Regeneration and Repair

Question 1

Give somewhere that unipotent stem cells can be found

Answer 1

Crypts of Lieberkuhns

Question 2

Give somewhere that multipotent stem cells can be found

Answer 2

Haemopoietic tissue

Question 3

Give somewhere that totipotent stem cells can be found

Answer 3

Embryo

Question 4

Describe the difference between labile, stable and permanent stem cells with examples.

Answer 4

Labile - constant division, rapid proliferation e.g. epithelia, haematopoietic cells

Stable - normally in Go, at rest. Is able to enter the cell cycle, varied rate of regeneration depending on location. e.g. hepatocytes, osteoblasts, fibroblasts

Permanent - unable to divide, permanently in Go. Tissue cannot regenerate. e.g. neurons, cardiac myocytes.

Question 5

Describe the role of growth factors in control of regeneration.

Answer 5

Promote proliferation, extracellular signals are transduced into the cell. Changes to transcription control the cell cycle.
Can be proteins - EGF, PGDF, FGF
Hormones - oestrogen, testosterone, growth hormone
Can be produced by many cell types e.g. inflammatory/mesenchymal

Question 6

Describe contact inhibition

Answer 6

Signalling occurs through adhesion molecules, anti-proliferation signals. When lost, proliferation increases until they become re-attached.

Question 7

Describe two situations in which fibrous repair and scarring is required.

Answer 7

Necrosis of permanent cells

Destruction of collagen framework by necrosis of labile/stable cells.

Question 8

Describe the different cell types involved in fibrous repair.

Answer 8

Inflammatory cells - neutrophils/macrophages for phagocytosis. Lymphocytes/macrophages produced chemical mediators.
Endothelial cells - angiogenesis
Fibroblasts/myofibroblasts - ECM protein secretion/wound contraction

Question 9

Describe angiogenesis.

Answer 9

Stimulated by VEGF.
Pre-existing vessels sprout new vessels, endothelial proteolysis of the basement membrane. Migration of endothelial cells by chemotaxis. Proliferate and form primitive blood vessels. They mature and remodel, linking back to the venous system. Supported by periendothelial cells.

Question 10

Why is angiogenesis essential in regeneration and repair?

Answer 10

Delivers oxygen, nutrients, inflammatory cells and fibroblasts.

Question 11

Describe the function of the ECM

Answer 11

Supports and anchors cells
Separates tissue compartments
Sequesters growth facts
Communication between cells
Facilitates cell migration

Question 12

Describe the synthesis of fibrillar collagen.

Answer 12

Synthesised in the endoplasmic reticulum, chain modified by enzymes. Vitamin C-dependent hydroxylation is important.
Alpha chains align and form a triple helix: soluble pro-collagen. This is secreted then cleaved to tropocollagen which aggregates to form collagen.

Question 13

What is the function of matrix glycoproteins?

Answer 13

Organise and orientate cells
Support cell migration.
e.g. fibronectin, laminin

Question 14

What is the function of proteoglycans?

Answer 14

Matrix organisation
Cell support
Regulate availability of growth factors
e.g. hepatin sulphate proteoglycan

Question 15

What is the function of elastin?

Answer 15

Provides tissue elasticity

Question 16

Describe the mechanism of fibrous repair

Answer 16

Damage causes a blood clot, leading to acute inflammation with neutrophils.
Then chronic inflammation occurs, macrophages and lymphocytes migrate into the clot and digest it.
The clot becomes granulation tissue and angiogenesis begins, myofibroblasts and fibroblasts recruited.
The proportion of contents changes over time: vascularity and cells decrease, ECM proteins increase. Myofibroblasts contract to draw the edges of the wound together and blood vessels mature.

Question 17

Describe the control of fibrous repair

Answer 17

Inflammatory cells are recruited by chemotaxis
Angiogenic cytokines (e.g. VEGF and bFGF) produced by platelets, ECM and others in response to hypoxia.
Macrophages produced by pro-fibrotic cytokines (e.g. TNF-alpha, IL-1, TGF-beta) causing fibroblast proliferation and ECM production.

Question 18

Describe a wound that heals via primary intention

Answer 18

Incised wound with minimal tissue damage, wound edges can be drawn together. Minimal haemorrhage.

Question 19

Describe a wound that heals via secondary intention

Answer 19

Large defect so the edges can’t be opposed. Large blood clot.

Question 20

Describe the process of repair in primary intention.

Answer 20

Loss of contact inhibition in the epidermis, fibrous repair in the dermis. Granulation tissue eventually creates scar tissue.
Minimal contraction and scarring, good tensile strength.

Question 21

Describe the process of repair in secondary intention.

Answer 21

Loss of contact inhibition, regenerate from the base upwards in the epidermis. Large amount of granulation tissue produces a large scar in the dermis, not necessarily weaker. Greater risk of complication.

Question 22

Describe healing in bone fractures

Answer 22

Haematoma forms in the marrow cavity and periosteum. Granulation tissue forms with the ingress of osteoblasts and necrotic tissue is removed by phagocytes.
Soft callus of chondrocytes forms
Hard callus of women bone with a few disorganised islands of cartilage.
Lamellar bone then replaces this, and remodelling by mechanical stresses occur.

Question 23

Give some local factors that influence healing.

Answer 23

Type, size and location
Apposition, lack of movement
Infection - suppuration, gangrene, systemic
Foreign material
Radiation damage - stops angiogenesis and affects myoblast/fibroblast recruitment

Question 24

Give some general factors that influence healing.

Answer 24

Age
Drugs (steroids)
Hormones
General dietary deficiency (protein)
Specific dietary deficiency (vitamin C/essential amino acids)
General health (chronic disease e.g. diabetes/rheumatoid arthritis)
General cardiovascular status

Question 25

Describe complications due to insufficient fibrosis

Answer 25

Wound dehiscence, herniation, ulceration
Seen in obese, elderly, steroids and malnutrition.
Inadequate strength with scarring.

Question 26

Describe complication due to excessive fibrosis

Answer 26

Coal worker’s pneumoconiosis - accumulation of coal dust in the lungs, fibrosis occurs to isolate the coal.
Cosmetic scarring
Keloids - high risk in afro-caribbeans
Liver cirrhosis - turns the liver into nodules of differentiated hepatocytes with dense fibrous tissue separating them. Decreased function.
Stricture - obstruction of tubes and channels caused by chronic inflammation and fibrous repair. Can also cause contractures which limits joint movement.

Question 27

Describe healing in cardiac muscle

Answer 27

Limited regenerative capacity and myocardial infarction followed by scar formation. This can compromise cardiac function.

Question 28

Describe healing in the liver

Answer 28

Has the capacity to regenerate.
If part of the liver is removed, compensatory growth of liver tissue and restoration of mass by enlargement of the lobes that remain.
Almost all hepatocytes replicate during regeneration. This is followed by replication of non-parenchymal cells.

Question 29

Describe healing in peripheral nerves

Answer 29

When a nerve is severed the axons degenerate by Wallerian degeneration.
Proximal stumps sprout and elongate. Use Schwann cells vacated by distal degenerated axons to guide them back to the tissue that the nerve innervates.
Grow at 1-3mm/day

Question 30

Describe healing in cartilage

Answer 30

Can’t heal well due to a lack of blood supply, lymphatic drainage and innervation.

Question 31

Describe healing in the central nervous system

Answer 31

Neural tissue is permanent and when tissue damage occurs this is replaced by glial cells.