A

A fibrous scar

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39
Q

List the components of the repair cascade

A

Haemostasis

Inflammation

Proliferation

Remodelling

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40
Q

When does haemostasis occur?

A

Within a few hours

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41
Q

What happens in haemostasis

A

Platelets aggregate and degranulation at sites of blood vessel damage

Fibrinogen is converted into fibrin and cross linked with fibronectin and other ECM proteins by Transglutaminases

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42
Q

Why is clotting important?

A

It provides temporary mechanical stability

Forms a barrier to invading microorganisms

Prevents desiccation and further loss of plasma

Provides provisional matrix where cells involved in repair migrate

Generates matrix rich in cytokines and growth factors like platelet derived growth factor, transforming growth factor-β and vascular endothelial growth factor

43
Q

What are the main cells involved in haemostasis

A

Platelets

44
Q

What are the proteins involved in haemostasis

A

Fibrin, fibronectin, Transglutaminases

45
Q

When does inflammation occur

A

Within a few days

46
Q

Why does inflammation occur

A

The removal of necrotic tissue must occur before repair

47
Q

What is debridement?

A

The removal of necrotic tissue

48
Q

Which cells proceed first? Which second?

A

Neutrophils, followed by macrophages

49
Q

What are the processes first carried out by neutrophils, and then by macrophages?

A

Phagocytose tissue debris, foreign material and bacteria

Secrete proteases like collagenases that liquefy necrotic tissue

Generate free radicals that inhibit microbial growth (and damage normal cells)

50
Q

What other things to macrophages do?

A

Phagocytose dead neutrophils

Secrete growth factors for fibroblasts, capillary endothelial cells and epithelial cells

Process antigens to activate immunity

51
Q

What type of cells also release growth factors that immediate repair ?

A

Platelets

52
Q

How long does proliferation take?

A

A few weeks

53
Q

Following injury, which cells proliferate?

A

Stromal and epithelial cells

54
Q

What is Granulation tissue ?

A

Highly vascular connective tissue

55
Q

Fibroblasts start proliferating and migrate where?

A

Into the provisional matrix

56
Q

What do fibroblasts do?

A

They form a new matrix including collagen III initially, followed by collagen I, fibronectin and glycosaminoglycams

57
Q

This new matrix formation is also termed what?

A

Repithelialisation

58
Q

Fibroblasts may differentiate into what kind of cells?

A

Myofibrobalsts

59
Q

What stimulates fibroblasts differentiation into myofibroblasts?

A

Platelet derived growth factor and transforming growth factor-β from platelets and macrophages

Contact with embryonic alternatively-spliced isoform of fibronectin , ED-A fibronectin which is synthesised in response to transforming growth factor - β

Mechanical tension

60
Q

What do myofibroblasts do?

A

They lay down collagen fibres, like fibroblasts

Express α-smooth muscle actin, smooth muscle myosin and bundles of contractile myofilaments (like smooth muscle cells)

Focal adhesions link intracellular actin micro filaments with extracellular fibronectin

Attach to each other and to ED-A fibronectin and contract to ull edges of wound together to accelerate healing

Die by apoptosis at end of granulation phase

61
Q

What features do myofibroblasts have which links intracellular actin micro filaments with extracellular fibronectin?

A

Focal adhesions

62
Q

What are stress fibres?

A

Intracellular actin myofilaments

63
Q

How does contraction improve healing

A

It reduces width of wound by 30-50% of original span

64
Q

What is angiogenesis?

A

Endothelial cells forming new capillaries in the granulation tissue

65
Q

Endothelial cells proliferate and migrate in what way?

A

Chemotactically

66
Q

Endothelial cells proliferate and migrate chemotactically in response to what?

A

Macrophage derived Vascular endothelial growth factor

67
Q

What do pericytes do?

A

Stabilise endothelial cells

68
Q

How are pericytes produced?

A

In response to platelet derived growth factors

69
Q

Where are plasma cells abundant?

A

In granulation tissue

70
Q

What do plasma cells do?

A

They produce antibodies, and suppress bacterial growth

71
Q

What is re-epithelialisation

A

Process by which epithelial cells recover an area from which they have been removed

72
Q

Under normal conditions epithelial cells adhere to the basement membrane laminin using what kind of receptors?

A

Integrin receptors

73
Q

Which two growth factors induce epithelial cells?

