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KERATINOCYTES AND KERATINOCYTES AND KERATINIZATIONKERATINIZATION
M.YOUSRY ABDEL-MAWLAM.YOUSRY ABDEL-MAWLA
SKIN STRUCTURESKIN STRUCTURE
SKIN or INTEGUMENT: Roles
chemical-mechanical PROTECTION water loss radiation
bugs immune
SENSORY
THERMOREGULATION
METABOLISM vitamin D fat storage
COMMUNICATION
MECHANICAL friction surface scratching
WABeresford
SKIN or INTEGUMENT: Structures
EPIDERMIS keratinized stratified squamous epithelium
DERMIS dense irregular, mostly collagenous CT
HYPODERMIS adipose connective tissue
ADNEXA (accessories) sweat & sebaceous glands, hair follicles & hairs, nails, mammary glands , nerves & nervous receptors, special blood vessels
EPIDERMIS: Cell types
Keratinocytes
Langerhans APC cell immunity
Melanocyte to make & transfer pigment
Merkel cell sensory
dead
alive
Nerve cell represented by its axon
EPIDERMIS: Layers & events
STRATUM CORNEUM of dead, but attached, ‘hardened & wrapped‘ cells , will slough offS. GRANULOSUM multiple syntheses
to make cornified cellsS. SPINOSUM upward migration of keratinocytes, while keratins IFs increase & change
S. BASALE mitosis of stem cells
Keratinocyte differentiation
}}
capillary loop
Meissner’s corpuscle
DERMIS Papillary layer}
}DERMIS Reticular layer
}HYPODERMISFat cells
Sweat gland
EPIDERMIS}duct
Pacinian corpuscle
THICK, HAIRLESS SKIN
capillary loop
EPIDERMIS}Pacinian corpuscle
THICK, HAIRLESS SKIN
no hair follicles no sebaceous glands
sweat gland opens at top of ridge
dermal papilla
dense thick collagen fibers + elastic fibers
secretory profiles of coiled tubule
coiled duct of sweat gland &
THIN HAIRY SKIN
Papilla of Hair follicle
Root sheath
Hair shaft Sebaceous gland
Arrector pili muscleSweat gland
D
E
R
M
I
S
Epidermis
HYPODERMIS
Matrix
Autonomic motor
Sweat gland
D
E
R
M
I
S
Epidermis
Vessel
vasomotor
THIN HAIRY SKIN: Innervation
Arrector pili muscle
pilomotorsudomotorSensory
SKIN or INTEGUMENT: Roles - Correlations
PROTECTION chemical- mechanical water loss, bugs
immune
SENSORY
THERMOREGULATION
METABOLISM vitamin D fat storage
COMMUNICATION
MECHANICAL
keratin, melanin, sebum thick epithelium , hair, dermal papillae
Langerhans cells dermal lymphocytes
sensory receptors & fibers
blood flow, sweat gands, hair, fat
keratinocytes adipocytes
blood flow, pigment, hair, facial skin
‘fingerprint’ ridges, sweat glands, nails
{
MOLECULAR EPIDERMIS
CORNEUM CELLS
ANCHORING FIBRILS
LAMINA DENSA
LAMINA LUCIDA
HEMIDESMOSOMES
BASAL CELL
type VII collagen
laminin type IV collagen
epiligrin BM 600anchoring
filaments
glycolipid cadherin-P T-transglutaminase 1
keratins
hemidesmosomal proteins integrin a6b4
{
MOLECULAR EPIDERMIS *
CORNEUM CELLS
ANCHORING FIBRILS
LAMINA DENSA
LAMINA LUCIDA
HEMIDESMOSOMES
BASAL CELL
type VII collagen
laminin type IV collagen
epiligrin BM 600anchoring
filaments
glycolipid cadherin-P T-transglutaminase 1
keratins
hemidesmosomal proteins integrin a6b4
{{
HAIR FOLLICLE: LAYERS at one cross-section
MedullaCortex
Cuticle
CuticleHuxley’s layer
Henle’s layer
OUTER ROOT SHEATH
CT sheath
INNER ROOT SHEATH
HAIR SHAFT
4
3
2
1
Before getting lost in the layering, note the 4 main parts. For the matrix & dermal papilla, see next
Hair bulb
HAIR FOLLICLE: LAYERS longitudinalHAIR SHAFTMedulla
OUTER ROOT SHEATH
CT sheath
CortexCuticle
DERMAL PAPILLA nourishes & controls the matrix
MATRIX
Cuticle
Huxley’s layerHenle’s layer
INNER ROOT SHEATH
1
2
3
4
5
6
OUTER ROOT SHEATH
Medulla
Cortex
Cuticle
CT sheath
Cuticle
Huxley’s layerHenle’s layer
INNER ROOT SHEATH
HAIR SHAFT
grows &
12
HAIR FOLLICLE 4
