MOD 4.1 - Healing and Repair Flashcards
What is the definition of regeneration?
The replacement of dead or damaged cells with functional/differentiated cells from stem cells
What is the definition of repair?
The response to injury with both regeneration and scar formation therefore permanently changing the normal structure
How does regeneration differ from repair?
- Normal tissue structure is restored
Provided that damage isn’t extensive and the collagen framework is still in tact
What is a stem cell?
An undifferentiated cell that can differentiate indefinitely to more cells of the same type/other types
What are the features of a unipotent stem cell? Give an example
- Produces ONE type of differentiated cell (for constant regeneration)
- Crypts of Lieberkuhn
What are the features of a multipotent stem cell? Give an example
- Produces several types of the same cell
- Haematopoietic cells
What are the features of totipotent stem cells? Give an example
- Can produce any type of cell
- Embryonic stem cells
What are the functions of stem cells? (3)
- 1 becomes a new stem cell
- 1 becomes a specific cell for a specialised function
- Derivatives replace lost cells that were terminally differentiated
What are the three tissue types for regeneration?
- Labile
- Stable/Quiescent
- Permanent
What are the features of labile cells?
- Divide continuously
- Rapidly reproduce throughout life
Why are labile cells significant?
Ensure that destroyed cells are constantly replaced
What are the features of stable cells?
- Low/no rate of division
- Can proliferate rapidly if exposed to the right stimulus
Why are quiescent cells significant?
- Response to a stimulus prevents premature differentiation
- Then maintains a constant supply of undifferentiated adult stem cells
What are the features of permanent cells?
- No mitotic division
- No regeneration
Give examples of:
i) Labile tissues
ii) Quiescent tissues
iii) Permanent tissues
i) Epithelial cells, haematopoietic cells
ii) Hepatocytes
iii) Neurones, cardiac myocytes
In which stage of the cell cycle are:
i) Labile tissues
ii) Quiescent tissues
iii) Permanent tissues ?
- Every stage as are in the cell cycle
- G0 (but can enter cell cycle)
- G0 (can’t enter cell cycle again)
What are the three mechanisms of control of regeneration and repair?
- Cell signalling
- Local mediators (growth factors)
- Contact inhibition
What are the three main mechanisms for cell signalling?
- Autocrine
- Paracrine
- Endocrine
What is autocrine signalling?
Cell makes and responds to its own signalling molecules
What is paracrine signalling?
A molecule is produced by ONE cell and acts upon adjacent cells with the appropriate receptors
What is endocrine signalling?
A hormone is synthesised by an endocrine gland and travels in the circulation to a distant site where it acts
Give examples of 4 growth factors and their functions
- Epidermal Growth Factor (EGF) - Mitogenic for keratinocytes and fibroblasts
- Platelet Derived Growth Factor (PDGF) - Promotes cells for inflammation and healing
- Vascular Endothelial Growth Factor (VegF) - Promotes blood vessel formation
- Tumour Necrosis Factor - Migration and proliferation of fibroblasts and secretion of collagenase
What is contact inhibition?
The inhibition of cell proliferation when cells come into contact with other cells
What are adhesion molecules and what is their function?
- Proteins on the cell surface membrane that enable contact inhibition
- Cell-cell = Cadherins
- Cell-Extra Cellular Matrix = Integrins
What happens if there is a lack of adhesion molecules?
- Tumour
- LAD-1 (leukocyte adhesion deficiency - deficiency of integrins, causes leukocytes to not be able to adhere to the vessel walls making fighting off infection difficult
What is fibrous repair? When does this occur?
- Replacement of functional tissue by scar tissue
- After the necrosis of permanent cells
- If the collagen framework of the tissue is destroyed after necrosis of labile/stable cells
What are the three stages of fibrosis repair?
- Infiltration of inflammatory cells
- Replacement of clot by granulation tissue
- Maturation
What happens prior to the infiltration of inflammatory cells during fibrous repair? Why is this significant?
- Formation of a blood clot
- Stops bleeding
- Promotes an inflammatory response
Which cells are involved in the inflammatory response during fibrous repair?
- Macrophages and neutrophils (for phagocytosis of debris/necrotic tissue)
- Lymphocytes and and macrophages (mediate chronic inflammation)
When is the clot replaced with granulation tissue?
Approximately 24-72 hours after initial injury
What are the two stages of replacement of the clot?
- Angiogenesis
- Migration and differentiation of myoblasts and fibroblasts
What is angiogenesis?
The formation of new blood vessels from pre-existing blood vessels
Describe the process of angiogenesis
Very Deep Enemas Puncture My Rectum
- Vasodilation of pre-existing vessels due to NO
- Degradation of the basement membrane
- Endothelial cells migrate towards the angiogenic stimulus (VegF)
- Proliferation of endothelial cells
- Maturation of cells and tubular remodelling
- Recruitment of outer cells e.g. smooth muscle cells
What is the significance of angiogenesis?
- Provides access for inflammatory cells and fibroblasts
- Delivers oxygen and nutrients
What is the significance of the migration and differentiation of myo/fibroblasts?
Necessary for the production of the extra cellular matrix
What is the composition of the ECM? How is this significant to function?