A

Epidermal growth factor and transforming growth factor -α

74
Q

What do EGF and TGF-α induce epithelial cells to do?

A

Upregulate the EGF receptor,

Express new set of integrins and migrate along wound margin

Move through cross linked fibrin attached to underlying stroma by activating proteolytic enzymes

Regain their original phenotype when they have formed a continuous layer

75
Q

What are the proteolytic enzymes that are activated by epithelial cells

A

Urokinase plasminogen activator

76
Q

What does uPA do?

A

Converts plasminogen into plasmin

77
Q

What does plasmin do?

A

Degrades fibrin and activates other proteases like matrix metalloproteinases

78
Q

How long does remodelling take?

A

Montsh

79
Q

What happens in the final phase of repair?

A

Granulation tissue is replaced with acellular scar tissue

80
Q

What else happens in remodelling?

A

Disogranised collagen III fibres are replaced by parallel bundles of collagen I

Collagen accumulates to a maximum after 2-3 months when the equilibrium between collagen doosition and degradation by matrix metalloproteinases is restored

Strength of collagen continues to increase cross linking

81
Q

What does excessive pathological scarring cause?

A

Disfigurement, pain, loss of mobility

82
Q

What type of ECM component can be over expressed?

A

Collagen

83
Q

What can over expression of ECM components arise from?

A

Excessive inflammatory response to injury resulting from infection or the presence of foreign bodies

Excessive production of fibrogenic cytokines like transforming growth factor β-1

Prolonged presence of myofibroblasts maybe as a result of reduced sensitivity to apoptosis

84
Q

Fibrotic diseases account for how much of deaths in the industrialised world

A

45%

85
Q

Why are these statistics under appreciated?

A

These deaths are reported as blocked arteries, pathological airway remodelling, chronic obstructive pulmonary disease, or heart/liver/kidney failure

86
Q

Wound repair can evolve into what? (If injury is prolonged or healing response is days regulated

A

Progressive development of fibrosis

87
Q

What are some agents that can cause sustained injury

A

Silica , other crystals like MSU, smoke in the lung

Inability to maintain telomeres, lung

Hypercholesterolemia, leading to liver damage

Alcohol abuse or viruses HBV, HCV causing liver damage

Obstruction of ureter leading to kidney fibrosis

88
Q

Fibrosis results from what kind of myofibroblast responses?

A

Exaggerated myofibroblast responses

89
Q

What kind of cells can contribute to fibrosis?

A

Macrophages, neutrophils and eosinophils

90
Q

What do macrophages, neutrophils and eosinophils release?

A

Inflammatory cytokines that are also pro-fibrotic

91
Q

What are some examples of these inflammatory cytokines released by macrophages neutrophils and eosinophils

A

Tumour necrosis factor
Interleukin-1
Transforming growth factorβ
Reactive oxygenated species

92
Q

What do these inflammatory cytokines do

A

Perpetuate damage and promotes fibrosis

93
Q

What are macrophages recruited by?

A

Persistent injury

94
Q

What do macrophages release?

A

Tumour necrosis factor
Interleukin -1β
Transforming growth factor β

95
Q

What is the effect of macrophages?

A

Pro fibrotic

96
Q

What are neutrophils recruited by?

A

Macrophages,

Tumour necrosis factor

Interleukin -1β

97
Q

What do neutrophils release?

A

Reactive oxidative species

Other toxin products

98
Q

What is the effect of neutrophils?

A

Perpetuate tissue damage

99
Q

What are eosinophils recruited by?

A

Allergic sensitisation

100
Q

What do they release?

A

Interleukin-1β

Transforming growth factor β

101
Q

What are the effects of eosinophils ?

A

Pro fibrotic

102
Q

What does fibrosis suppress?

A

Blood flow

103
Q

What is the effect of suppressed blood flow in the liver?

A

This can lead to portal hypertension aka elevated blood pressure

And endothelial cell damage

104
Q

What is the effect of portal hypertension and EC damage

A

Create a cycle of tissue damage, macrophage/neutrophil recruitment and further fibrosis

105
Q

Where can additional myofibroblasts differentiate from?

A

Fibroblasts

Bone marrow-derived monocytes via fibre yetis

Epithelial cells which may undergo epithelial-to-mesenchymal transition in the presence of mechanical tension, transforming growth factor β and hyaluronan

NancyMEDSCI203 (12 decks)

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