Cell Biology

Question 1

What are the 2 anatomical compartments in the skin?

Answer 1

-Epidermis (50-100 micrometres thick)
-Dermis (1-1.25mm/1000-1250 micrometres thick)

Question 2

Cell types in the epidermis

Answer 2

-Major: keratinocyte
-Langerhans cells (bone marrow derived macrophages)
-Melanocytes (neural crest derived pigment producing cells)
-Merkel cells (neuroendocrine cells associated with particular nerve endings in epidermis)
-Immunocompetent cells (occasional lymphocytes)
-No vascular elements

Question 3

Cell types in dermis

Answer 3

-Bulk acellular material (collagen, elastin, glycosaminoglycans)
-Major: fibroblast (mesenchymal derived, function: production and remodelling of extracellular protein collagen)
-Mast cell (type of tissue basophil, contains and degranulates vasoactive chemicals like histamine)
-Inflammatory: lymphocytes, polymorphs, dermal macrophages, APC
-Nerves: either in free or highly structured endings in the dermis, or passing via the dermis into the epidermis
-Vessels: including capillaries, arterioles and venules

Question 4

What are appendageal structures and pilosebaceous units?

Answer 4

-Appendageal= hair follicles, sebaceous glands, eccrine glands and apocrine glands.
=Epidermal derived structures that arise during embryonic development towards the end of the first trimester
=Cannot be formed after the early second trimester— so if they are destroyed, they are gone forever

-Pilosebaceous unit= both hair follicle and sebaceous gland. In man, most sebaceous glands exit directly into a hair follicle

Question 5

Layers of the epithelium

Answer 5

Stratified squamous epithelium

-Basal layer (aka stratum basale) DEEP
-Spindle cell layer (aka prickle cell layer or stratum spinosum)
-Granular cell layer (aka stratum granulosum)
-Stratum corneum (horny cell layer) SUPERFICIAL

Question 6

Describe the basal layer of the epidermis

Answer 6

-Basal cells= cuboidal keratinocytes sitting on the basement membrane that separates the epidermis from the dermis.
-Only one cell layer thick
-Stem cells undergo asymmetrical cell division, with one daughter cell being another stem cell, and the other a transient amplifying cell.
=Transient amplifying cells can undergo several rounds of division before they lose their ability to divide and differentiate into terminally differentiated keratinocytes.
=INTERFOLLICULAR STEM CELL POOL

Question 7

Describe the spindle layer

Answer 7

-Spindle shape cells
-Prickle cell layer= tight desmosomal attachments between cells after fixation tend to resemble spines, or prickles, under the microscope
=Histopathological fixation often shrinks tissues, so the cells pull away from each other, except where the desmosomes ‘glue’ the cells together

-Layer forms the bulk of the thickness of the epidermis, and has multiple layers (>4).

Question 8

Describe the granular layer

Answer 8

-Granules made of keratohyalin (comprised of the proteins filaggrin and keratin)
-Lipid lamellae= intracellular membrane bodies which discharge epidermal lipids into the intercellular space in the high epidermis (lipid extrusion)

Question 9

Describe the stratum corneum layer

Answer 9

-Made up of multiple layers of flattened keratinocytes: cornified envelopes (corneocytes, or squames)
=begin to form in the granular layer, with the plasma membrane being replaced by covalently cross-linked proteins including keratins and filaggrin (and other proteins).
=The enzyme transglutaminase is essential to this process
=Cells are dead and have no nuclei (i.e. they are anucleate)

-Individual squames (dead cells) of the stratum corneum eventually break off and fall into your surroundings
=Desquamation relies on a protease mediated breaking down of the desmosomes.
=If this final process is deranged, such that instead of individual cells falling off, large chunks of cells stick together, then this will be visible as ‘scale’

Question 10

What are the 2 pools of keratinocyte stem cells in the skin?

Answer 10

-Interfollicular stem cell pool (basal layer)
-Other situated in the hair follicle close to where the sebaceous glands join the follicle.

=Independent, but if the pool situated in the Interfollicular skin is removed, stem cells from the hair follicle can repopulate the interfollicular stem cell pool.

Question 11

Describe epidermal differentiation

Answer 11

-As keratinocytes move from the basal layer to their terminally differentiated dead state in the stratum corneum (horny) layer, they produce a range of different proteins (including different keratins and filaggrin) and a variety of lipids

Question 12

What are keratins?