There are two cuticles, so that the hair’s can separate from the follicle’s for the hair to move & be coated with greasy sebum
HAIR SHAFTMedulla
OUTER ROOT SHEATH
CT sheath
CortexCuticle
DERMAL PAPILLA
MATRIX
13
4
5
6
Medulla
Cortex
Cuticle
Cuticle
Huxley’s layerHenle’s layer
INNER ROOT SHEATH
HAIR SHAFT
OUTER ROOT SHEATH
is continuous with the epidermis
2
includes pigment cells for hair color
CYCLE OF HAIR GROWTH
Rate of growth
ANAGENCATAGEN
ANAGENTimeTELOGEN
TELOGEN (end) quiescence
shedding
ANAGEN regrowth of matrix & papilla, then hair
ANAGEN growth
CATAGEN breakdown
EPIDERMAL CHARACTERISTICS EPIDERMAL CHARACTERISTICS
TISSUE RENEWALTISSUE RENEWALTISSUE STRENGTHTISSUE STRENGTHCORNIFICATIONCORNIFICATIONSTRUCTURESTRUCTUREFUNCTIONFUNCTIONSEQUENCES OF FAILURESEQUENCES OF FAILURE
FUNCTIONS OF THE EPIDERMISFUNCTIONS OF THE EPIDERMIS
Form a protective barrier from physical insultsForm a protective barrier from physical insults ChemicalChemical BiologicalBiological TemperatureTemperature MechanicalMechanical -Protect body homeostasis-Protect body homeostasis Temperature regulationTemperature regulation Prevent fluid lossPrevent fluid loss -Immune surveillance-Immune surveillance -Sensory organ-Sensory organ
CONSEQUENCES OF EPIDERMAL CONSEQUENCES OF EPIDERMAL FAILURE:FAILURE:DEATHDEATH
Toxic Epidermal NecrolysisToxic Epidermal Necrolysis –life-threatening –life-threatening consequences are dehydration and infectionconsequences are dehydration and infection
Mutations in genes that severely compromise Mutations in genes that severely compromise epidermal function are embryonic/neonatal lethalepidermal function are embryonic/neonatal lethal
CHARACTERISTICS OF THE CHARACTERISTICS OF THE EPIDERMIS EPIDERMIS
TISSUE RENEWAL–Continuous self-TISSUE RENEWAL–Continuous self-renewal of keratinocytesrenewal of keratinocytes
STRENGTH–Both intracellular and STRENGTH–Both intracellular and intercellular strengthintercellular strength
CORNIFICATION–Process that creates a CORNIFICATION–Process that creates a water impermeable barrierwater impermeable barrier
Self-renewing tissue requiresSelf-renewing tissue requires
A highly regulated process A highly regulated process that balances cellular that balances cellular proliferation and cell deathproliferation and cell death
TISSUE RENEWALTISSUE RENEWAL
Stem cellsStem cells Proliferating cellsProliferating cells Terminal Terminal
differentiationdifferentiation
Two functions required of proliferating cells in a self-Two functions required of proliferating cells in a self-renewing tissue:renewing tissue:
Maintain the integrity of the Maintain the integrity of the genomegenome
Stem cellsStem cells - -located within located within the bulge region of the hair the bulge region of the hair follicle and at the base of follicle and at the base of rete ridgesof interfollicularrete ridgesof interfollicular
epidermisepidermis Maintain the correct cell Maintain the correct cell
number in epidermisnumber in epidermis
Transient amplifying cellsTransient amplifying cells - -located immediately located immediately adjacent to clusters of adjacent to clusters of stem cellsstem cells
KERATINOCYTE STEM CELLSKERATINOCYTE STEM CELLS pluripotent cellspluripotent cells slowly replicating cells slowly replicating cells
(label retaining cells)(label retaining cells) replicate replicate
symmetrically (a stem symmetrically (a stem cell can divide into cell can divide into two equal daughter two equal daughter stem cells)stem cells)
How does a stem cell remain a stem How does a stem cell remain a stem cell?cell?
