MoD S5 - Healing and Repair Flashcards Preview

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Flashcards in MoD S5 - Healing and Repair Deck (48):

What is the definition of regeneration?

The replacement of dead or damaged cells by functional, differentiated cells derived from stem cells


What are stem cells?

What happens to a stem cell when it divides?

Undifferentiated cells with limitless proliferation potential

Daughter cells either:

- Remain as stem cells

- Differentiate into specialised cells


What are stem cells used for?

Internal repair system that replaces lost or damaged cells

Can possibly be used to treat degenerative disease


What are the three major types of stem cell?



Where can stem cells be found in the gut?

What is their function there?

At the base of crypts in the mucosa

Replace cells lost from the mucosa


Blood cells are derived from what type of stem cell?

Multipotent haemopoietic stem cells


What is the function of stem cells in the embryo?

Differentiate into the different tissues of the body


How are cells classified by propensity to regeneration?

Give a breif description and example of each type

Labile cells:
- Normally in active cell division
- Rapid proliferation
- E.g. Epithelial cells

Stable cells:
- Resting state - G0, but can divide in the right conditions
- Speed of regeneration variable
- E.g. Hepatocytes

Permanent cells:
- Unable to divide - G0
- Unable to regenerate
- E.g. Neurones, Cardiomyocytes


Give two examples of stable cell proliferation

Renal tubular epithelium, when damaged can proliferate and replace lost and damaged cells

Hepatocytes can regenerate when they are damaged during cirrhosis of the liver (nodules)


What factors control regeneration?

Growth factors
Contact between cell and basement membrane and adjacent cells


What do growth factors do?

Promote proliferation in the stem cell population via extracellular signals that are transduced into the cell hence promoting expression of genes controlling the cell cycle


Give some examples of growth factors

- Epidermal GF
- Platelet derived GF
- Fibroblast GF
- Some Cytokines

- Oestrogen & Testosterone
- Growth hormone


What types of cell signalling do growth factors use?



Give an example mechanism by which a growth factor might induce cell proliferation

Binds to extracellular receptor

Receptor has intrinsic enzyme activity and will autophosphorylate (tyrosine kinase)

This sets of a phosphorylation cascade which results in increased transcription of genes which regulate the cell cycle


How is contact between cell and basement membrane and adjacent cells involved in regulating regeneration?

Signalling is done through adhesion molecules

Signals inhibit proliferation when the cell being signalled is in contact with other cells (Contact inhibition)

Loss of contact will promote proliferation


In what group of pathologies do the mechanisms controlling cellular proliferation become deranged?



Give an example of a mechanism by which contact inhibition is achieved

E-cadherin is a protein spanning the cell membrane that will dimerise with other E-cadherin molecules on adjacent cells

The end result of this dimerisation is contact inhibition


What is 'fibrous repair'?

The replacement of functional tissue by scar tissue


What are the 2 main outcomes of inflammation or injury and how do they come about?

Hint: relate this back to proliferation potential of the cells that were damaged

When injury leads to necrosis of permanent cells:
- Fibrous repair and scarring occurs

When injury leads to necrosis of stable or labile cells:
- If collagen framework preserved, insult is resolved
- If collagen framework destroyed, Fibrous repair and scarring


What are the 3 main components of fibrous repair and all together, what do they form?

Cells that migrate in
Blood vessels - Angiogenesis
Extracellular matrix protein production and remodelling

Granulation tissue


What are the important cell types in fibrous repair?

How is each type involved?

Inflammatory cells:
- Phagocytosis of debris - neutrophils and macrophages
- Chemical mediators - lymphocytes and macrophages

Endotheial cells:
- Angiogenesis

- Produce extracellular matrix proteins E.g. Collagen
- Myofibroblasts can contract the wound


Why is angiogenesis vital to wound healing?

Provides access to the wound for inflammatory cells and fibroblasts as well as oxygen and nutrients


How does angiogenesis begin?

Endothelial proliferation induced by proangiogenic growth factors such as VEGF

Pre-existing blood vessels will sprout off new blood vessels (they don't arise de novo)


Describe the process of angiogenesis

Growth factors such as VEGF produced at sites of chronic inflam, tissue injury or hypoxia

Endothelial proteolysis of basement membrane

Migration of endothelial cells into surrounding interstitium via chemotaxis

Endothelial proliferation into primitive tubular structures

Maturation and tubular remodelling

Linkage with venous system

Recruitment of periendocardial cells


How is angiogenesis involved in malignancy?

Tumours require rich blood supply

Tumours require angiogenesis to supply metabolic demand once tumour has grown to a larger size

Potential therapeutic target


What are the functions of the extracellular matrix?

Supports and anchors cells
Separates tissue components (E.g. basement membrane)
Sequesters growth factors
Facilitates cell communication and migration


Describe collagen


Provides extracellular framework
Composed of triple helices of various polypeptide alpha chains
Fibrillar collagens (I - III)
Amorphous collagen (IV - VI)
Remodelled by specific collagenases


Describe the synthesis of collagen fibres


Polypeptide alpha chains synthesised in ER

Enzymatic modification steps including Vit C dependent hydroxylation

Alpha chains align and cross link to form procollagen triple helix

Soluble procollagen secreted from cell

After secretion cleaved to form tropocollagen

Tropocollagen will polymerise to form fibrils

Bundles of fibrils form fibres


List 4 major defects of collagen synthesis

Vit C Deficiency - Scurvy!
Ehlers-Danos syndrome
Oseogenesis imperfecta
Alport syndrome


Describe some of the features of scurvy

Inadequate Vit C dependent hydroxylation of alpha chains leads to defective helix formation

Lacks strength, vunerable to enzymatic degradation

Causes heamorrhage due to affecting collagen supporting blood vessels


What is the major defect in Ehlers-Danos syndrome?