- Collagen and elastin fibres (tensile strength and recoil)
- Proteoglycans (adhesion)
- Adhesive proteins
What are some of the functions of the extracellular matrix?
- Mechanical support
- Separation of tissues
- Cell communication
How is collagen synthesised?
CHADPOGRL
- Cleavage of signal by signal peptidase to form preprocollagen
- Hydroxylation of proline residues by prolyl hydrolase (Fe2+ and Vit C)
- Addition of N-liked oligosaccharides
- Disulphide bond formation by protein disulphide isomerase
- Procollagen forms
- O-linked glycosylation
- Golgi packaging then exocytosis
- Removal of N&C peptides with procollagen peptidases
- Lateral aggregations and cross-linking by lysyl oxidase (Cu2+ and Vit B)
Which types of collagen are used in the framework?
- Fibrillar (1-3, dermis, bone and cartilage) - Uninterrupted alpha helices that form fibrils
- Amorphous (4-6, basement membrane) - Interrupted helices that form sheets
What happens to collagen production if a patient has scurvy?
- Little or no hydroxylation of proline residues
- Weak collagen that is vulnerable to enzymatic degradation
- Blood vessel collagen is particularly vulnerable which can lead to haemorrhage
What happens to collagen production if a patient suffers from Ehlers-Danlos syndrome?
- Conversion of procollagen to tropocollagen is defective
- If in types 1-3 gives no tensile strength of skin
- Hyperextension of joints
What happens in the maturation stage of fibrous repair?
- High collagen deposition
- Neutrophils are replaced by macrophages (unless infected)
- Myofibroblasts contract which reduces the size of the wound
- Differentiation and reduction of vessels
When can a wound heal by primary intention? Why?
If it is:
- Clean and uninfected
- Made surgically
- Has easily opposable edges
- Limited cell death and basement membrane interruption
Describe the healing process by primary intention. What does this lead to?
- Contraction of myofibroblasts leads to decrease in size of clot
- Decrease in amount of granulation tissue
- Reepithelialisation from the top down
- Fibrous repair of dermis
- Results in a fine, thin scar
What is a potential negative of healing by primary intention?
Can trap infection at the site of the wound which can result in an abscess
When can a wound heal by secondary intention? Why?
- When edges can’t be opposed easily/at all
- Abscess
- Ulceration
- Large wound
- There is an extensive loss of all cells
Describe the healing process by secondary intention. What does this lead to?
- Formation of a large clot that dries to form a scab
- Large inflammatory response resulting in the formation of a lot of granulation tissue
- Reepithelialisation from the base up with a high collagen deposition
- Larger contraction of myofibroblasts to reduce volume eventually results in a large scar
Describe the stages of bone fracture healing
1) Formation of a haemotoma
2) Soft tissue callus forms
3) Bony callus forms
4) Bone is remodelled in the direction of mechanical stress to allow for controlled weight bearing
What is the purpose of the haemotoma?
- To fill the gap left by the fracture
- To provide a fibrin mesh for: macrophages, endothelial cells, fibroblasts and osteoblasts
Describe the formation of the soft tissue callus
- Formation of granulation tissue
- Ingrowth of vascular tissue
- Inward migration of mesenchymal cells
- Collagen matrix is laid down and osteoid is secreted by osteoblasts
- Osteoid mineralises which leads to the soft callus
What is the purpose of the bony callus?
- Bridges gap between the two edges of bone
What is a myofibroblast?
A cell that has features of both smooth muscle and fibroblasts which gives a contracting element to the wound
What are the local factors that influence the efficacy of healing and repair?
- Type, size and location of wound
- Lack of movement
- Blood supply
- Infection
- Foreign material
What are the systemic factors that influence the efficacy of healing and repair?
- Age
- Drugs and hormones (steroids)
- Deficiencies e.g. Vit C, amino acids
- General health e.g. diabetes
Describe the complications of insufficient fibrosis (2)
- Wound dehiscence (bulging) - especially on abdomen due to pressure
- Ulceration
Describe the complications of excessive fibrosis (2)
- Keloid scars (extend beyond boundaries of original wound and don’t fade)
- Liver cirrhosis (chronic irritation by e.g. alcohol)
Describe the complications of excessive contraction (2)
- Strictures (obstruction of a tube or channel)
- Contractures (limitation of joint movement)
Describe the regenerative capacity of cardiac muscle. When can cardiac muscle become damaged and what happens as a result?
- Capacity is low, if any at all
- After MI - leads to scar formation which can compromise cardiac function
Describe the regenerative capacity of the liver
- Very, very good
- Up to 60% can be removed and the liver will double in size within 1 month
- Compensatory hyperplasia (increase in cell size)
Describe the regenerative capacity of the PNS
- Severing of nerve = Wallerian degeneration
- Regeneration can happen by elongation of proximal nerve stumps
- Schwann cells from distal degenerated axons guide end to tissue that was initially innervated
What is the growth rate of axons?
1-3mm per day
What is the regenerative capacity of connective tissue?
- Poor
- Due to lack of blood supply, lymphatic drainage and nerve innervation
What is the regenerative capacity of the CNS?
- Poor as nerve tissue is permanent
- Damaged cells are instead replaced by glial cells
- Loss of function