Most agree the local microenvironment Most agree the local microenvironment (including both mesenchymal and (including both mesenchymal and keratinocyte cell-cell interactions. But right keratinocyte cell-cell interactions. But right now there are very few details on what now there are very few details on what keeps the cellskeeps the cells “stemness”“stemness”
Example of two proteins implicated in the Example of two proteins implicated in the maintenance ofmaintenance of stemnessstemness
β-cateninβ-catenin mycmyc
β-cateninβ-catenin - -Identified as part of the cytoplasmic Identified as part of the cytoplasmic plaque in adherens junctions “structural protein” plaque in adherens junctions “structural protein” link between cadherins and actin filamentslink between cadherins and actin filaments
Keratinocyte stem cells have a high level of free, Keratinocyte stem cells have a high level of free, non-cadherin -associatednon-cadherin -associated β-catenin β-catenin
KERATINOCYTE STEM CELLSKERATINOCYTE STEM CELLS
β-cateninβ-catenin Constitutively active β-Constitutively active β-
catenincatenin leads to highly enriched leads to highly enriched
stem cell populationβstem cell populationβ
Dominant-negative β-Dominant-negative β-catenincatenin
stimulates exit from stem stimulates exit from stem cellcell
compartment into transientcompartment into transient amplifying cellsβ-amplifying cellsβ-
KERATINOCYTE STEM CELL SKERATINOCYTE STEM CELL Smyc (c-myc)myc (c-myc)Proto-oncogene involved with induction of Proto-oncogene involved with induction of
cell proliferationIn the epidermis.cell proliferationIn the epidermis. mycmyc stimulates exit from the stem cell stimulates exit from the stem cell
compartment into transient amplifying cellscompartment into transient amplifying cells
Stem cell failure in epidermisStem cell failure in epidermis Loss of stem cells may lead to phenotype of aged Loss of stem cells may lead to phenotype of aged
epidermis?epidermis? -flattening of the epidermal/dermal junction-flattening of the epidermal/dermal junction -keratinocyte cell size becomes variable-keratinocyte cell size becomes variable -nuclear atypia-nuclear atypia -loss of melanocytes-loss of melanocytes -loss of Langerhanscells-loss of Langerhanscells -slowed injury response-slowed injury response -slowed chemical clearance-slowed chemical clearance -decreased immune response-decreased immune response -decreased resistance to mechanical stress-decreased resistance to mechanical stress -increased incidence of cancer-increased incidence of cancer
KERATINOCYTE ProliferationKERATINOCYTE Proliferation
most of proliferation most of proliferation done by transient done by transient amplifyingcells (amplifyingcells (TA TA cellscells))
-in normal epidermis, -in normal epidermis, all TA cells remain all TA cells remain attached to basement attached to basement membranemembrane
-transition from stem -transition from stem cell to TA cell is the cell to TA cell is the first step in first step in keratinocytes keratinocytes differentiationdifferentiation
Epidermal proliferationEpidermal proliferation
in normal epidermis, all in normal epidermis, all TATA cells remain cells remain attached to basement attached to basement membranemembrane
-transition from stem -transition from stem cell to cell to TATA cell is the first cell is the first step in keratinocyte step in keratinocyte differentiationdifferentiation
-TA-TA cells migrate cells migrate laterally along the laterally along the basement membranebasement membrane
Epidermal proliferationEpidermal proliferation
--TATA cells migrate cells migrate laterally along the laterally along the basement basement membranemembrane
--TATA cells have a cells have a restricted ability to restricted ability to proliferate -usually proliferate -usually divide only 3-5 timesdivide only 3-5 times
