Regeneration And Repair

Question 1

What is the underlying principle of would healing?

Answer 1

1. Close the gap
2. Repair it with a scar
3. The smaller the scar the better

Question 2

What processes are involved in wound healing?

Answer 2

Haemostasis - as vessels are open

Inflammation - as there has been tissue injury

Regeneration (resolution, restitution) and/or fibrous repair (organisation) - as structures have been injured or destroyed

Question 3

What is regeneration?

Answer 3

Restitution with no or minimal evidence that there was previous injury.

• Healing by primary intention
• Superficial abrasion

Question 4

What is the difference between an abrasion and an ulcer?

Answer 4

Abrasion - damage is superficial and tissue can repair itself completely.

Ulcer - Greater amount of damage, Not repair fully.

Question 5

Which cells replicate in regeneration?

Answer 5

New differentiated cells are mainly derived from stem cells (many terminally differentiated cells can’t divide)

Question 6

What are stem cells?

Answer 6

• Prolonged proliferation activity
• Show asymmetric replication
• Internal repair system to replace lost or damaged cells in tissues.

Question 7

Whereabouts in the tissues are the stem cells?

Answer 7

Varies between tissues..

• Epidermis - Basal layer adjacent to the basement membrane
• Intestinal mucosa - bottoms of crypts
• Liver - between hepatocyte and bile ducts.

Question 8

What are the classifications of stem cells?

Answer 8

• Unipotent
• Multipotent
• Totipotent

Question 9

What are unipotent stem cells?

Answer 9

Most adult stem cells.

They only produce one type of differentiated cell eg epithelia

Question 10

What are multipotent stem cells?

Answer 10

Produce several types of differentiated cell e.g. Haematopoietic stem cells.

Question 11

What are totipotent stem cells?

Answer 11

• Embryonic stem cells.
• They can produce any type of cell and therefore any tissue in the body.

Question 12

Can all tissues regenerate?

Answer 12

No! It depends on whether the tissues are:

—Labile tissues e.g. surface epithelia, haematopoietic tissues.

• These contain short-lived cells that are replaced from cells derived from stem cells.

—Stable tissues e.g. liver parenchyma, bone, fibrous tissue, endothelium.

• They normally undergo low levels of replication but, if necessary, can undergo rapid proliferation. Both stem cells and mature cells proliferate.

—Permanent tissues e.g. neural tissue, skeletal muscle, cardiac muscle.

• Mature cells can’t undergo mitosis and no or only a few stem cells are present.

Question 13

Where abouts on the cell cycle are the three types of cell depending on proliferative activity?

Answer 13

Labile cells are continuously going around the cell cycle.

Stable tissues are in G0 so they are not currently undergoing mitosis but can join if needed.

Permanent tissues are not in the cell cycle.

Question 14

In what circumstances can regeneration take place?

Answer 14

If damage occurs in a Labile or stable tissue.

If the tissue damage is not extensive as regeneration requires an intact connective tissue scaffold.

Question 15

What is fibrous repair (organisation) and when does it occur?

Answer 15

Healing with the formation of fibrous connective tissue - scar

• Specialised tissue is lost
• Healing by secondary intention

Occurs with: -

• Significant tissue loss
• If permanent or complex tissue is injured

Question 16

Will the cell undergo regeneration or fibrous repair?

Answer 16

Question 17

How does a scar form?

Answer 17

Haemostasis (seconds- minutes)

Acute inflammation (minutes-hours)

Chronic inflammation (1-2 days)

Granulation tissue then forms (3 days)

Early scar (7-10 days)

Scar maturation (weeks - 2 years)

Question 18

What is granulation tissue?

Answer 18

Has a granular appearance and texture

Consists of:

• Developing capillaries
• Fibroblasts and myofibroblasts
• Chronic inflammatory cells

Functions:

• FIll the gap
• Capillaries supply oxygen, nutrients and cells
• Contracts and closes the hole

Question 19

How does fibrous repair occur?

Answer 19

1. Blood clots
2. Neutrophils infiltrate and digest clot
3. Macrophages and lymphocytes are recruited
4. Vessels sprout and Moyo/fibroblasts make glycoproteins
5. Vascular network, collagen synthesised, macrophages reduced.
6. Maturity, cells much reduced, collagen matures, contracts and remodels.

