Repair and Regeneration Flashcards
What is ‘resolution’ in cell injury?
The ideal outcome of healing - cells can regrow and regenerate, restoring normal function and structure
What does resolution depend on?
Removal of damage, severity of damage
What happens if the damaged cells cannot regrow?
Scar formation (fibrous repair) and loss of function
What are the 2 most important factors in determining the outcome of injury?
- the ability of the cells to replicate
2. the ability to rebuild complex architectural structures
What are labile cells?
Cells that multiply constantly throughout life, are only alive for a short period of time
E.g. epidermis (skin), GI tract epithelium
What are stable cells?
What phase of the cell cycle do they spend most of their life in?
Examples?
Stable cells are cells that only replicate when needed.
They spend most of their life in the ‘quiescent’ G0 phase of the cell cycle but can be stimulated to enter the cell cycle when needed
E.g. hepatocytes, renal tubules
What are permanent cells? Examples?
Cells that are incapable of regeneration (or very little capacity)
E.g. neurons, cardiac myocytes, skeletal muscle cells
What is the regenerative capacity like of labile cells?
Very good - high normal turnover
What are stem cells?
cells that are able to develop into many different cell types
Describe the stem cell population of labile cells?
Very active stem cell population
What is the regenerative capacity like of stable cells?
Low physiological turnover BUT this turnover can be increased if needed
Good regenerative capacity e.g. if some if liver is removed, it can grow back
What is the regenerative capacity like of permanent cells?
No physiological turnover, no regenerative capacity
How are cells lost from injury or cells that have come to end of lifespan replaced?
Replaced from stem cell pool which is present in may labile and stable cell populations
What is the product when a stem cell undergoes mitotic division?
2 daughter cells
Describe the 2 daughter cells of a stem cell after mitotic division?
What is this called?
1 of the daughter cells retains stem cell characteristics.
The other cell progresses along a differentiation pathway e.g. epidermis
This is called asymmetric replication
What is asymmetric replication?
The process by which a stem cell undergoes differentiation or division.
The final result of which are two daughter cells. One cell is identical to the mother cell and the other a totally differentiated one.
Can complex structures (e.g. lung, glomeruli) be easily replaced?
No - evidence of scarring
Survival of the connective tissue framework is essential and if this isn’t present then the usual architecture of the organ cannot be maintained
What can cause a cirrhotic liver?
End result of persistent long term damage to the liver by a noxious agent that persists over a long period
E.g. alcohol, some hepatitis viruses, autoimmune damage)
In a cirrhotic liver, why can the regeneration of liver cells not repopulate the normal architecture?
There is collapse of the reticulin (connective tissue) framework of the liver
As the liver cells cannot repopulate the normal architecture, what forms?
This leads to the formation of regenerative nodules divided by fibrous septa
What are regenerative nodules?
A form of non-neoplastic nodules that arise in a cirrhotic liver.
What is cirrhosis?
Scarring (fibrosis) of the liver caused by long-term liver damage –> imbalance between hepatocyte regeneration and failure to reconstruct the architecture
What is contact inhibition?
A regulatory mechanism that keeps cells growing into a layer one cell thick. If a cell has plenty of available substrate space, it replicates rapidly and moves freely. This process continues until the cells occupy the entire substratum.
How do labile cells use contact inhibition?
Cells at edge of defect multiply to cover. Proliferation stops once the cells cover defect.
Control of regeneration involves many factors (growth factors, contact inhibition etc). What happens in neoplasia?
These mechanisms are lost in neoplasia - uncontrolled cell growth
Difference between healing by regeneration and healing by repair?
Tissue returns to normal = healing by regeneration
Fibrosis and scarring = healing by repair
Can the normal structure of organ/tissue be replaced during repair?
No - healing by non-specialised fibrous tissue (scar)
What are the a) mechanical and b) electrical consequences of a scar in the interventricular septum as a result of healing of a myocardial infarct by repair?
- Mechanical: There has been a loss of pumping capacity
- Electrical: Any scar may be a focus of abnormal electrical activity and lead to arrhythmia or might disrupt the cardiac conducting system if in a critical point (eg His bundles), giving heart block.
What is ‘organisation’ used to describe?
The repair of specialised tissue by formation of a fibrous scar
What does ‘organisation’ result in the production of?
A granulation tissue (often on scaffold of fibrin)
How is the dead tissue in ‘organisation’ removed?
By phagocytosis
How does the granulation tissue then form a scar?
Granulation tissue contracts and accumulates collagen –> forming a scar
Organisation is a common consequence of pneumonia and infarction.
