Session 4 - healing and repair Flashcards
Where are the differentiated cells of regeneration derived from?
-Stem cells
What is asymmetric division?
-The division undergone by stem cells; One daughter cell remains as a stem cell and the other differentiates into a specialist cell type
Define unipotent
-Cells only produce one type of differentiated cell, eg epithelia
Define multipotent
-Can produce several types of differentiated cell, eg haematopoietic
Define totipotent
-Can produce any type of cell eg embryonic stem cell
What is a labile cell population?
-A cell population which undergoes rapid active proliferation eg epithelia
What is a stabile cell population?
- A population of cells which are in a resting state, yet have the ability to exit G0 and enter the cell cycle
- Eg renal tubule epithelium/hepatocytes
What is a permanent cell population?
-The cels are unable to divide and thus unable to regenerate
What are the two main factors which control regeneration?
- Growth factors
- Contact between basement membrane and adjacent cells
How do growth factors control regeneration?
-Promote proliferation in the stem cell population via extracellular signals which are transduced into the cell and control the expression of genes which control cell cycle
What type of molecules are growth factors?
- Hormones (eg oestrogen,testosterone, GH)
- Proteins (EGF, PDGF, FGF)
How does contact with basement membranes and adjacent cells control regeneration?
- Contact inhibition -> signalling through adhesion molecules inhibits proliferation in intact tissues
- Loss of contact promotes proliferation
What are E-cadherins?
- Calcium-dependant adhesion transmembrane proteins which dimerise with E-cadherins of other cells and link the actin cytoskeletons together
- Play a role in contact inhibition through regulatory proteins
What is fibrous repair?
-Replacement of functional tissue by scar tissue
When does fibrosis repair and scarring occur?
- When there is cell injury to permanent populations
- When the collagen framework is destroyed in labile and stable cell population
What are the three key components of fibrous repair?
- Cell migration
- Angiogenesis
- Extracellular matrix production and remodelling
What tissue forms before fibrous repair?
-Granulation tissue
What cell types migrate during fibrous repair?
- Inflammatory cells (neutrophils/macrophages/lymphocytes)
- Endothelial cells
- Fibroblasts/myofibroblasts
What role do inflammatory cells play in fibrous repair?
- Responsible for phagocytosis of deris
- Release chemical mediators to influence repair
Why do endothelial cells migrate to the site of injury in fibrous repair?
-For angiogenesis
Why are fibroblasts/myofibroblasts involved in fibrous repair?
- Extracellular matrix production
- Wound contraction
What is angiogenesis?
-The development of a new blood supply
Why is angiogenesis critical in wound healing?
- Delivery of oxygen and nutrients
- Provides access for inflammatory cells and fibroblasts
What are proangiogenic growth factors?
-GF which induce endothelial proliferation eg VEGF
Describe angiogenesis
1) Endothelial proteolysis of BM in exsisting BVs
2) Migration of endothelial cells via chemotaxis
3) Endothelial proliferation
4) Endothelial maturation + tubular remodelling -link to venous system
5) Recruitment of periendothelial cells for support
What is the function of the ECM produced in fibrous repair?
- Supports and anchors cells
- Sequesters growth factors
- Allows communication between cells
- Facilitates cell migration
What is ECM composed of?
NB. Revise MGD session 8
- Collagen/Elastin
- GAGs
- Proteoglycans
Describe collagen sysnthesis
1)Preprocollagen synthesised in ribosome
2)Translocated to ER and signal sequence cleaved producing procollagen
3)Hydroxylation of selected proline/lysine residues
4)N-linked Glycosylation
5)Alignment of procollagen subunits and DSB formation at C terminal initiates folding of helices into procollagen helix ->C and N terminal peptides not incorporated in helix
7)Translocation to the golgi
8)O linked glycosylation
9)Packaged into vesicle
10)secreted via constitutive pathway
11)Procollagen peptidases cleave C and N terminal peptides producing tropocollagen units
12)Lysine residues converted to aldehyde derivative allowing crosslinks between subunits
130 Tropocollagen units assemble into collagen fibrils stabilised by H bonds and cross-links and bundles of fibrils form collagen fibres
Define regeneration
-The replacement of dead/damaged cells by functionally differentiated stem cells
How is scurvy a defect of collagen?
