KERATINIZATION Yousry Power point

KERATINOCYTES AND KERATINIZATION : 

KERATINOCYTES AND KERATINIZATION M.YOUSRY ABDEL-MAWLA

EPIDERMAL CHARACTERISTICS : 

EPIDERMAL CHARACTERISTICS TISSUE RENEWAL TISSUE STRENGTH CORNIFICATION STRUCTURE FUNCTION SEQUENCES OF FAILURE

FUNCTIONS OF THE EPIDERMIS: 

FUNCTIONS OF THE EPIDERMIS Form a protective barrier from physical insults Chemical Biological Temperature Mechanical -Protect body homeostasis Temperature regulation Prevent fluid loss -Immune surveillance -Sensory organ

CONSEQUENCES OF EPIDERMAL FAILURE:DEATH: 

CONSEQUENCES OF EPIDERMAL FAILURE:DEATH Toxic Epidermal Necrolysis –life-threatening consequences are dehydration and infection Mutations in genes that severely compromise epidermal function are embryonic/neonatal lethal

CHARACTERISTICS OF THE EPIDERMIS : 

CHARACTERISTICS OF THE EPIDERMIS TISSUE RENEWAL–Continuous self-renewal of keratinocytes STRENGTH–Both intracellular and intercellular strength CORNIFICATION–Process that creates a water impermeable barrier

Self-renewing tissue requires: 

Self-renewing tissue requires A highly regulated process that balances cellular proliferation and cell death

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TISSUE RENEWAL Stem cells Proliferating cells Terminal differentiation

Two functions required of proliferating cells in a self-renewing tissue:: 

Two functions required of proliferating cells in a self-renewing tissue: Maintain the integrity of the genome Stem cells -located within the bulge region of the hair follicle and at the base of rete ridgesof interfollicular epidermis Maintain the correct cell number in epidermis Transient amplifying cells -located immediately adjacent to clusters of stem cells

KERATINOCYTE STEM CELLS: 

KERATINOCYTE STEM CELLS pluripotent cells slowly replicating cells (label retaining cells) replicate symmetrically (a stem cell can divide into two equal daughter stem cells)

How does a stem cell remain a stem cell?: 

How does a stem cell remain a stem cell? Most agree the local microenvironment (including both mesenchymal and keratinocyte cell-cell interactions. But right now there are very few details on what keeps the cells “stemness” Example of two proteins implicated in the maintenance of stemness β-catenin myc

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β-catenin -Identified as part of the cytoplasmic plaque in adherens junctions “structural protein” link between cadherins and actin filaments Keratinocyte stem cells have a high level of free, non-cadherin -associated β-catenin

KERATINOCYTE STEM CELLS: 

KERATINOCYTE STEM CELLS β-catenin Constitutively active β-catenin leads to highly enriched stem cell populationβ Dominant-negative β-catenin stimulates exit from stem cell compartment into transient amplifying cellsβ-

KERATINOCYTE STEM CELL S: 

KERATINOCYTE STEM CELL S myc (c-myc) Proto-oncogene involved with induction of cell proliferationIn the epidermis. myc stimulates exit from the stem cell compartment into transient amplifying cells

Stem cell failure in epidermis: 

Stem cell failure in epidermis Loss of stem cells may lead to phenotype of aged epidermis? -flattening of the epidermal/dermal junction -keratinocyte cell size becomes variable -nuclear atypia -loss of melanocytes -loss of Langerhanscells -slowed injury response -slowed chemical clearance -decreased immune response -decreased resistance to mechanical stress -increased incidence of cancer

KERATINOCYTE Proliferation: 

KERATINOCYTE Proliferation most of proliferation done by transient amplifyingcells (TA cells) -in normal epidermis, all TA cells remain attached to basement membrane -transition from stem cell to TA cell is the first step in keratinocytes differentiation

Epidermal proliferation: 

Epidermal proliferation in normal epidermis, all TA cells remain attached to basement membrane -transition from stem cell to TA cell is the first step in keratinocyte differentiation -TA cells migrate laterally along the basement membrane

Epidermal proliferation: 

Epidermal proliferation -TA cells migrate laterally along the basement membrane -TA cells have a restricted ability to proliferate -usually divide only 3-5 times

Epidermal proliferation: 

Epidermal proliferation Once TA cells stop proliferating, they lose their attachment to the basement membrane Proceed towards terminal differentiation

Vitamin D in epidermis proliferation: 

Vitamin D in epidermis proliferation Vitamin D and the Vitamin D receptor –active molecule is 1α,25(OH)2D3 -binds to VDR inside of cell -functions as a homodimer, or heterodimer with RXR, RAR, THR -Dimers are transcriptional factors

Vitamin D in the epidermis:: 

Vitamin D in the epidermis: Activation of the VDR in quiescent or slowly cycling cells stimulates a proliferative response -activation of the VDR in prfolierating cells stimulates a differentiation response

Epidermal proliferation: 

Epidermal proliferation NF-κB transcription factor associated with response to cell stress -maintained inactive in cytoplasm through association with IκB cell stress activates IKK complex of IKKα, IKKβ, and IKKγleads to phosphorylation of IκB -phosphorylation of IκB leads to degradation and release of NF-κB -NF-κBis now free to enter nucleus and activate transcription

