Lecture 7 - Regeneration And Repair Flashcards
What is repair?
(Fibrosis)
When tissue has been substantially damaged leading to repair with connective tissue
What are the general stages of wound healing?
Injury occurs
Haemostasis (blood clot when blood vessels damaged)
Inflammation
Then either Regeneration and/or repair
What is regeneration?
Re growth of cells with minimal evidence of injury (cant tell injury has happened)
What type of injuries can be regenerated?
Minor injuries (skin incision/abrasion)
What area the 3 criteria for regeneration to happen?
1.) Injury must be minor (skin abrasion/incision)
2.) Connective tissue architecture must be intact
3.) Tissue must have ability of regeneration
What is an example of physiological regeneration (normal)?
Haematopoiesis
(Production of blood cells from bone marrow)
What type of cells do new cells come from?
Stem cells
What are the features of stem cells?
Differentiation
Self-renewal
What is meant by potency of a stem cell?
The ability of the stem cell to differentiate into different types of cell
What is a Totipotent stem cell?
Where can they be found?
Can differentiate into all cell types
Embryonic stem cells
What is a Multipotent stem cell?
Where can they be found?
Can differentiate into several cell types but NOT ALL
Haematopoietic stem cells (Bone marrow)
What is a Unipotent stem cell?
Where can they be found?
Can only differentiate into ONE cell type
Epithelial stem cells (only into epithelium)
What are the 3 categories of tissue when referring to their ability to regenerate?
Labile Tissue
Stable Tissue
Permanent Tissue
What is the regenerative ability of Labile tissue?
Continuously replicating and regenerating
What are some examples of Labile tissues?
Epithelium
Haematopoietic tissue
What is the regenerative ability of stable tissue?
Normally undergoing low level replication but can rapidly replicate and regenerate if required
What are some examples of Stable tissue?
Liver
Kidneys
Pancreas
Smooth muscle
Bone
What is the regenerative ability of Permanent tissue?
Cells do not replicate (regenerate)
If damaged must undergo repair (scarring)
How do Labile cells navigate the cell cycle?
Continuously cycling
How do Stable cells navigate the cell cycle?
Enter G0 (Left cell cycle)
But can re-enter the cycle
How do Permanent cells navigate the cell cycle?
Cell permanently in G0
Cannot re-enter the cell cycle
Can regeneration occur with on going chronic inflammation?
No only FIbrous scar REPAIR
What is meant by fibrous repair?
The replacement of functioning tissue with a scar
What are the 4 phases to scar formation?
Bleeding + Haemostasis
Inflammation
Proliferation
Remodelling
What is the Haemostasis stage of scar formation?
Formation of blood clots to prevent blood loss
What is the inflammation stage of scar formation?
Acute then chronic inflammation
Digestion of blood clot occurs
What is the proliferation stage of scar formation?
Increase in the number of cells forming granulation tissue:
Capillaries (Angiogenesis)
Fibroblasts
Myofibroblasts
Extracellular matrix
Which proliferated cells produce the increased amount of Extracellular matrix in scar formation?
Fibroblasts
Myofibroblasts
What is Granulation tissue?
The tissue that proliferates in scar formation consisting of:
Fibroblasts
Myofibroblasts
Extracellular matrix
Capillaries
What is the function of Granulation tissue?
Capillaries supply oxygen and nutrients
Contracts (myofibroblasts) and closes the defect
Essentially fills the gap
What is the remodelling phase of scar formation?
Reduced cell population
Increased collagen in ECM
Myofibroblasts contract
What type of cell proliferates which causes Angiogenesis?
Endothelial cell
What is the role of neutrophils and macrophages in Fibrous repair?
Phagocytosis
Release of mediators that control the inflammatory and repair process
APCs
What is the role of lymphocytes in fibrous repair?
Eliminate pathogens (killer cytotoxic)
Co-ordinate other cells
T and B cells involved in cytokine production
What are the characteristic features of a Fibroblast?
Elongated/spindle/ovoid shaped nuclei
Cytoplasmic extensions
What is the function of the fibroblast tin Fibrous repair?
Secrete collagen and elastin for Extracellular Matrix
What is a myofibroblast?
A fibroblast containing intracellular actin
A cross between fibroblast and smooth muscle cell
What is the function of a myofibroblast?
WOUND CONTRACTION
At a basic level what are the steps of collagen synthesis?
Pre-pro collagen
Pro collagen
Tropocollagen
Collagen
How is pre-procollagen (alpha polypeptide chain) converted to pro collagen?
Hydroxylation
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Crosslinking of 3 hydroxylated alpha chains
What vitamin is an essential cofactor for the enzyme that carries out hydroxylation of pre-pro collagen to pro collagen?
Vitamin C
What is the structure of Pro collagen?
3 alpha chains in a triple helix
What are the amino acids that get hydroxylated when converting from pre-pro collagen to pro collagen?
Proline
Lysine
How is pro collagen converted into tropocollagen?
Procollagen pumped OUT of cytoplasm
Terminal ends (C ends and N ends) cleaved
How does Tropocollagen go onto form collagen?
Cross links (polymerisation) form with other Tropocollagens leading to formation of microfibrils, fibrils and then collagen fibres
What is Tropocollagen with respect to collagen?
The structural unit of tropocollagen made up of a triple helix of alpha chains
What amino acid is found at every third position in collagen?
Glycine
What is an example of an acquired defect of collagen?
Scurvy
How is Scurvy acquired?
Vitamin C defect
Why does a vitamin C defect cause defective collagen in Scurvy?
Vit C needed in hydroxylation of pre-pro collagen
Triple helix defective due to infective cross linking
Weak tensile strength
What do people usually present with in scurvy?
Inefficient wound healing
Tendency to bleed
Tooth loss
What are 3 Inherited collagen disorders?