Defective conversion of procollagen to tropocollagen


Apart from collagen what are some of the other constituents of the ECM in fibrous repair?

Matrix glycoproteins:
- Organise and orientate cells
- Support cell migration
- E.g. Fbronectin, laminin

- Matrix organisation, cell support, regulate availability of growth factors

- Provides elasticity


What are the 3 main stages of fibrous repair?

Inflammatory cells infiltrate

Clot replaced by granulation tissue



Describe the process of Fibrous repair

- Blood clot forms
- Acute inflammation occurs, neutrophils digest clot
- Chronic inflammation begins and macrophages and lymphocytes are recruited

Granulation tissue replaces clot:
- Capillaries begin to sprout and infiltrate in response to pro-angiogenic growth factors
- Myo/fibroblasts migrate and differentiate and begin producing ECM (Collagen and friends)

- Cell population falls
- Collagen increases, matures and remodels
- Myofibroblasts contract, reducing volume of defect
- Vessels differentiate and are reduced
- Left with fibrous scar


How is fibrous repair controlled?

Complex and poorly understood:
- Inflammatory cells recruited via chemotaxis

- Pro-angiogenic factors release by platelets and ECM in response to hypoxia E.g. VEGF

- Macrophages produce pro-fibrotic cytokines (E.g. IL-1, TNF-alpha) leading to fibroblast proliferation and ECM production


What is healing by primary intention?

Occurs following an incised wound in the skin with apposed edges

Minimal clot and granulation tissue

Epidermis regenerates

Dermis undergoes fibrous repair (granulation tissue transitions to scar tissue)

Sutures out at 10 days (when tissue has approx 10% strength)

Maturation of scar continues for up to 2yrs resulting in minimal scarring with good strength

Risk of trapping infection


What is healing by secondary intention?

Occurs after infarct, ulcer or any large wound

Unapposed wound edges

Large clot dries to form as scar or eschar

Epidermis regenerates from base up

Produces far more granulation tissue than primary intention healing and produces a larger scar (takes longer)

Myofibroblasts must produce much more contraction to reduce defect volume


What are the 4 stages of bones repair?

Haemotoma formation
Procallus formation
Bony callus formation


Describe healing of bone after a fracture

- Forms from ruptured periosteal and marrow cavity vessels
- Provides framework for ingress of macrophages, endothelial cells, fibroblasts and osteoblasts
- Necrotic tissue removed by macrophages
- Capillaries develop

- Normal granulation tissue forms + osteoblasts and osteoblast matrix
- Bones is laid down in irregular woven pattern sometimes with islands of cartilage
- Mineralisation begins
- External Hyaline cartilage callus provides support

Bony callus and remodelling:
- Woven bones gradually replaced by lamellar bones
- Lamellar bone remodelled to direction of mechanical stress


What local factors affect wound healing?

Type, size, location of wound
Apposition (important in skin, bone, nerves)
Lack of movement
Blood supply
Infection (gangrene, systemic)
Foreign material (dirt, glass, sutures, necrotic tissue)
Radiation damage


What are the general or systemic factors affecting healing?

Drugs (steroids, hormones)
Dietary deficiency (general e.g. proteins, Vit.C, essential amino acids)
General health (Diabetes, rheumatoid arthritis)
Cardiovascular health


What are the common complication of wound healing?

Insufficient fibrosis:
- Wound dehiscence (rupture of sutures)
- Hernia, ulceration
- Risk factors: Obesity, malnutrition, steroids

Excessive fibrosis:
- Cosmetic scarring, keloids
- Cirrhosis, lung fibrosis

Excessive contraction:
- Obstruction of tubes or channels (strictures)
- Limitation of joint movement (contractures)


Describe regeneration of the liver following acute and chronic damage

- Only organ capable of regeneration of lost tissue
- Can completely regerate lost hepatocytes and structural damage

- Liver cirrhosis
- Fibrous tissue replaces damaged liver tissue
- Normal hepatic structure lost, hepatocytes form 'nodules' of regenerating tissue between fibrous tissues


Describe the healing response to acute tubular necrosis

Death of kidney tubule cells

Due to toxins or hypoxia

Some epithelial cells remain due to patchy necrosis of tissue, structural framework also remains intact

Epithelial regeneration via mitosis occurs and epithelia is regrown on the basement membrane

This leads to complete regeneration


Describe healing of the heart post MI

Myocardium is completely incapable of regeneration of damaged tissue

Healing will always occur via fibrous repair

This leads to a loss of contractile force the heart can generate, may lead to heart failure or cardiogenic shock


Describe the healing of cartilage

Cannot normally regenerate

Chondrocytes cant migrate to damaged areas due to being trapped in lacunae

Avascular, so deposition of new matrix is slow

Hyaline cartilage damage may result in fibrocartilagenous scar tissue repair


What is Wallerian degeneration?

What follows?

Degeneration of a nerve fibre distal to a cut or crushing injury

Neurolemma doesn't degenerate leaving a hollow tube

Axonal regrowth (sprouting) can occur in the CNS and PNS

If neurolemma is held in good apposition then the proximal nerve axon can sprout into the distal neurolemma and regenerate and reinnervate the target

If neurolemma is lost or not held in apposition, this is not possible


What is the response to CNS damage?


Macrophages and microglia invade site of damage and begin clearing cell debris (E.g. Degenerating axons)

Oligodendrocytes precursor cells then invade and begin the process of remyelination of demyelinated neurones

Surrounding astrocytes will proliferate and form a glial scar

This process will inhibit axonal regrowth, but can have other positive effects