Epidermal proliferationEpidermal proliferation
Once Once TA TA cells stop cells stop proliferating, they proliferating, they lose their lose their attachment to the attachment to the basement basement membrane membrane
Proceed towards Proceed towards terminal terminal differentiationdifferentiation
Vitamin DVitamin D in epidermis proliferation in epidermis proliferation
Vitamin DVitamin D and the and the Vitamin D receptorVitamin D receptor
––active molecule is active molecule is 1α,25(OH)2D31α,25(OH)2D3
-binds to VDR inside of -binds to VDR inside of cellcell
-functions as a -functions as a homodimer, or homodimer, or heterodimer with RXR, heterodimer with RXR, RAR, THRRAR, THR
-Dimers are -Dimers are transcriptional factorstranscriptional factors
Vitamin DVitamin D in the epidermis in the epidermis::
Activation of the VDR inActivation of the VDR in quiescent quiescent or or slowly cycling cells stimulates a slowly cycling cells stimulates a proliferativeproliferative response response
-activation of the VDR in -activation of the VDR in prfolieratingprfolierating cells cells stimulates a stimulates a differentiationdifferentiation response response
Epidermal proliferationEpidermal proliferation
NF-κBNF-κB
transcription factor associated with response to cell stresstranscription factor associated with response to cell stress -maintained inactive in cytoplasm through association -maintained inactive in cytoplasm through association
with IκBwith IκB
cell stress activates IKK complex of IKKα, IKKβ, and IKKγleads cell stress activates IKK complex of IKKα, IKKβ, and IKKγleads to phosphorylation of IκBto phosphorylation of IκB
-phosphorylation of IκB leads to degradation and release of -phosphorylation of IκB leads to degradation and release of NF-κBNF-κB
-NF-κBis now free to enter nucleus and activate transcription-NF-κBis now free to enter nucleus and activate transcription
Epidermis proliferation sequences Epidermis proliferation sequences of failureof failure
Dysregulation of proliferation can lead to Dysregulation of proliferation can lead to hypo-proliferativehypo-proliferative
&& hyperproliferative diseaseshyperproliferative diseases
KERATINOCYTE TERMINAL KERATINOCYTE TERMINAL DIFFERENTIATIONDIFFERENTIATION
--when awhen a keratinocyte releases from the keratinocyte releases from the basement membrane, it undergoes changes basement membrane, it undergoes changes in morphology and gene expressionin morphology and gene expression
-gradual change in cell strength and water -gradual change in cell strength and water impermeabilityimpermeability
-terminally differentiated keratinocytes -terminally differentiated keratinocytes synthesize asynthesize a cornifiedcornified cell envelope and cell envelope and undergoundergo programmed cell deathprogrammed cell death
Keratinocyte morphology and functionKeratinocyte morphology and function
Stratum corneum–keratinocytesStratum corneum–keratinocytes contain contain thickened cell envelopes, contain no nucleus, thickened cell envelopes, contain no nucleus, imbedded in lipid matriximbedded in lipid matrix
Stratum granulosumStratum granulosum–cells–cells become elongated, become elongated, usually 1-2 cell layers thick,accumulate amorphous usually 1-2 cell layers thick,accumulate amorphous keratohyaline granuleskeratohyaline granules
Stratum spinosumStratum spinosum–cells–cells increase in increase in size,increased cytoplasm:nucleus ratio, cell layer4-size,increased cytoplasm:nucleus ratio, cell layer4-6 cells thick, no further cell division6 cells thick, no further cell division
Stratum basaleStratum basale–cuboidal cells–cuboidal cells, cells within this , cells within this layer proliferate, all cells attached to thebasement layer proliferate, all cells attached to thebasement membrane, one cell layer thick.membrane, one cell layer thick.