What does the organised area look like?
Firm and puckered
What is granulation tissue?
Immature connective tissue with many capillaries (neovascularisation) and fibroblasts that forms on the surfaces of a wound during the healing process.
Granulation tissue is mixed with phagocytic cells (neutrophils, macrophages). What is the purpose of this?
Clear away debris in injured area
Granulation tissue also contains fibroblasts. What is purpose of this?
These migrate to the damaged area to synthesise collagen and ECM
What are fibroblasts?
A fibroblast is a cell that synthesises the extracellular matrix and collagen, produces the structural framework (stroma) for animal tissues, and plays a critical role in wound healing.
Granulation tissue then acquires myofibrils. What is purpose of this?
Contractile ability –> wound contraction
What is purpose of wound contraction?
Wound contraction is important for reducing volume of tissue for repair – can reduce it by 80%
Describe changes in:
- Vascularity
- Collagen, ECM, wound strength
- Cellularity
of granulation tissue as it matures?
- Vascularity decreases
- Collagen, ECM, wound strength increases
- Cellularity decreases
What are the 2 wound healing processes?
- First (primary) intention
2. Second (secondary) intention
Wen does healing by primary intention occur?
- Clean, uninfected surgical wound
- Good haemostasis
- Dermal edges that are close together (e.g a scalpel incision)
What is haemostasis?
The action of platelets and cytokines forms a haematoma and causes vasoconstriction, limiting blood loss at the affected area
What are the 4 stages of wound healing (both 1ary and 2ary)?
- Haemostasis
- Inflammation
- Proliferation
- Remodelling
Describe the haemostasis stage in 1ary wound healing
The action of platelets and cytokines forms a haematoma and causes vasoconstriction, limiting blood loss at the affected area
The close proximity of the wound edges allows for ease of clot formation and prevents infection by forming a scab
Describe the inflammation stage in 1ary wound healing
A cellular inflammatory response acts to remove any cell debris and pathogens present
Describe the proliferation stage in 1ary wound healing
Cytokines released by inflammatory cells drive the proliferation of the fibroblasts and the formation of granulation tissue
Angiogenesis is promoted by the presence of growth mediators (e.g VEGF), allowing for further maturation of the granulation tissue; the production of collagen by fibroblasts allows for closure of the wound after around a week
Describe the remodelling stage in 1ary wound healing?
Collagen fibres are deposited within the wound to provide strength in the region, with the fibroblasts subsequently undergoing apoptosis
What is the end result in 1ary wound healing?
a complete return to function, with minimal scarring and loss of skin appendages.
In what direction is epidermis rebuilt?
From base up
What is a keratin filled cyst? How does it form?
If the wound is gaping, epidermal cells can grow down into defect. These usually stop growing and become reabsorbed but can remain and grow to form a keratin filed cyst –> implantation dermoid
What is the only residual defect after 1ary healing?
the inability to reconstruct the elastic network within the dermis
End result after 1ary intention healing?
Neat scar
What will any wound made by a scalpel will heal by? primary intention.
How can surgeons aid this?
Primary intention
Surgeons can aid healing by ensuring adequate opposition of the wound edges, through use of surgical glue, sutures, or staples.
When does 2ary intention healing occur?
When wound edges are not opposed, therefore healing must occur from the bottom of the wound upwards.
E.g. extensive loss of tissue so apposition not physically possible, infection, large haematoma
What does healing by 2ary intention result in?
- More granulation tissue
- More extensive scarring
- Broad fibrous scar
What cells are vital in healing by 2ary intention?
Myofibroblasts - They are modified smooth muscle cells that contain actin and myosin, and act to contract the wound; decreasing the space between the dermal edges. They also can deposit collagen for scar healing.
What are keloid scars?
When can they occur?
An uncommon complication from wound healing (particularly in people with darker skin). There is excessive fibroblast proliferation and collagen production, leading to extensive scarring.
What are contractures? When can they occur?
Contractures develop when normally elastic tissues such as muscles or tendons are replaced by inelastic tissues (fibrosis). This ultimately causing rigidity, joint deformities and a total loss of movement around the joint.
Can be a serious complication of burns: contractures occur when the burn scar matures, thickens, and tightens which can prevent movement. Often occurs when a burn occurs over a joint.
What are oesophageal peptic strictures? What are they caused by?
Caused by severe gastroesophageal reflux disease and continuous damage of the lining of the oesophagus by the stomach acid refluxing into the oesophagus.
This results in scar and narrowing of the lumen of the oesophagus.
