MoD session 4: regeneration and repair

Question 1

What is regeneration?

Answer 1

Growth of cells and tissues to replace lost structures

Question 2

Examples of cells that can regenerate

Answer 2

Epithelia of the skin and GI tract, as long as the stem cells aren’t destroyed

Question 3

Labile tissues?

Answer 3

Cells constantly dividing throughout life replacing cells that are destroyed. Normal state: G1-M-G1. Rapid proliferation. Cells short-lived, constantly replaced by cells derived from stem cells

E.g. surface epithelia, mucosa lining secretory ducts of glands,cells of bone marrow

Question 4

Stable tissues?

Answer 4

Low level of replication but cells can rapidly divide in response to stimuli and can reconstruct the tissue of origin. Resting state: G0, activated to replicate sometimes. Mature, usually quiescent or v slow but can divide persistently when required

E.g. parenchymal cells of liver/kidneys/pancreas, mesenchymal cells e.g. fibroblasts, WBCs, vascular endothelial cells, osteoblasts

Question 5

Permanent tissues?

Answer 5

Non-dividing (stuck in G0). Cells have left the cell cycle and can’t undergo mitosis. No stem cells that can be recruited to replace.

E.g. neurones, skeletal muscle, cardiac muscle

Question 6

Different types of stem cell?

Answer 6

Totipotent: can divide into any cell type. Found in zygotes (give rise to entire organism)

Pluripotent: can divide into any cell type. In embryonic stem cells

Multipotent: can produce several types of differentiated cells from within their lineage e.g. haematopoietic cells

Unipotent: can only give rise to one type of cell

Question 7

Describe fibrous repair (organisation)

Answer 7

1. Phagocytosis of necrotic tissue debris
2. Angiogenesis
3. Wound contraction (FBs and MFBs synthesise collagen producing granulation tissue)
4. Granulation tissue becomes less vascular and starts to form fibrous scar
5. Scar matures and shrinks due to fibril contraction in MFBs, fewer vessels, more collagen, fewer cells

Question 8

Growth factors?

Answer 8

Most important local mediators, act over a short distance.Bind to specific receptors to stimulate transcription of genes that regulate the entry of the cell into the cell cylce and its passage through.

Effects: stimulate/inhibit proliferation, differentiation, cell locomotion, contractility, angiogenesis and others

Question 9

Epidermal growth factor?

Answer 9

Mitogenic for epithelial cells, hepatocytes and fibroblasts. Binds to EDGFR. Produced by keratinocytes, macrophages and inflammatory cells

Question 10

Vascular endothelial growth factor?

Answer 10

Induces vasculogenesis and role in angiogenesis in wound healing and tumours

Question 11

Platelet-derived growth factor?

Answer 11

Stored in platelet alpha granules and released on platelet activation. Also produced by macrophages, endothelial cells, smooth muscle cells and tumours.
Causes migration and proliferation of FBs, smooth muscle cells and monocytes

Question 12

Tumour necrosis factor?

Answer 12

Induces FB migration and proliferation and collagenase secretion

Question 13

What is contact inhibition?

Answer 13

When normal cells are isolated they replicate until they have cells touching them: so form a monolayer sheet with no overlap
Loss of contact promotes proliferation e.g. in wound healing
This quality is altered in neoplasia

Question 14

How do cells adhere?

Answer 14

By adhesion molecules:

• to each other by CADHERINS
• to the ECM by INTEGRINS

Question 15

Scenario for healing by primary intention?

Answer 15

Clean wounds with apposed edges & minimal tissue loss. Disrupted basement membrane continuity, only a few cell deaths, minimal granulation tissue
E.g. in incisional, non-infected and sutured wounds

Question 16

Describe the process of healing by primary intention

Answer 16

1. s-min: haemostasis and scab (dehydration of surface clot)
2. m-hours: acute inflammation
   3.

Question 17

Risk of healing by primary intention?

Answer 17

Infection gets trapped–>abscess

Question 18

How do the epidermis and dermis regenerate in primary intention healing?

Answer 18

Dermis undergoes fibrous repair

Epidermis regenerates from superficial to deep

Question 19

Scenario for healing by secondary intention

Answer 19

Excisional wounds or wounds with tissue loss and separated edges (unapposed). Takes longer
Often in infected wounds, infarcted areas, ulcers or abscesses

Question 20

Process of healing by secondary intention

Answer 20

1. Open wound has lots of granulation tissue growing inwards from wound margins
2. Big inflammatory reaction (clots and necrotic cells)
3. Scab contracts and shrinks
4. Substantial scar formation, new epidermis often thinner

Question 21

Risk of healing by secondary intention?