Answer 12

-Family of alpha-helical proteins, which are bound together in pairs, one acidic with one basic.
=Structural proteins that provide physical support for the cell (dynamic structures for when cell divides as dissolved and reformed)
=There are over 60 different types of keratins, each coded for by a different gene.

-Keratins are aggregated together by filaggrin (filament aggregating protein)
=The combination of keratins and filaggrin is visible under the light microscope as keratohyalin granules

-In epidermis, keratins attach to desmosomes (points of cell adhesion between keratinocytes)

Question 13

What do mutations in keratins and filaggrin cause?

Answer 13

-Types of epidermolysis bullosa, a blistering disorder.
-Filaggrin; atopic eczema, and ichthyosis vulgaris

Question 14

How do blisters form?

Answer 14

-Breakdown of the normal processes by which cells are attached to each other, or to the basement membrane, or to other anchoring structures in the superficial dermis- under frictional stress
=Breakdown of physical integrity of skin in response to frictional force
=Pathological processes that affect desmosomes or keratins

Question 15

How do callouses form in response to repeated frictional stress?

Answer 15

-Repeated frictional forces on the skin provoke thickening of the epidermis:
=increase in proliferation in the basal layer (more mitoses are visible)
=increase in daughter cells moving up into the spindle cell layer
==thickening of the spindle layer (aka acanthosis)
==thickening of the stratum corneum (aka hyperkeratosis).

Question 16

Disease processes that cause blistering

Answer 16

-Molecules concerned with mediating attachment within the epidermis
= Functionally inactive due to mutation (epidermolysis bullosa are due to mutations in keratins/ desmosomal proteins)
=Acquired blistering disorders such as pemphigus, auto-antibodies inactivate desmosomal proteins

Question 17

How is the skin a relatively impermeable barrier? (Bricks and mortar)

Answer 17

-Bricks = individual dead keratinocytes in the stratum corneum. The cornified envelope of these anucleate cells is comprised of various components including cross-linked and aggregated keratins.
=hydrophobic protein rich box.

-Mortar: the lipid.

=Hydrophobic barrier that is relatively impermeable to water

Question 18

What disease do disturbances to the skin barrier lead to?

Answer 18

-Atopic eczema/ contact irritant eczema: barrier function is impaired
=Foreign material penetrate into the epidermis= inflammatory or immunologically mediated response

-Damage or assault to the skin, whether from friction, or toxic assaults (sunburn or direct contact with alkali or acids) leads to an increase in proliferation of the basal keratinocytes and thickening of the spindle layer (acanthosis) and the stratum corneum (hyperkeratosis)

Question 19

What are melanocytes?

Answer 19

-Neural crest derived cells that migrate into skin at around 10-12 weeks of gestation.
–Melanocytes are highly dendritic and produce a complex polymer caller melanin.

Question 20

2 main classes of melanin

Answer 20

-Eumelanin, which is brown or black
-Pheomelanin, which is red or yellow (as in red hair)

Question 21

Why are hair and skin colours different?

Answer 21

-Ratio types of melanin, and the total amount of each, is the chief determinant of skin and hair colour.

=If you have predominantly pheomelanin in your hair, your hair is red.
=If you have mainly eumelanin, it is black.
= If you have only small amounts of either melanin, your hair is blonde

-Individuals with different skin colour have the same number of melanocytes in their skin: the colour differences are due to differences in the amount and type of melanin produced by the same number of melanocytes

Question 22

What are melanosomes?

Answer 22

-Lysosome like organelles in melanocytes: produces melanin as biosynthesis toxic to cell
-Melanosomes are then passed down the dendrites of the melanocytes into the surrounding keratinocytes.
=Colour of skin largely reflects the amount and characteristics of melanosomes that are passed into the surrounding keratinocytes.
=Because keratinocytes greatly outnumber melanocytes, skin colour reflects the melanin within the keratinocytes rather than the melanin within the melanocytes

Question 23

What is the function of melanin?

Answer 23

Protect interfollicular skin against ultraviolet radiation

Question 24

Other pigments contributing to skin colour

Answer 24

-Melanin is the main determinant of skin colour, along with haemoglobin.
-Other contributors to skin colour include bilirubin (in jaundice), extraneous pigments from drugs or heavy metals, and ingested pigments from food (e.g. carotenoids)

Question 25

What is albinism?

