a) covers entire body making up about 20% of body weight and is the largest organ in the body
b) functions:

i) thermal regulation
ii) protection from outside environment (bugs and water soluble toxins)
iii) vapor barrier
iv) mechanical barrier
v) excretion of some waste products
vi) involved in vitamin D synthesis
vii) sensory function (temperature and touch)
viii) lipid soluble drug delivery
ix) appearance

a) epidermis:

i) outermost layer of skin that is avascular
ii) made of 4 (thin) or 5 (thick) layers of cells
iii) variable thickness depending on location

-thick (epidermal layer) skin on soles and palms (hairless or glabrous)
-thin (epidermal layer) skin in other regions (haired or pileous)

iv) responsible for barrier properties of skin

b) dermis:

i) inner layer of skin
ii) links epidermis to hypodermis
iii) sweat glands, sebaceous glands and hair follicles reside mostly in this layer
iv) roughly two layers
v) variable thickness over different regions of the body

c) hypodermis (subcutaneous layer):

i) not a true layer of the skin but attached to it, so-called subcutaneous fascia
ii) links skin to body proper
iii) variable thickness in different regions of the body
iv) allows for movement of skin over body proper

III. Epidermis

a) cells

i) keratinocytes:

-most abundant (about 90%) cell of epidermis
-cuboidal to squamous morphology depending on location
-abundant cell/cell linkages via desmosomes
-pronounced cell/basement membrane linkages via hemidesmosomes in the basal cell layer
-cell functions primarily as a intermediate filament factory:

-intermediate filaments called keratins and are of various size and charge depending on location in epidermis
-as cells migrate to outermost layer, the content and aggregation status of keratins increases
-intermediate filaments called tonofilaments
-tonofilaments cross-linked by protein called filaggrin giving tonofibrils which embed in matrix and form keratin
- up to 50% of total cell protein can be keratins

-cells synthesize lamellar granules:

-0.1 - 0.3 micron ovoid structures
-made of lipid bilayers (different composition than plasma membrane, contain acylglucosocerimide)
-extruded into intercellular space and contributes significantly to vapor barrier properties of skin

-cells synthesize keratohyaline granules:

-basophilic, non-membrane bounded, protein granules distinct to a layer of the epidermis
-contain phosphate and cystine rich protein called profilaggrin (soft keratin) that is proteolyzed to filaggrin during keratinocyte maturation
-involved in forming tonofibrils and their aggregates to give the intracellular matrix called keratin

-take up melanin (skin pigment) from melanosomes

ii) melanocytes:

- about 5% of the living cells of the epidermis
- near base of epidermis and attached to basal lamina via hemidesmosomes but do not attach to neighboring keratinocytes by desmosomes
-dendritic cells which send processes up (superior) and between keratinocytes
- derived from neural crest cells
- synthesize melanin:

- two different forms:

- eumelanin (brown pigment)
- pheomelanin (red pigment)

-tyrosine converted into 3,4-dihydroxyphenylalanine (dopa) by tryrosinase in vesicles
-continued processing occurs in vesicles (dopa converted to dopaquinone and subsequent intermediates then into melanin)
-once mostly filled with melanin it is called melanosome which are dense vesicles visible in the light microscope
-melanosomes develop/mature distal to the cell body
-melanosomes move through dendritic process possibly via acto/myosin interactions and are “injected” into keratinocytes
-melanosome migrate to an apical, perinuclear location in the keratinocyte (near Golgi, how would they get there?)

-melanocyte density varies with location in body
-melanocyte number does not vary between people of different color, rather, the keratinocyte processing of melanosomes differs or the activity of the melanocytes differ

iii) Langerhan’s cells:

- 2 to 3 % of epidermal cells

- found within the basal and superior layers of the epidermis
- star-shaped cells (dendritic) cells

- attach to keratinocytes via E-cadherins (adherens type junctions) in a regulated manner
- bone-marrow derived, macrophage-like cells that have MHC II on the cell surface
- responsible for presenting antigen to T-cells in non-epidermal sites thus, they have to " crawl" out of the epidermis, into lymphatic vessel, and migrate to the pericortical region of local lymph nodes to present antigen
-important in contact allergic response via recruiting and stimulating other myeloid cells

iv) Merkel cells:

- few in number (< 1%)

- found in the basal layer of the epidermis and form macula adherens junctions with keratinocytes
- located over entire surface but more prominent on palms and soles of feet (glabrous skin)
- cells contain small dense granules similar to neuroendocrine cells
- function thought to be of sensory or neuroendocrine nature

- in glabrous skin, the Merkel cell is close apposition to a plate like nerve ending from a ? neuron

b) layers (from base to surface) of epidermis:

i) stratum basale:

-basal cell layer of epithelia which rests upon thick basal lamina
-single layer of basophilic cuboidal cells
-keratinocytes most numerous
-melanocytes are located here only
-keratinocytes and melanocytes link to basal lamina with hemidesmosomes
-keratinocytes divide in the region between the stratum basale and stratum spinosum in a layer called the malpighian layer
-melanin from melanocytes cap nuclei in this layer

ii) stratum spinosum:

-cuboidal to squamous cells with central nuclei
-contain aggregates of keratin called tonofilaments
-tonofilaments linked cell/cell by desmosomes which give a spiny appearance to the cells (nodes of Bizzozero)
-responsible for mechanical strength of epidermis
-variable number of cell layers depending on location

iii) stratum granulosum:

-cells mostly squamous
-usually 3 - 5 cell layers thick
-keratinocytes contain keratohyalin granules in this layer
-granules appear as basophilic granules giving granular appearance in light microscope
-lamellar granules conspicuous at the EM level

iv) stratum lucidum:

-not obvious in thin skin
-thin layer of very flat, eosinophilic, anucleate cells
-somewhat translucent layer

v) stratum corneum:

-outermost layer
-15 - 20 (thin skin) or more (thick skin) layers of flattened, anucleate cells
-mostly composed of keratin filaments with interfilament matrix and glycolipid

c) life cycle of keratinocyte:

- keratinocytes mitotic in the stratum basale and malpighian layer
- once in stratum spinosum they are post-mitotic
- differentiate and are pushed towards surface by inferior (lower) cell division and growth
- differentiation includes accumulation of keratin filaments, aggregation of filaments into tonofibrils, synthesis of lamellar granules and release at cell surface
- nuclei begin to degenerate in the outer layer of the stratum granulosum (apoptosis), release of lysosomal enzymes which degrade intracellular organelles
- final result is a fibrillar meshwork of keratin filaments and interfibrillar matrix which give the keratin layer

d ) coloration of keratinocytes:

-melanin synthesized in melanocytes in stratum basale
-melanin taken up by keratinocytes mostly in the stratum basale and the melanosome localizes to the apical perinuclear region to protect the mitotic nuclei from UV light
-some skin coloration anomalies caused by a lack of tyrosinase activity or ability of melanocyte to take up tyrosine

a) cells:

i) fibroblasts, lymphocytes, macrophages, mast cells
ii) secretory cells and ducts form glands (derived from the epidermis)
iii) smooth muscle attached to hair follicles (pilosebaceous units from epidermis) and in skin covering the penis, scrotum, and areola around nipples

b) topology (two layers):

i) papillary layer: peg or rows of pegs (ridges) outline of loose CT just below the epidermis

- increases surface area of contact between epidermis and dermis
- special collagen fibrils link basal lamina of epidermis to collagen fibers in dermis, called anchoring fibrils

- abundant capillary networks within the papilla

ii) reticular layer: layer between papillary layer and hypodermis

-dense irregular CT

c) composition:

i) mainly collagen type III in papillary layer, mainly type I in reticular
ii) small elastic fibers in papillary layer and larger elastic fibers in the reticular layer
iii) interfibrillar space filled primarily with dermatan sulfate

iv) rich supply of arteries and veins that supply and drain capillary beds in the papilla, sensory nerve endings and motor nerves innervating vasculature and glands of skin

a) cells:fibroblasts, fat cells, lymphocytes, macrophages, mast cells

b) topology:

-variable thickness depending on location and nutritional status
-site of deposition of the majority of body fat

c) composition:

- loose CT containing fat cells

- arteries, veins, lymphatics, and nerves that supply and drain the skin

VI. Skin appendages

a) pilosebaceous unit

b) finger nail

c) glands

a) terminal (adult) hair anatomy

i) cuticle: outermost layer, thin, fish-scale appearing with free-end facing the same direction as hair growth, heavily keratinized
ii) cortex: middle layer, keratinized
iii) medulla: pigmented, non-keratinized

b) types of hair:

i) lanugo: neonatal, form at 7 mo and shed by 8 mo in utero, fine, soft, hair without a medulla (non pigmented)
ii) vellus: post-natal, short, fine shaft, no medulla (non-pigmented),
iii) intermediate: post-natal to 2 years of age, intermediate between vellus and terminal hair
iv) terminal: post-natal and on, long, course shaft, medullated (pigmented), most common visible hair

c) terminal hair, pilosebaceous unit anatomy

i) hair shaft

ii) hair follicle:

- invagination of epithelia (with its basal lamina) into dermis (or lower), exterior to the basal lamina is a connective tissue sheath called the dermal sheath
- for the superior 1/3 of the follicle, the hair shaft is not attached to the follicle, around (but not attached to) the follicle is the outer (external) root sheath
- side-branch develops into sebaceous gland about 1/3 the way down the follicle
- smooth muscle (arrector pili muscle) attaches to the dermal sheath of the follicle just below the sebaceous gland
- inferior to the sebaceous gland, the shaft is attached to an epithelial layer called the inner root sheath
- exterior to the inner root sheath is a continuation of the outer (external) root sheath
- inner root sheath contains three layers:

-cuticle: 1 cell layer of thin cells adjacent and linked to the developing hair shaft cuticle
- Huxley’s layer: predominant layer, 2 - 3 cell layers, molds hair cross-section
- Henle’s layer: 1 cell layer thick, encloses shaft/sheath structure and is at the interphase between the outer root sheath and inner root sheath

- interior to the internal root sheath is the developing shaft with its cuticle, cortex and medulla

- follicle base is bulb-like with the epithelia surrounding a tuft of dermal tissue called the dermal papilla, the dermal papilla is enriched in capillaries
- the epithelia are separated (mostly) from the dermal papilla by a basal lamina
- the epithelial cells surrounding the papilla are called matrix cells as they give rise to the cells that make the matrix (hard keratin) of the shaft
- these cells differentiate and grow to give the hair shaft and inner root sheath:

- the epithelia at the tip of the papilla give rise to the cells of the shaft medulla
- the epithelia just down from the tip give rise to the cells of the shaft cortex
- the epithelia further from the tip give rise to the cells of the shaft cuticle
- the epithelia at the base of the papilla give rise to cells of the inner root sheath
- melanocytes in the bulb provide melanosomes for medulla cells to give hair coloration

d) hair development and growth:

i) follicle develops by a down-growth of epidermal cells into the underlying dermis during fetal development, full complement of follicles is developed pre-natally and not many are lost throughout life
ii) once the follicle has developed, growth can be subdivided into 4 stages:

- anagen: hair growth, duration of this phase determines hair length
- catagen: regression, cell division ceases in the bulb, the papilla shrinks, and the shaft and inner root sheath detach from the dermal papilla and are pulled/pushed up the follicle by programmed cell death, the follicle shrinks but a strand of the external root sheath remains in association with the papilla
- telogen: rest, the proximal terminus of the hair shaft has migrated to just below the sebaceous gland and the proximal hair terminus is club-shaped instead of bulb shaped
- exogen: exit of hair shaft from follicle, can have more than one hair in a follicle but will only have one bulb hair and one or more club hairs

iii) androgens influence the growth of hair both + and - , can result in change of terminal hair to vellus hair in androgen-dependent baldness
iv) length of anagen cycle determines hair length
v) cells of hair follicle serve as a cell reserve to supply keratinocytes upon loss of epidermis

a) anatomy:

i) nail root:stratum basale and spinosum of epidermis are present here forming nail matrix cells which synthesize the nail plate
ii) nail bed: stratum spinosum of nail, does not contribute to nail synthesis
iii) nail plate: closely compacted, keratin enriched with hard interfibrillar material, it is the stratum corneum of the nail
iv) eponychium: junction between skin stratum corneum and base of nail plate
v) hyponychium: junction between the skin stratum corneum and the tip of the nail plate
vi) lunula: light or white region at the base (eponychium) of nail plate

b) nail growth:

i) keratinocytes in the nail bed (matrix cells) proliferate, grow, synthesize hard keratin, dye, and form the matrix of the nail
ii) lunula is thought to represent immature hard keratin of the developing nail and is an indicator of nail growth
iii) growth is usually fastest in the longest digit

a) sweat glands:

i) secretory portion located in deep dermis to hypodermis
ii) simple, coiled, tubular merocrine gland
iii) secretory portion includes dark and clear cells and myoepithelial cells

-dark cells secrete glycoprotein
-clear cells secrete plasma ultrafiltrate (primarily salts)
-myoepithelial cells contract and squeeze out secretory products

iv) duct lined by stratified cuboidal epithelia

-removes some of the salt from the sweat prior to release upon surface

v) sweat: water, NaCl, urea, ammonia and uric acid

-functions to cool body
-cholinergic innervation controls secretion

vi) cells of glands serve as a reservoir of keratinocytes upon epidermal damage

b) sebaceous glands:

i) essentially part of the hair follicle
ii) release secretory product (sebum) onto hair shaft
iii) mechanism of secretion is holocrine
iv) sebum composed of lipids, triglycerides, waxes, squalene, cholesterol and cell remnants
v) secretion controlled by testosterone in men and androgens in women
vi) inflammation of gland results in acne

c) appocrine sweat glands:

i) empty contents onto hair follicles in the axillary, areolar, and anal regions of the body
ii) derivative of the sebaceous glands (off-shoot of gland with duct connecting to hair follicle)
iii) larger than sweat glands with a prominent lumen
iii) secrete viscous product which is made odiferous by bacterial action

-responsible for socially-offensive body odor

iv) adrenergic innervation controls secretion

a) integument is richly innervated with the sensory system being highly developed to act as the eyes of the skin and to allow for high-fidelity use of tools

b) types of sensory nerve endings include free endings, hair follicle receptors, endings at Merkel cells, Meissner's corpuscle, Krauses end bulb (Golgi tendon organ), Pacinian corpuscle, and Ruffini endings

i) free nerve endings: nerve terminal looses its myelin sheath at the epidermal/dermal junction, and pass into the epidermis ending in the stratum granulosum, sense pain and temperature

ii) hair follicle receptors: axon looses myelin sheath and bare axon coils around the shaft within the external root sheath, senses hair motion and its direction

iii) Merkel cell endings: axon looses its myelin and forms a disc like structure with the Merkel cell at the base of the epidermis (stratum basale), senses edges, corners, and curvature (pins and needles), slowly-adapting type response (do not readily de-activated)

iv) Meissner’s corpuscle: encapsulated nerve ending in the dermal papilla of skin, sense dynamic deformation of skin with high sensitivity but poor special resolution, rapidly adapting type response (readily de-activate), sense slip of surface over skin (tools)

v) Krauses end bulb: axon looses myelin and passes into a capsule then branches within the capsule, found in the papillary layer of the dermis of skin and in the epidermis of oral mucosa and tongue, sense tension (force), slowly-adapting type response

vi) Pacinian corpuscle: axon looses myelin and passes into a capsule and a single process continues into the core of the corpuscle, corpuscle is multilayered with a thin sheet of cells separated by a gelatinous material, found deep in the dermis and in the hypodermis, sense high frequency, low amplitude displacements (10 nm displacement at 200 Hz, vibrations) with poor spatial resolution (tools again), rapidly adapting response

vii) Ruffini endings: axon looses myelin and penetrates an oblong, thinly capsulated structure then branches profusely within the capsule, found in the deep dermis and in the hypodermis especially in the plantar glabrous skin, corpuscle is oriented with the long axis of collagen fibers and is attached to them, sense displacement/tension in collagen fibers in the dermis/hypodermis, slowly adapting type response