Ehlers-Danlos Syndrome
Osteogenesis Imperfecta
Alport Syndrome
What is Ehlers-Danlos syndrome?
Group of 6 disorder where collagen fibres lack adequate tensile strength
How do patients present with Ehlers-Danlos syndrome?
Poor wound healing
Hyper mobile joints
Predisposition to join dislocation
Hyperextensible skin
Prone to colon or artery rupture (collage in organs also affected)
Corneal rupture
Retinal detachment
What is Osteogensis imperfecta and what is it caused by?
Brittle bone disease (Prone to fractures)
COL1A gene mutation
Defective Type 1 Collagen
How do people with osteogenesis imperfecta present?
Fragile bones
Blue sclera
Dental impairments
Hearing impatients
(Due to bone instability some times bowing)
What is Alport syndrome?
Abnormal Type IV Collagen
X-linked disease
How do patients with Alport syndrome usually present?
Usually male
Haematuria ——— Chronic renal failure
Neural deafness
Eye disorders
Why do patients with Alport syndrome usually present with Haematuria then chronic renal failure, neural deafness and eye disorders?
Type IV collagen essential for basement membrane formation
Basement membrane of glomerulus, cochlea of ear and lens of eye affected
What are the 3 ways that cells signal/communicate with each other to stimulate of inhibit proliferation in regeneration or repair?
Direct cell-cell contact
Local mediators (Growth factors, autocrine or Paracrine signalling)
Hormones (endocrine signalling)
What is autocrine signalling?
When cell produces and secretes a chemical signal that binds to and affects itself
What is Paracrine signalling?
When a cell releases chemical signals like growth factors affecting nearby cells
What is endocrine signalling/
Release of hormones/chemical signals acting on cells in different anatomical locations
How does cell to cell contact inhibit cell proliferation?
Cadherins of 2 cells come into contact signalling both cells to stop proliferating
In cancer how are Cadherins affected?
Defective
Will continue proliferation even when in contact
Instead of normal monolayer being formed multilayer forms
How do growth factors stimulate proliferation?
Polypeptides that bind to a cell triggering it to enter cell cycle
What is the function of Vascular Endothelial growth factor?
Stimulates Angiogenesis
What type of molecule is Tumour Necrosis Factor TNF?
Growth factor
What is meant by healing by Primary Intention?
Healing that occurs with Incisional injuries
Closed
Non infected
Clean wounds with Opposed edges
What occurs during healing by primary intention?
Minimal clot and granulation tissue
Epidermis regenerates
Dermis undergoes Fibrous repair since some connective tissue architecture damaged
When does healing with Secondary intention happen?
Significant tissue loss
Unopposed edges
Infections/ulcers/abscesses
What happens in healing of skin via Secondary intention?
Abundant clot, inflammation and granulation tissue
Lots of wound contraction needed (myofibroblasts)
Dermis needs significant repair
Epidermis regenerates from edges and bottom up
What are the 4 stages to Fracture healing?
Haematoma
Soft callus
Hard callus
Remodelling
What happens in the Haematoma stage of fracture healing?
Blood collects in and around fracture and Granulation tissue accumulates
What happens in the Soft Callus (Week 1)?
Fibrous tissue and cartilage produced creating weak woven bone (Soft bone)
What happens in the Hard callus stage of fracture healing? (Several weeks)
Woven bone gradually organised into strong lamellar bone
What happens in the remodelling phase of fracture healing?
Lamellar bone remodelled to original outline of bone
What are the local factors affecting wound healing?
Size
Location (what’s damaged)
Blood supply (good = better healing)
Local infection (slower with infection, has to deal with infection and healing)
Foreign bodies
What are the systemic factors influencing wound healing?
Age (weaker collagen strength)
Anaemia, hypoxia, hypovolaemia (blood supply issues = worse healing)
Obesity
Drugs
Diabetes
Vitamin deficiency
Malnutrition
How does diabetes affect wound healing?
High blood sugar makes you prone to infections
Blood vessels damage reducing O2 no nutrient supply to wound
Nerve damage may lead to further damage to wound since you can’t feel it
What is Wound dehiscence and why does it occur?
When a wound opens up an contents start to push out
Insufficient fibrosis
Where is wound dehiscence most common?
Obesity
Elderly
Malnutrition
Steroid usage
What is a Keloid scar and how does it happen?
Excessive fibrosis where the fibrosis exceeds the boundary of the scar
What are Adhesions?
Inappropriate scar formation in tubes
Fibrous bands can form after surgery obstruction the tube
How does fibrous repair lead to loss of function of tissue?
Any specialised cells that are replaced are lost
E.g special conducting cardiac myocytes lost following ischaemic damage of the heart
How do myocardial infarctions usually lead to future cardiac arrhythmias?
Cardiac myocytes replaced with non conducting fibrous scar tissue
Interferes with the conductance of the heart
How does fibrous repair of the liver disrupt its architecture?
Regeneration occurs which produces the Nodules
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Repair occurs producing the fibrous cirrhotic parts
Why is excessive scar contraction dangerous?
Tubes constricted
Scar over a joint may limit movement (Reduced Flexion)
What is the healing of Cardiac muscle like?
Very poor
Scar formation allows follows myocardial infarction
What is the livers ability to regenerate?
Lobes with functioning hepatocytes that remain enlarge
If severely damaged cirrhosis occurs
What is the ability of peripheral nerves to regenerate?
Axon regrows VERY VERY slowly but can regenerate
What is cartilages ability to regenerate?
Cant since it Lacks blood supply, innervation and lymphatic drainage
What is the CNS ability to regenerate?
Neural tissue is permanent
Damaged CNS replaced by proliferation of CNS supportive cells like glial cells