Differentiation-specificDifferentiation-specificproteins expressed proteins expressed
Stratum corneumStratum corneum: : no new protein expressionno new protein expression ....
StratumStratum granulosumgranulosum : :keratins K1 and K10keratins K1 and K10, , loricrin, filaggrin, transglutaminase3loricrin, filaggrin, transglutaminase3
Stratum spinosumStratum spinosum: : keratins K1 and keratins K1 and K10,involucrin,envoplakin,periplakin, 14-3-3σK10,involucrin,envoplakin,periplakin, 14-3-3σ
Stratum basalStratum basal: : keratins K5 and K14integrins, keratins K5 and K14integrins, p63p63
Regulation of keratinocyte cell Regulation of keratinocyte cell transitionstransitions
Stem cells intoStem cells into TATA: : upregulation of upregulation of catenin,integrins andcatenin,integrins and vitamin Dvitamin D
TATA cells into squamous cellscells into squamous cells: : lossloss ofof integrins integrins and and vitamin Dvitamin D
Squamous cell into Granular cellSquamous cell into Granular cell: Epidermal : Epidermal differentiation complexdifferentiation complex((EDCEDC))
Epidermal Differentiation ComplexEpidermal Differentiation ComplexChromosome 1q21Chromosome 1q21
InvolucrinInvolucrin : :scaffolding protein, lipid scaffolding protein, lipid attachmentattachment
FilaggrinFilaggrin : :bundles keratin filamentsbundles keratin filaments LEP/XP-5SPR familyLEP/XP-5SPR family: : cross-bridging proteinscross-bridging proteins LoricrinLoricrin major reinforcement protein of CERmajor reinforcement protein of CER RepetinsRepetins : :cross-bridging proteincross-bridging protein S100 A1-A13S100 A1-A13 : :create membrane environment create membrane environment
of CE initiationof CE initiation SmallSmall proline rich SPRproline rich SPR : :cross-bridging cross-bridging
proteinsproteins TrichohyalinTrichohyalin : :flexible cross-bridging proteinflexible cross-bridging protein
Epidermis Tissue StrengthEpidermis Tissue Strength
1- 1- Intracellular –Intermediate FilamentsIntracellular –Intermediate Filaments2-Intracellular -Adhesion Molecules2-Intracellular -Adhesion Molecules
KERATINOCYTE KERATINOCYTE INTRACELLULAR STRENGTHINTRACELLULAR STRENGTH
Keratins are members of the intermediate Keratins are members of the intermediate filament (IF) gene familyfilament (IF) gene family
there are over 50 members of the IF gene there are over 50 members of the IF gene family that are expressed in a tissue-and family that are expressed in a tissue-and differentiation-specific mannerdifferentiation-specific manner
KERATINOCYTE KERATINOCYTE INTRACELLULAR STRENGTHINTRACELLULAR STRENGTH
--IF proteins have a conserved central rod domain of IF proteins have a conserved central rod domain of helical coiled-coil segmentshelical coiled-coil segments
-the amino-and carboxy-terminal sequences of IF -the amino-and carboxy-terminal sequences of IF proteins are variableproteins are variable
keratins heterodimerize with specific pairing keratins heterodimerize with specific pairing partners:partners:
one Type I familyone Type I family one Type II familyone Type II family -the heterodimers then oligomerize into longer fibrils-the heterodimers then oligomerize into longer fibrils
fibrils continue to assemble until IF is 10-12 nm in fibrils continue to assemble until IF is 10-12 nm in diameterdiameter
--keratin filaments extend from the keratin filaments extend from the nuclear membrane to desmosomal nuclear membrane to desmosomal plaques at the cell membraneplaques at the cell membrane
-keratins enable keratinocytes to -keratins enable keratinocytes to sustain mechanical and non-sustain mechanical and non-mechanical stressmechanical stress