What are local factors that can inhibit healing?
- Infection
- Haematoma
- Blood supply
- Foreign bodies
- Mechanical stress
How can age affect healing?
Children heal better than adults (older people can have co-existent disease such as ischaemia)
How can vitamin C deficiency lead to poor wound healing?
Vitamin C is involved in collagen synthesis –> scurvy leads to problems with wound healing
How can malnutrition lead to poor wound healing?
Protein deficiency
How can steroids affect wound healing?
Steroids have immunosuppressive actions, and interfere with formation of granulation tissue
How can a large transmural scar in the left ventricle lead to an aneurysm?
The scar can stretched to form a non-contractile cardiac aneurysm due to a process of continued thinning and fibrosis of the necrotic tissue of the ventricular wall
Why can an aneurysm lead to a thrombus
Endothelial damage –> thrombus
What happens when a bone is fractured?
There is haemorrhage around and within the bone –> haematoma
What then happens to the haematoma around the fractured bone?
Becomes organised
What is a haematoma?
a localised bleeding outside of blood vessels
Describe bone fracture healing
- There is haemorrhage around and within the bone –> haematoma
- Haematoma becomes organised
- Osteoblasts lay down disorganised woven bone (callus)
- Remodelling according to mechanical stress
- Replacement by more orderly lamellar bone
What is lamellar bone?
A mature bone that results from the remodelling of immature woven bone - is highly organised
What is immature woven bone?
It is the first bone laid down in prenatal life or in the repair of bone fractures.
In this type of bone, the matrix immediately surrounding the osteoblast is called osteoid and is not mineralised.
What is callus?
Bony and cartilaginous material forming a connecting bridge across a bone fracture during repair
What can cause fractures to not heal properly?
- Fractures are misalignment
- Movement (can result in excess callus formation)
- Infection (more common inc compound fracture)
What is a compound fracture?
A fracture in which there is an open wound or break in the skin near the site of the broken bone.
Most often caused by a fragment of bone breaking through the skin at the moment of the injury.
What is a pathological fracture?
A broken bone that’s caused by a disease, rather than an injury. Some conditions weaken your bones, which makes them more likely to break
E.g. metastases
Neurons are terminally differentiated. What does this mean?
Has irreversibly lost its ability to proliferate
Difference between supporting tissue in the brain and in the body?
Brain - glial cells
Body - collagen and fibroblasts (these can proliferate)
In the brain, what is left when damaged tissue is removed?
Often leaves a cyst surrounded by reactive gliosis –> gliosis rather than scarring
What is gliosis?
Gliosis is a nonspecific reactive change of glial cells in response to damage to the brain. In most cases, gliosis involves the proliferation or hypertrophy of several different types of glial cells (astrocytes, microglia, and oligodendrocytes)
What does blood coagulation and platelet degranulation release? What does this attract?
Growth factors - attracts macrophages and activate epidermal basal cells
What happens when macrophages migrate into wound?
Phagocytose bacteria and necrotic debris
What are epidermal growth factors released from?
Platelets, macrophages, saliva, plasma
Effect of epidermal growth factors?
Mitogenic for keratinocytes and fibroblasts. Stimulates granulation tissue formation
What are transforming growth factors released from?
Platelets, T lymphocytes, macrophages, endothelial cells, keratinocytes, smooth muscle cells, fibroblasts
Effect of transforming growth factors?
Chemotactic for PMNs, macrophages, lymphocytes, fibroblasts, and smooth muscle cells; stimulates TIMP synthesis, angiogenesis, and fibroplasia; inhibits production of MMPs and keratinocyte proliferation
What are keratinocyte growth factors released by?
Fibroblasts
What do keratinocyte growth factors stimulate?
Stimulates keratinocyte migration, proliferation, and differentiation
What is tumour necrosis factor released by?
Macrophages, mast cells, T lymphocytes
Effect of TNF?
Activates macrophages; regulates other cytokines; multiple functions
What are the 3 types of cells involved in tissue repair and regeneration?
- Labile cells
- Stable cells
- Permanent cells
What are labile cells?
Have high physiological turnover
E.g. skin epithelial cells, hepatocytes
What are stable cells?
Slow physiological turnover but turnover can increase if injured
E.g. renal tubular cells
What are permanent cells?
No turnover
E.g. neurons
An incision wound where the edges of the wound can be rejoined (surgical or not) will heal by ..?
First intention
A wound with irregular edges or tissue loss will heal by …?
Second intention
What are the 3 stages of wound healing?
- Inflammation
- Proliferation
- Maturation
What forms in inflammation during wound healing?