Question 20

What cells are involved in fibrous repair?

Answer 20

Inflammatory cells -

Phagocytosis of debris - neutrophil, macrophages

-Production of chemical mediators - lymphocytes, macrophages

Endothelial cells

-Proliferation results in angiogenesis

Fibroblasts and myofibroblasts

• Produce extracellular matrix proteins e.g. collagen
• Responsible for wound contraction - Contraction of fibrils within myofibroblasts.

Question 21

What is collagen?

Answer 21

• It is the most abundant protein in animals and there are 27 different types.
• They account for almost 1/3 of mammalian body proteins
• They provide an extracellular framework for all multicellular organisms
• They are composed of triple helices of various polypeptide a-chains, rope-like appearance
• Fibrillar collagens: I-III responsible for tissue strength
• Amorphous collagens: IV-VI eg basement membrane

Question 22

What is type I collagen?

Answer 22

Type I is most common.

It is found in hard and soft tissue including: bones, tendons, ligaments, skin, sclera cornea, blood vessels, hollow organs.

Question 23

What is type IV collagen?

Answer 23

Makes up basement membranes -Secreted by epithelial cells

Question 24

How are fibrillar collagens made?

Answer 24

• The whole process takes about 1-2 hours.
• Polypeptide a chains are synthesised in ER of fibroblasts and myofibroblasts.
• Enzymatic modification steps inc. Vit C dependant hydroxylation
• A-chains align and cross-link to form procollagen triple helix
• Soluble procollagen is secreted.

Question 25

What happens after the secretion of procollagen?

Answer 25

* After secretion, procollagen is cleaved to give tropocollagen. * Tropocollagen polymerises to form microfibrils and then fibrils. * Bundles of fibrils form fibres * Cross-linking between molecules produce tensile strength * Slow remodelling by specific collagenases.

Question 26

What diseases are the result of defective collagen synthesis?

Answer 26

**_Acquired_**: * Scurvy **_Inherited_**: * Ehlers-Danilo’s syndrome * Osteogenesis Imperfecta * Alport syndrome

Question 27

What is scurvy?

Answer 27

* Vitamin C deficiency * Inadequate vitamin C dependant hydroxylation of procollagen a-chain leads to reduced cross-linking and defective helix formation. * Lacks strength, vulnerable to enzymatic degradation. * Particularly affects collagens supporting blood vessels.

Question 28

What are the consequences of scurvy?

Answer 28

* Unable to heal wounds, tendency to bleed * Tooth loss * Collage in periodontal ligament has a short half life and normal collagen is replaced by defective collagen. * Old scars break down and open up as fresh wounds. * Collagen turnover in scars remains high long after healing process appears clinically complete.

Question 29

What is Ehlers Danilo’s syndrome?

Answer 29

* **Defective conversion of pro collagen to tropocollagen** * Collagen fibres lack adequate tensile strength * Wound healing poor * Skin - hyperextensible, thin, fragile and susceptible to injury. * (Skin can still recoil because the elastic fibres are normal, it is just missing the tethering effect of normal collagen fibres.) * It causes: Hypermobile joints that have a predisposition to dislocation. * Sometimes: Rupture of colon, large arteries or cornea Retinal detachment.

Question 30

What is osteogenesis Imperfecta?

Answer 30

* **Brittle bone disease** * Too little bone tissue and therefore extreme skeletal fragility. * Affected people have to try and avoid mechanical stress * Some develop severe, progressive deformation of long bones. * Blue sclerae- too little collagen within then and they are translucent. * Hearing impairment and dental abnormalities.

Question 31

What is Alport syndrome?

Answer 31

* X-linked so patient is normally male. * Abnormal type IV collagen * Dysfunction of glomerular basement membrane, cochlea of ear and lens of eye * Presents with haematuria in children / adolescents and progresses to renal failure. * Also neural deafness and eye disorders.

Question 32

How are regeneration and repair triggered and controlled?

Answer 32

It is complex and poorly understood Cells communicate with each other to produce a proliferative response. Cell to cell signalling can be via: * Hormones * Local mediators (e.g. growth factors) * Direct cell-cell or cell-Stroma contact.

Question 33

What are growth factors?