Genodermatoses Keratin Genodermatoses Keratin (mutation identified)(mutation identified)
Epidermolysis Bullosa SimplexEpidermolysis Bullosa Simplex : :K5, K14K5, K14 Epidermolytic hyperkeratosis:K1Epidermolytic hyperkeratosis:K1, K10, K10 Palmoplantar keratodermaPalmoplantar keratoderma, , epidermolytic:K1, epidermolytic:K1,
K9K9 Palmoplantar keratoderma, diffuse non-Palmoplantar keratoderma, diffuse non-
epidermolyticepidermolytic: K1: K1 Palmoplantar keratoderma, focal non-Palmoplantar keratoderma, focal non-
epidermolyticepidermolytic: : K16K16 Ichthyosis hystrix type Curth-MacklinIchthyosis hystrix type Curth-Macklin : : K1K1
KERATINOCYTEKERATINOCYTE INTERCELLULAR INTERCELLULAR STRENGTHSTRENGTH
Five types of interactions hold keratinocytes Five types of interactions hold keratinocytes together in epidermal sheets:together in epidermal sheets:
HemidesmosomesHemidesmosomes DesmosomesDesmosomes AdherensJunctionsAdherensJunctions Tight JunctionsTight Junctions Gap JunctionsGap Junctions
DesmosomesDesmosomes adhesion site that links the adhesion site that links the
keratincyto keratincyto skeletalcomponents of two skeletalcomponents of two cellscells
-Transmembrane components:-Transmembrane components: desmogleinsdesmogleins desmocollinsdesmocollins -Plaque components:-Plaque components: DesmoplakinDesmoplakin splakoglobin splakoglobin plakophilin plakophilin keratoclamin-keratoclamin- Cytoskeletal component:Cytoskeletal component: keratinkeratin
Adherens JunctionsAdherens Junctions::
1.1. -adhesion site that -adhesion site that links the actin links the actin cytoskeletal cytoskeletal components of two components of two cells-cells-
2.2. Transmembrane Transmembrane components:E-components:E-cadherincadherin
3.3. Plaque Plaque components:catenincomponents:catenin
4.4. -Cytoskeletal -Cytoskeletal component: actinscomponent: actins
Tight JunctionsTight Junctions --form at the apical form at the apical
end of lateral end of lateral membranes forming membranes forming paracellular paracellular diffusion barriersdiffusion barriers
-transmembrane -transmembrane components: components: junctional adhesion junctional adhesion molecules (JAM), molecules (JAM), claudins, occludinsclaudins, occludins
Tight JunctionsTight Junctions
intercellular channels intercellular channels between adjacent cells that between adjacent cells that allow the direct passage of allow the direct passage of low molecular weight low molecular weight metabolites between cells-metabolites between cells-
major protein -connexins, 15 major protein -connexins, 15 different human genes, different human genes, hexameric hemichannels hexameric hemichannels dock with similar proteins dock with similar proteins on adjacent cell-on adjacent cell-
three major classes of three major classes of connexin proteins: Gjα, connexin proteins: Gjα, GJβ, and GJγGJβ, and GJγ
CORNIFICATIONCORNIFICATION
--process that begins in cells of the upper process that begins in cells of the upper spinouslayersspinouslayers
-the induction of proteins that comprise the -the induction of proteins that comprise the cornifiedcell envelope (CCE) are expressed cornifiedcell envelope (CCE) are expressed as intracellular [Ca2+] rise in differentiating as intracellular [Ca2+] rise in differentiating keratinocyteskeratinocytes
-chromosome 1q21 contains cluster of genes -chromosome 1q21 contains cluster of genes called the Epidermal Differentiationcalled the Epidermal Differentiation Complex Complex
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