Healing And Repair

Question 1

Define regeneration

Answer 1

Growth of cells and tissues to replace lost structures following injury, provided the stem cells are still intact

Question 2

What are labile cells? Give 3 examples

Answer 2

• Cells which are continuously proliferating throughout life to replace lost/damaged cells
• e.g. Surface epithelia of the epidermis, bone marrow, columnar epithelia of the gut mucosa and uterus

Question 3

Can stable tissues undergo regeneration?

Answer 3

• Yes, cells remain in the quiescent G0 phase of the cell cycle and can re-enter in response to stimuli and undergo rapid division
• e.g. Parenchymal cells of the liver, kidney and pancreas, mesenchymal cells, fibroblasts, macrophages

Question 4

Why can permanent tissues not regenerate?

Answer 4

• Cells leave the cell cycle permanently and cannot undergo mitotic division in postnatal life, as the tissues contain no stem cells that can replace damaged tissue
• e.g. cardiac myocytes cannot regenerate following infarction

Question 5

Describe the replication pattern in stem cells

Answer 5

• ASYMMETRIC

- Following mitosis, one of the daughter cells remains a stem cell and the other differentiates

Question 6

Why can stem cells proliferate indefinitely without senescence? Are there any other cells which are capable of this?

Answer 6

• Stem cells produce TELOMERASE which maintains the length of the telomeres during continuous mitotic division (telomeres are shortened during each division until they become a critical length and cells undergo apoptosis)
• Cancer cells can also produce telomerase and can replicate indefinitely

Question 7

What is the difference between totipotent, multipotent and unipotent cell types?

Answer 7

• Totipotent cells can differentiate into ANY cell type e.g. embryonic stem cells
• Multipotent cells can produce several different types of cells within the same lineage e.g. haematopoietic cells
• Unipotent cells can only differentiate into a SINGLE cell type e.g. epithelia

Question 8

Give 2 instances where a fibrous scar may form

Answer 8

• If collagen framework of tissue is destroyed
• If there is ongoing chronic inflammation
  (Cells cannot be replaced at an effective rate to exceed cell loss, resulting in formation of a fibrous scar)

Question 9

Describe the process of fibrous repair (granulation tissue formation)

Answer 9

• Phagocytosis of necrotic debris
• Proliferation of endothelial cells, forming small capillaries (angiogenesis, stimulated by VEGF)
• Proliferation of fibroblasts/myofibroblasts which form granulation tissue (collagen and GAGs) and cause wound contraction
• Scar maturation (becomes less vascular and shrinks due to contraction)

Question 10

Name 4 diseases which affect collagen synthesis

Answer 10

• Scurvy (vitamin C deficiency)
• Ehler’s Danlos syndrome (lysyl oxidase deficiency)
• Osteogenesis imperfecta (type I collagen deficiency)
• Alport syndrome (type IV collagen deficiency)

Question 11

Describe the symptoms of osteogenesis imperfecta

Answer 11

• Deficiency in type I collagen causes bones to be brittle and extremely fragile and prone to fractures
• Type 1 OI have blue sclerae, as the lack of collagen in the sclera makes them appear translucent

Question 12

Describe the pathophysiology of Ehler’s Danlos syndrome

Answer 12

• Deficiency in lysyl oxidase so collagen is unable to form stable cross links so lack tensile strength
• Skin is hyperextensible and joints are hypermobile as a result and wound healing is poor
• Rupture of colon, cornea and large arteries is not uncommon due to lack of tensile strength of collage

Question 13

Why might patients with Alport syndrome present with haematuria?

Answer 13

• Deficiency in type IV collagen which affects the basement membrane in the glomerulus of the kidney (Bowman’s capsule)
• Dysfunction of the membrane causes filtration of RBCs which would normally not enter filtrate and are therefore present in the urine
• This may progress to kidney failure

Question 14

Give 3 examples of how cells can communicate via local mediators or hormones

Answer 14

• Autocrine (cell responds to signals that they themselves produce)
• Paracrine (cells respond to signals produces by adjacent cells within the local vicinity, often a different type)
• Endocrine (cells respond to hormones produced by endocrine organs which travel in the bloodstream to distant target cells)

Question 15

What are growth factors?