Formation of a blood clot
What occurs during proliferation in wound healing?
Re-epithelialisation, angiogenesis, granulation tissue, extracellular matrix (ECM)
What occurs during maturation in wound healing?
Tissue remodelling and wound contraction
Describe the inflammation process during wound healing
- Formation of a blood clot on the wound surface
- Release of VEGF (vascular endothelial growth factor) leads to increased vessel permeability –> oedema
- Within 24 hours, neutrophils are recruited
Describe the proliferation process during wound healing
- Over the next 24-72 hours, fibroblasts and vascular endothelial cells proliferate
- Over 5-7 days, granulation tissue fills the wound
- Neutrophils are replaced by macrophages
- ECM is deposited
- Re-epithelialisation
What are neutrophils replaced by?
Macrophages
Describe the maturation phase during wound healing
- Granulation tissue converts into fibrous tissue
2. In large wounds, wound contraction occurs
What is granulation tissue converted into?
Fibrous tissue (scar)
Are sutures used in 1st/2nd intention healing?
1st - yes
2nd - no
Describe volume of granulation tissue in 1st/2nd intention healing?
1st - small volume
2nd - large volume
Describe margins of wound healing in 1st/2nd intention?
1st - smooth margins
2nd - irregular
Describe scar of wound healing in 1st/2nd intention?
1st - fine, tends to be straight
2nd - irregular
Describe complications of wound healing in 1st/2nd intention?
1st - uncommon
2nd - often
What are the 3 stages of bone healing?
- Inflammation
- Repair
- Remodelling
Describe the inflammation process during bone healing
- Haematoma forms and provides fibrin mesh
- Neutrophils migrate
- Cytokines stimulate osteroblasts
Describe the repair process during bone healing
- Soft callus forms
2. Enchondral ossification converts soft callus into a hard callus (woven bone)
Describe the remodelling process during bone healing
- The hard callus slowly matures and is subjected to weight-bearing forces
- The sites of the callus that have less physical stress are resorbed and slowly the shape of new bone is formed
How is healing in the brain different?
Neurons are terminally differentiated cells. They do not regenerate.
What are glial cells?
Provide support and protection for neurons amongst other functions.
What is gliosis?
When glial cells proliferate in the brain in response to injury.
Since neurons cannot regenerate, glial cells proliferate.
What cytokines are released during healing?
- IL-1
- TNF-a
Effect of IL-1?
Promotes the recruitment of inflammatory cells at the site of inflammation by inducing the expression of adhesion molecules on endothelial cells and through the release of chemokines
Effect of TNF-a?
TNF-α participates in vasodilatation and oedema formation, and leukocyte adhesion to epithelium through expression of adhesion molecules; it regulates blood coagulation, contributes to oxidative stress in sites of inflammation, and indirectly induces fever
What growth factors are involved in healing?
- EGF
- VEGF
- HGF
- FGF-7
What is EGF?
Epidermal growth factor - a protein that stimulates cell growth and differentiation
What is VEGF?
Vascular endothelial growth factor - signalling protein that promotes the growth of new blood vessels.
What is HGF?
Hepatocyte growth factor - regulates cell growth, cell motility, and morphogenesis
What can deficient scar formation lead to?
- Wound ulcers (commonly due to inadequate vascular supply)
- Wound dehiscence (when a surgical incision reopens either internally or externally)
What can excessive repair tissue lead to?
- Hypertrophic scars
- Keloids
When do keloids occur?
If a hypertrophic scar tissue grows past the original wound borders and does not regress
What can tissue contracture during healing lead to?
Wound contraction is a physiological process of wound healing but if the contraction involves surrounding tissue and extends past the wound borders, it can result in a contracture deformity
Prone to occur in palm and soles –> can result in joint deformities
What is the quiescent phase of the cell cycle?
G0 (quiescent phase) also known as the inactive stage of the cell cycle, is the stage when the cell remains metabolically active, but do not proliferate unless called on to do so.
The regenerative capacity of cells permits classification into three groups. What are these?
- Labile - continue to proliferate throughout life
- Stable - retain this capacity but do not normally replicate
- Permanent - cannot reproduce themselves after birth
Describe the stem cell population in;
a) labile
b) stable
c) permanent
cell populations?
a) high
b) relatively high
c) almost 0
Which growth factor is the key mediator of angiogenesis?
VEGF
Effect of a local increase in TNF?
A local increase in concentration of TNF will cause the cardinal signs of Inflammation to occur: heat, swelling, redness, pain and loss of function.