- Inadequate vit C-dependant hydroxylation of proline residues by prolyl hydroxylase
- Reduction in H bonds between polypeptide chains of Collagen
- Collagen fibres lack strength and resistance to degredation
What is Ehlers-Danlos Syndrome caused by?
- Defective converison off procollagen to tropocollagen by lysyl oxidase (aldehyde derivatives not formed and not crosslinked)
- Weak collagen
What is osteogenesis imperfecta?
-Brittle bone disease caused by T1 collagen mutation
Describe the mechanism of fibrous repair
1) Exudate clots, neutrophils infiltrate (Acute inflammation) Macrophages and lymphocytes infiltrate (Chronic inflammation)
2) Area becomes more cellular with fibroblasts and endothelial cells migrating too and angiogenesis begins -> granulation tissue replaces the clot
3) Myo/fibroblasts differentiate and produce ECM and contract
4) Vascular network and inflammatory cells reduce
5) Maturation of fibrous scar as ECM increases and collagen matures, contracts and remodels
How is fibrous repair controlled?
- Inflammatory cells recruited by chemotaxis
- Angiogenesis occurs in response to growth factors
- ECM production by fibroblasts controlled by cytokines
When does healing by ‘primary intention’ occur?
-Incised wounds with apposed edges
Describe the characteristics of a skin wound healing by primary intention
- Minimal clot and granulation tissue
- Epidermis regenerates and dermis undergoes fibrous repair with minimal contraction and scarring
When does healing be secondary intention occur?
-When there is an infact, ulcer, abscess or any large wound with unopposed edges
Describe the characteristics of a skin wound healing by secondary intention
- Large clot which dries to form a scab
- Epidermis regenerates from the base up with a high amount of granulation tissue
- Produces more contraction and scarring as wound needs to reduce in volume
What are the 4 stages of healing of bone fractures?
NB revise TOB session 6
1) Haematoma formation
2) Soft callus formation
3) Bony callus formation
4) Remodelling
What local factors influence wound healing?
- Size, type and location of wound
- Apposition
- Blood suply
- Infection and foreign material
What general factors influence wound healing?
- Age
- Drugs and hormones
- Dietary deficiencies and general state of health
What happens if there is insufficient fibrosis within a wound?
-The wound has insufficient strength and can lead to herniation, ulceration and wound dehiscence (splitting open)
What are risk factors of insufficient fibrosis occuring?
- Obesity
- Elderly
- Steroids
What are the consequences of excessive fibrosis?
- Induced chronic inflammation
- Keloid formaiton
- Cirrhosis
- Impaired functions of organs
What are some possible consequences of excessive contraction?
- Obstruction of tubes or channels by strictures
- Contractures
What is alport syndrome?
-X-linked disease where type IV collagen is abnormal resulting in dysfunction of basement membrane
What is the function of EGF?
-mitogenic for epithelia cells, hepatocytes and fibroblasts
What is the function of VEGF?
-Potent inducer of blood vessel development and angiogenesis
What is the function of PDGF?
-Causes migration and proliferation og fibroblasts, smooth muscle and monocytes
What is the function of TNF?
-Induces fibroblast migration, fibroblast proliferation and collagenase secreion
Does cardiac muscle have regeneration capacity?
- Limited, if any
- MI is followed by scar formation which can comprimise cardiac function
Describe the liver’s ability to regenerate
- Almost all hepatocytes are replicate during regeneration, replacing any damaged/dead tissue.
- Followed by the replication of non-parenchymal cells
Can peripheral nerves regenerate?
-Yes, the severed nerve undergoes wallarian degeneration and then the proximal stump grows back to the tissue, guided by the now vacant distant schwann cells at approximately 1-3mm/day
Can cartilage regenerate?
-Limited regeneration as there is a poor blood supply, lymphatic drainage and innervation
Can the CNS regenerate?
- No, neural tissue is a permanent cell population
- Dead/damaged tissue is replaced by the proliferation of glial cells
What is a neuroma?
-Overproliferation of nervous tissue, arranged in a disordered and unorganised manner due to loss of scaffold and rapid regeneration
What local factors may cause a delay in healing of a fracture?
- Anatomical location
- Size of break
- Blood supply
- Infection or foreign material
- surrounding soft tissue injury
Which people are at risk of developing a keloid?
-Afro-carribeans
How does a keloid differ from a hypertrophic scar?
- In a keloid , fibrous proliferation goes beyond the boundaries of the wound to healthy tissue
- Hypertrohpic scars are contained