Answer 15

• “Local polypeptide hormones” coded for by proto-oncogenes and act on cells via paracrine signalling over short distances
• Bind to specific receptors and stimulate/inhibit cell proliferation and angiogenesis

Question 16

Give 4 examples of growth factors and their associated actions

Answer 16

• EGF (mitogenic for epithelia, hepatocytes and fibroblasts)
• VEGF (induces vasculogenesis, role in angiogenesis of tumours, chronic inflammation and wound healing)
• PDGF (migration and proliferation of fibroblasts, monocytes and smooth muscle cells)
• TNF (induces fibroblast migration and proliferation, secretion of collagenase)

Question 17

What is contact inhibition? Name 2 important proteins involved in this

Answer 17

• Normal cells (when isolated) replicate until they are touching other cells and then stop
• Involves expression of adhesion molecules (cadherins which bind cell-cell, integrins which bind cell-stroma)
• Adhesion molecules are abnormally expressed in cancer cells, allowing them to invade surrounding tissues

Question 18

When does healing by primary intention occur?

Answer 18

Incisional, closed, non-infected wounds with opposed edges and minimal loss of connective tissue scaffold

Question 19

What are the 5 stages of healing by primary intention?

Answer 19

• Haemostasis (severed arteries contract and space fills with clotted blood)
• Inflammation (neutrophils and leucocytes invade to kill of any bacteria present)
• Migration of cells (macrophages migrate and remove neutrophils; release cytokines which attract fibroblasts and endothelial cells)
• Regeneration (epithelial cells proliferate and granulation tissue invades the space; angiogenesis progresses)
• Scarring and maturation (vascular channels regress, leaving an excess of fibrous tissue which matures)

Question 20

When does healing by secondary intention occur?

Answer 20

Excisional or infected wounds with a large amount of tissue loss and unopposed edges

Question 21

Describe the process of healing by secondary intention

Answer 21

• Inflammation (more intense response as infection is likely)
• Granulation tissue (abundant and fills open wound; grows in from the margins)
• Wound contraction (myofibroblasts contract into centre to close the wound)
• Scar formation (substantial but depends on the size of wound, no skin appendages present and skin is often thinner)

Question 22

Explain the stages involved in fracture healing

Answer 22

• Haematoma formation and migration of macrophages
• Macrophages secrete cytokines which attract fibroblasts which secrete ECM of granulation tissue and osteoprogenitor cells
• Fibroblasts differentiate into chondroblasts which lay down hyaline cartilage, forming a fibrocartilaginous callus (procallus)
• Endochondral ossification of cartilage forming woven bone. Osteoblasts lay down new woven bone which forms lamellar bone
• Bone remodelling in response to mechanical stress and normal outline is restored

Question 23

Name 5 local factors which may impair wound healing

Answer 23

• Blood supply
• Local infection
• Size, location and type of wound
• Denervation
• Presence of foreign bodies or necrotic tissue

Question 24

Name 5 systemic factors that affect wound healing

Answer 24

• Age
• Diabetes/Obesity
• Malignancy due to cachexia
• Drugs e.g. Steroids
• Vitamin deficiency/malnutrition

Question 25

What are the complications of fibrous repair?

Answer 25

- Formation of fibrous adhesions or replacement of parenchymal tissue with fibrous, which can compromise organ function - Distortion of tissue architecture e.g. cirrhosis - Keloid scar formation - Wound dihisence - Excessive scar contraction (cause strictures or fixed flextures)

Question 26

Describe the process of healing following a myocardial infarction

Answer 26

- Cardiac myocytes are permanent cells which cannot proliferate and undergo regeneration - Damaged myocardium undergoes fibrous repair and scar tissue is formed

Question 27

Why is healing of cartilage poor?

Answer 27

Lacks blood supply, lymphatic drainage and innervation

Question 28

Describe 2 instances where permanent cells may be replaced by supporting cells

Answer 28

- CNS - damaged neurones are replaced by glial cells via process of gliosis - Skeletal muscle - damaged myocytes are reinforced by satellite cells which fuse with existing muscle fibres and cause hypertrophy

Question 29

Describe the healing of a peripheral neve

Answer 29

- Severed axons undergo Wallerian degeneration - Proximal stumps sprout and elongate and use Schwann cells from the distal stump to guide them back (grow 1-3mm/day) - May require surgery if the axon ends are unopposed