Answer 25

-Collection of genetic disorders in which the amount of melanin produced by melanocytes is reduced.
-Number of melanocytes is normal.
-One of the commonest types of albinism is due to recessive mutations in the gene for tyrosinase, a key enzyme in the biosynthesis of melanin.
=Lack of melanin in albinism results in an abnormal sensitivity to ultraviolet radiation and therefore an increase in the rate of skin cancer.

Question 26

Describe Langerhans cells

Answer 26

-Professional APC
=Antigens/haptens are gathered and metabolised by Langerhans cells before being presented to T-cells in the regional lymph node
=On further exposure to the antigen in skin, sensitised T-cells mediate an immunological response.
-May play a role in down regulating certain aspects of the cutaneous immune system

Question 27

Describe Merkel cells

Answer 27

-Neuroendocrine cells, derived from keratinocytes, that are found in the basal layer
=Highly innervated and are involved in mechanoreception

Question 28

Describe the basement membrane

Answer 28

-Complex acellular protein structure made of many modified proteins situated between the epidermis and the dermis.
=Basal keratinocytes are attached to the basement membrane by hemidesmosomes.
=Basement membrane is attached to the deeper collagen fibres in the dermis using smaller “adapter” collagen molecule

Question 29

Layers of the dermis

Answer 29

-Superficial papillary dermis (finer, fibre structure)
-Deeper reticular dermis (coarser)

Question 30

Describe collagen

Answer 30

-Synthesised by, secreted by, and remodelled by fibroblasts
-Triple alpha helix rich in glycine and proline, which is initially secreted as procollagen by fibroblasts.
-Modifications at the extracellular level involve cleavage of amino and carboxyl extensions and crosslinking of individual fibres.
-Individual molecules are then built up into complex microfibrils, which are then twisted into collagen fibres
-Vitamin C is essential for normal collagen production acting as an enzyme cofactor (scurvy)

Question 31

Clinical relevance of different collagens and collagen biosynthesis/ assembly

Answer 31

-Mutations in collagens that attach the basement membrane to the dermis will result in blistering disorders (collagen VII =dystrophic (scarring) epidermolysis bullosa)
-Mutations in a range of collagens will produce diseases such as Ehlers-Danlos syndrome
-Corticosteroids act so as to reduce the amount of collagen present in skin
-Chronic ultraviolet exposure results in increased cross-linking of collagen and an apparent loss of collagen content that is clinically evident as a reduction in skin (dermal) thickness and a tendency to easy bruising (solar purpura)

-Loss of collagen= tendency to bruise= loss of padding around dermal vessels

Question 32

Describe elastic fibres

Answer 32

-Impart a resilience and stretchability to the skin.
-Microfibril proteins are found in association with elastin fibres: fibrillin, mutations of which underlie Marfan’s syndrome.
-Ultraviolet radiation also changes elastic fibres with age, contributing to the differences in appearance of skin with age.

Question 33

Describe the extracellular material in the dermis

Answer 33

-Surrounding the fibroblasts and the various structural proteins are proteoglycans incorporating core proteins and glycosaminoglycans (mucopolysaccharides).
=The main glycosaminoglycans in skin are hyaluronic acid, heparin sulphate, chondroitin sulphate and keratin sulphate.

Question 34

Describe mast cells

Answer 34

-Tissue basophil-like cells that migrate into skin. They contain a range of inflammatory mediators; histamine, prostaglandins, leukotrienes and various other cytokines.
-Many of these inflammatory mediators are grouped together within granules within the mast
=Particular triggers lead to mast cell degranulation with release of the mediators into the surrounding extracellular area.
=Mechanism of degranulation involves crosslinking of IgE molecules that are found on the surface of mast cells (type I hypersensitivity reactions)

Question 35

Clinical lesions of mast cell degranulation

Answer 35

-Weal (aka hive)= nettle sting/ collection of dermal oedema (transient increase in permeability in small vessels causing local oedema)
-Initial erythema close to site (direct effect of histamine on vessel walls)
-Larger flare of erythema (axon reflex in which stimulation by histamine of peripheral nerves is transmitted along sensory nerves and then travels ‘backwards’ along other sensory nerves causing release of mediators at the distal nerve endings resulting in vasodilation /antidromic stimulation)

=Triple response

Question 36

Other inflammatory cells in the dermis

Answer 36

Circulation of inflammatory cells, particularly T-cells through skin, is a key component of the cutaneous immune system

Question 37

Vascular system of the dermis

Answer 37

-Rich vascular network comprising superficial and deeper plexuses.
-Blood supply to skin > brain