Answer 21

Extensive collagen deposition can cause a big scar and deformity–>more contraction

Question 22

Describe the bone healing process

Answer 22

1. Following fracture a HAEMATOMA forms around the injury (rupture of vessels in marrow cavity and periosteum)
2. SOFT CALLUS at ~1w: not for weight-bearing but splints the fracture on the outside as extends beyond the injury, sometimes has islands of cartilage
3. HARD/BONY CALLUS after several weeks. Laid down by osteoblasts; initially woven bone then more organised & stronger lamellar bone
4. REMODELLING of bone in response to mechanical stresses. Bone that is not physically stressed gets resorbed

Question 23

Give some local factors that can affect wound healing

Answer 23

Size/location/type of wound-indicates type of healing
Blood supply-atherosclerosis and low vascularity impede healing
Denervation
Local inflammation
Foreign bodies-persistent inflammation, favour infection
Haematoma-large can slow healing
Necrotic tissue-body needs to clear
Mechanical stress-can pull apart delicate tissue
Protection-e.g. dressings help keep clean
Surgical techniques-can promote rapid healing
Infection-supparation (pus), gangrene, systemic

Question 24

Give some systemic factors that can affect wound healing

Answer 24

Age
Anaemia/hypoxia/hypovolaemia
Obesity (more tension on wound and wound dehiscence)
Malignancy
Diabetes (microangiopathy impairs blood and decreases infection resistance)
Genetic disorders
Drugs (steroids, cytotoxics decrease, antibiotics increase healing)
Vitamin deficiency-e..g vit C deficiency decreases collagen synthesis
Malnutrition-lack of essential substances e.g. amino acids for protein synthesis
Other co morbidities e.g. RA, cardiovascular disease

Question 25

State the possible complications of fibrous repair

Answer 25

Fibrous adhesions-block tubes or compromise organs
Loss of function-replacement of cells by collagenous scar tissue
Disrupted tissue architecture
Keloid scar
Excess scar contraction
Insufficient fibrosis-causes wound dehiscence

Question 26

Healing in cardiac muscle?

Answer 26

Limited/no regeneration

MI results in a scar that doesn’t heal; can compromise function

Question 27

Liver healing?

Answer 27

High regenerative capacity: if part of the liver is removed, compensatory liver tissue growth occurs via enlargement of the lobes that remain

Question 28

What is Wallerian degeneration?

Answer 28

Axon degeneration when a nerve is severed

Question 29

Peripheral nerve healing?

Answer 29

Proximal stumps of degenerated axons sprout and elongate. Schwann cells guide them back to the tissue the nerve innervates

Question 30

How fast do peripheral nerves grow?

Answer 30

1-3mm per day

Question 31

Cartilage healing?

Answer 31

Heals poorly: lack of blood supply, lymphatic drainage and innervation

Question 32

CNS healing?

Answer 32

Neural tissue is permanent. When neural tissue is damaged it is replaced by glial cells

Question 33

Scurvy?

Answer 33

Vitamin C deficiency results in symptoms including swollen/bleeding gums, peripheral skin haemorrhage and susceptibility to bruising.
Vitamin C is a cofactor for prolyl hydroxylase which is used in the production of hydroxyproline from proline in collagen synthesis

Question 34

Ehlers-Danlos syndrome?

Answer 34

Fragile connective tissue due to disrupted collagen synthesis.
Symptoms: bruising, dissecting aortic aneurysm, joint laxity, hernias, hyperelasticity of skin

Question 35

Osteogenesis imperfecta?

Answer 35

Inborn error of type I collagen synthesis. Dominant or recessive
Type I collagen most abundant in bone, so disease causes skeletal weakness and deformity, fracture susceptibility and blue sclerae (as they are thinned)

Question 36

Marfans syndrome?

Answer 36

Defect in the gene for fibrillin (a protein essential for elastic fibre integrity)
Signs: unusually tall, long arm span, dislocation of eye lenses, aortic and mitral valve incompetence, weakness of aortic media, predisposed to dissecting aneurysms

Question 37

Alport syndrome?

Answer 37

Genetic abnormality in type IV collagen, so glomeruli are abnormal. Blood not filtered properly so protein and blood pass into the urine
Causes kidney disease, hearing loss and eye abnormalities

Question 38

Liver cirrhosis?

Answer 38

Presence of fibrous septa that subdivide the parenchyma into nodules.
Is the end stage of all chronic liver disease
Irreversible
Associated with symptoms of liver failure + portal hypertension

Question 39

Coal worker’s pneumocconiosis?

Answer 39

Coal dust phagocytosed by alveolar macrophages and aggregates around the bronchioles. Black pigment seen in lungs. Can be asymptomatic or cause large irregular nodules which may contract leading to emphysema and lung disruption

Question 40

Keloid scar?

Answer 40

Excess proliferation of fibroblasts and excess collagen production, that moves outside the borders of an injury/scar. Often raised
Does not regress, and excision will just create another one. Different from a hypertrophic scar as moves outside the boundary of the wound
Common in Afro-Caribbean individuals

Question 41

Oesophageal strictures?

Answer 41

Narrowing or tightening of the oesophagus due to inflammation/fibrosis/neoplasia/lymph node enlargement/diseases affecting oesophageal smooth muscle

Question 42

Contractures?

Answer 42

Tissue distortion resulting in permanent shortening of a muscle. Excess contraction of the wound during healing

Question 43

Traumatic neuroma?

Answer 43

Growth of nerve tissue due to acute or chronic nerve injury, especially happens after surgery
Causes a focal area of pain tender on palpation with a firm skin nodule

Question 44

What is ‘proud flesh’?

Answer 44

Excess persistent granulation tissue above the surface of the skin that blocks re-epithelialisation

Question 45

What is a pressure sore?

Answer 45

Area of persistently red, broken, blistered or necrotic skin. Commonly over bony prominences such as the sacrum. Common in bed-bound patients due to pressure and friction.