Epidermis proliferation sequences of failure: 

Epidermis proliferation sequences of failure Dysregulation of proliferation can lead to hypo-proliferative & hyperproliferative diseases

Psoriasis: 

Psoriasis

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KERATINOCYTE TERMINAL DIFFERENTIATION

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-when a keratinocyte releases from the basement membrane, it undergoes changes in morphology and gene expression -gradual change in cell strength and water impermeability -terminally differentiated keratinocytes synthesize a cornified cell envelope and undergo programmed cell death

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Keratinocyte morphology and function Stratum corneum–keratinocytes contain thickened cell envelopes, contain no nucleus, imbedded in lipid matrix Stratum granulosum–cells become elongated, usually 1-2 cell layers thick,accumulate amorphous keratohyaline granules Stratum spinosum–cells increase in size,increased cytoplasm:nucleus ratio, cell layer4-6 cells thick, no further cell division Stratum basale–cuboidal cells, cells within this layer proliferate, all cells attached to thebasement membrane, one cell layer thick.

Differentiation-specificproteins expressed : 

Differentiation-specific proteins expressed Stratum corneum: no new protein expression .. Stratum granulosum :keratins K1 and K10, loricrin, filaggrin, transglutaminase3 Stratum spinosum: keratins K1 and K10,involucrin,envoplakin,periplakin, 14-3-3σ Stratum basal: keratins K5 and K14integrins, p63

Regulation of keratinocyte cell transitions: 

Regulation of keratinocyte cell transitions Stem cells into TA: upregulation of catenin,integrins and vitamin D TA cells into squamous cells: loss of integrins and vitamin D Squamous cell into Granular cell:Epidermal differentiation complex(EDC)

Epidermal Differentiation ComplexChromosome 1q21: 

Epidermal Differentiation Complex Chromosome 1q21 Involucrin :scaffolding protein, lipid attachment Filaggrin :bundles keratin filaments LEP/XP-5SPR family: cross-bridging proteins Loricrin major reinforcement protein of CER Repetins :cross-bridging protein S100 A1-A13 :create membrane environment of CE initiation Small proline rich SPR :cross-bridging proteins Trichohyalin :flexible cross-bridging protein

Epidermis Tissue Strength: 

Epidermis Tissue Strength 1- Intracellular –Intermediate Filaments 2-Intracellular -Adhesion Molecules

KERATINOCYTE INTRACELLULAR STRENGTH: 

KERATINOCYTE INTRACELLULAR STRENGTH Keratins are members of the intermediate filament (IF) gene family there are over 50 members of the IF gene family that are expressed in a tissue-and differentiation-specific manner

KERATINOCYTE INTRACELLULAR STRENGTH: 

KERATINOCYTE INTRACELLULAR STRENGTH -IF proteins have a conserved central rod domain of helical coiled-coil segments -the amino-and carboxy-terminal sequences of IF proteins are variable keratins heterodimerize with specific pairing partners: one Type I family one Type II family -the heterodimers then oligomerize into longer fibrils fibrils continue to assemble until IF is 10-12 nm in diameter

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-keratin filaments extend from the nuclear membrane to desmosomal plaques at the cell membrane -keratins enable keratinocytes to sustain mechanical and non-mechanical stress

Genodermatoses Keratin (mutation identified): 

Genodermatoses Keratin (mutation identified) Epidermolysis Bullosa Simplex :K5, K14 Epidermolytic hyperkeratosis:K1, K10 Palmoplantar keratoderma, epidermolytic:K1, K9 Palmoplantar keratoderma, diffuse non-epidermolytic:K1 Palmoplantar keratoderma, focal non-epidermolytic:K16 Ichthyosis hystrix type Curth-Macklin :K1

KERATINOCYTE INTERCELLULAR STRENGTH: 

KERATINOCYTE INTERCELLULAR STRENGTH Five types of interactions hold keratinocytes together in epidermal sheets: Hemidesmosomes Desmosomes AdherensJunctions Tight Junctions Gap Junctions

Desmosomes: 

Desmosomes adhesion site that links the keratincyto skeletalcomponents of two cells -Transmembrane components: desmogleins desmocollins -Plaque components: Desmoplakin splakoglobin plakophilin keratoclamin- Cytoskeletal component: keratin

Adherens Junctions:: 

Adherens Junctions: -adhesion site that links the actin cytoskeletal components of two cells- Transmembrane components:E-cadherin Plaque components:catenin -Cytoskeletal component: actins

Tight Junctions: 

Tight Junctions -form at the apical end of lateral membranes forming paracellular diffusion barriers -transmembrane components: junctional adhesion molecules (JAM), claudins, occludins

Tight Junctions: 

Tight Junctions intercellular channels between adjacent cells that allow the direct passage of low molecular weight metabolites between cells- major protein -connexins, 15 different human genes, hexameric hemichannels dock with similar proteins on adjacent cell- three major classes of connexin proteins: Gjα, GJβ, and GJγ

CORNIFICATION: 

CORNIFICATION -Process that begins in cells of the upper spinouslayers -The induction of proteins that comprise the cornifiedcell envelope (CCE) are expressed as intracellular [Ca2+] rise in differentiating keratinocytes -Chromosome 1q21 contains cluster of genes called the Epidermal Differentiation Complex (EDC)

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