Answer 33

* Particularly important in wound healing. * Polypeptides that act on cell surface receptors. * Coded by protooncogenes. * ‘Local hormones’ * Bind to specific receptors, and stimulate the transcription of genes that regulate the entry of cells into the cell cycle and the cell’s passage through it.

Question 34

What types of growth factors are there?

Answer 34

* Epidermal growth factor * Vascular growth factor * Platelet derived growth factor * Tumour necrosis factor. They are produced by cells such as platelets, macrophages, endothelial cells BUT names can be misleading!

Question 35

Apart from cell proliferation, what other effects can growth factors have?

Answer 35

* Inhibition of division * Locomotion * Contractility * Differentiation * Viability * Activation * Angiogenesis

Question 36

What is the role of cell-cell and cell-stroma contact?

Answer 36

**Contact inhibition** * Signalling through adhesion molecules * Cadherins bind cells to each other * Integrins bind cells to the extracellular maxtrix * Inhibits proliferation intact tissue, promotes proliferation in damaged tissues. * Altered in malignant cells.

Question 37

What is ‘healing my primary intention’ and ‘healing by secondary intention’?

Answer 37

Describing of wound healing related to the size of the wound and the amount of lost tissue. 'Secodnary intention' is a bigger wound with more tissue lost. Most often used for skin wounds.

Question 38

What is healing by primary intention?

Answer 38

Incised, closed, non-infected and sutured wound. Eg cut in the skin by a scalpel. Disruption of the basement membrane continuity but death of only small number of epithelial and connective tissue cells. Minimal clot and granulation tissue.

Question 39

What occurs in healing by primary intention?

Answer 39

* Epidermis regenerates * Basal epidermal cells at edge of cut creep over denude cells, appoximately 0.5mm/day, deposit basement membrane, fuse in midline beneath scap, indermine scab which falls off. * Dermis undergoes fibrous repair. * Sutures out at about 10 days - appox 10% normal strength * Minimal contraction and scarring, good strength

Question 40

What is healing by secondary intention?

Answer 40

Excisional wound, wounds with tissue loss and separated edges, infected wounds e.g. infarct, ulcer, abcess Open wound filled by abundant granulation tissue - grows in from wound margins.

Question 41

What occurs in healing by secondary intention?

Answer 41

* Same process as primary intention but more so: * Considerable wound contraction must take place to close wound. * Initially occurs as scab contracts when it dries and shrinks. * After a week myofibroblats appear and contract * Contracts as if margins are drawn into the centre - final shape of scar depends on orgional shape of wound * Longer to heal so increased risk of complications * Substantial scar formation, new epidermis often thinner than usual.

Question 42

How does bone heal?

Answer 42

**Haematoma**: fills gap and surrounds injury **Granulation tissue forms**: cytokines activate osteoprogenitor cells **Soft callus**: at 1 week, fibrous tissue and cartilage within which woven bone forms **Hard callus**: after several weeks, initially woven bone - weaker and less organised than lamellar bone but can form quickly. **Lamellar bone**: replaces woveb bone, remodelled to direction of mechanican stress, bone not stressed is resorbed and outline is re-established.

Question 43

What local factors can influence would healing?

Answer 43

* Type, size and location of wound * Mechanical stress * Blood supply * Local infection * Foreign bodies

Question 44

What general factors can influence wound healing?

Answer 44

* Age * Anaemia, hypoxia and hypovolaemia (decreased blood volume) * Obesity * Diabetes * Genetic disorders * Drugs * Vitamin deficiency * Malnutrition

Question 45

What are the complications of fibrous repair?

Answer 45

* **Insufficient fibrosis** * -Wound dishiscence, hernia, ulceration * -Eg obesity, elderly, malnutrition and steroids * **Formations of adhesions** * -Comprimising organ functions or blocking tubes. * **Loss of function** * -Due to replacement of specialised functional parenchyma cells by scar tissue * **Disruption of complex tissue relationships within an organ** * -distortion of architecture interfering with normal function * **Overproduction of fibrous scar tissue** * -keloid scar * **Excessive scar contraction** * **-**can cuase obstruction of tubes, disfiguring scars following bursn or joint contractures

Question 46

How do you predict the type of healing that will occur?

Answer 46

It will depend on: * Type of tissue * Extent of injury * Presence of persistent infection