K E R A T I N I Z A T I O N

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  • 1. KERATINOCYTES AND KERATINIZATION M.YOUSRY ABDEL-MAWLA
  • 2. SKIN STRUCTURE
  • 3. 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
  • 4. 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
  • 5. EPIDERMIS: Cell types Keratinocytes Langerhans APC cell immunity Melanocyte to make & transfer pigment Merkel cell sensory dead alive Nerve cell represented by its axon
  • 6. EPIDERMIS: Layers & events STRATUM CORNEUM of dead, but attached, ‘hardened & wrapped‘ cells , will slough off S. GRANULOSUM multiple syntheses to make cornified cells S. SPINOSUM upward migration of keratinocytes, while keratins IFs increase & change S. BASALE mitosis of stem cells Keratinocyte differentiation } }
  • 7. capillary loop Meissner’s corpuscle DERMIS Papillary layer } } DERMIS Reticular layer } HYPODERMIS Fat cells Sweat gland EPIDERMIS } duct Pacinian corpuscle THICK, HAIRLESS SKIN
  • 8. 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 &
  • 9. THIN HAIRY SKIN Papilla of Hair follicle Root sheath Hair shaft Sebaceous gland Arrector pili muscle Sweat gland D E R M I S Epidermis HYPODERMIS Matrix
  • 10. Autonomic motor Sweat gland D E R M I S Epidermis Vessel vasomotor THIN HAIRY SKIN: Innervation Arrector pili muscle pilomotor sudomotor Sensory
  • 11. 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
  • 12. { MOLECULAR EPIDERMIS CORNEUM CELLS ANCHORING FIBRILS LAMINA DENSA LAMINA LUCIDA HEMIDESMOSOMES BASAL CELL type VII collagen laminin type IV collagen epiligrin BM 600 anchoring filaments glycolipid cadherin-P T-transglutaminase 1 keratins hemidesmosomal proteins integrin a6b4 {
  • 13. MOLECULAR EPIDERMIS * CORNEUM CELLS ANCHORING FIBRILS LAMINA DENSA LAMINA LUCIDA HEMIDESMOSOMES BASAL CELL type VII collagen laminin type IV collagen epiligrin BM 600 anchoring filaments glycolipid cadherin-P T-transglutaminase 1 keratins hemidesmosomal proteins integrin a6b4 Clinical significance: genetic defects in, or autoimmune attack on, a particular kind of molecule may cause dysfunction. For instance, trouble with collagen VII allows the epidermis to separate from the dermis - a blister or ‘bullous’ state genetic form is dystrophic epidermolysis bullosa { {
  • 14. HAIR FOLLICLE: LAYERS at one cross-section Medulla Cortex Cuticle Cuticle Huxley’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
  • 15. HAIR FOLLICLE: LAYERS longitudinal OUTER ROOT SHEATH CT sheath Cortex Cuticle DERMAL PAPILLA nourishes & controls the matrix MATRIX Cuticle Huxley’s layer Henle’s layer INNER ROOT SHEATH 1 2 3 4 5 6 OUTER ROOT SHEATH grows & 1 2 HAIR SHAFT Medulla Medulla Cortex Cuticle CT sheath Cuticle Huxley’s layer Henle’s layer INNER ROOT SHEATH HAIR SHAFT
  • 16. 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 SHAFT Medulla OUTER ROOT SHEATH CT sheath Cortex Cuticle DERMAL PAPILLA MATRIX 1 3 4 5 6 Medulla Cortex Cuticle HAIR SHAFT OUTER ROOT SHEATH is continuous with the epidermis 2 includes pigment cells for hair color Cuticle Huxley’s layer Henle’s layer INNER ROOT SHEATH
  • 17. CYCLE OF HAIR GROWTH Rate of growth ANAGEN CATAGEN ANAGEN Time TELOGEN TELOGEN (end) quiescence shedding ANAGEN regrowth of matrix & papilla, then hair ANAGEN growth CATAGEN breakdown
  • 18. EPIDERMAL CHARACTERISTICS
    • TISSUE RENEWAL
    • TISSUE STRENGTH
    • CORNIFICATION
    • STRUCTURE
    • FUNCTION
    • SEQUENCES OF FAILURE
  • 19.  
  • 20. 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
  • 21. 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
  • 22. 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
  • 23. Self-renewing tissue requires
    • A highly regulated process that balances cellular proliferation and cell death
  • 24.
    • TISSUE RENEWAL
    • Stem cells
    • Proliferating cells
    • Terminal differentiation
  • 25. 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
  • 26. KERATINOCYTE STEM CELLS
    • pluripotent cells
    • slowly replicating cells (label retaining cells)
    • replicate symmetrically (a stem cell can divide into two equal daughter stem cells)
  • 27. 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
  • 28.
    • 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
  • 29.  
  • 30. 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-
  • 31. 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
  • 32. 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
  • 33.  
  • 34. 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
  • 35. 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
  • 36. Epidermal proliferation
    • - TA cells migrate laterally along the basement membrane
    • - TA cells have a restricted ability to proliferate -usually divide only 3-5 times
  • 37. Epidermal proliferation
    • Once TA cells stop proliferating, they lose their attachment to the basement membrane
    • Proceed towards terminal differentiation
  • 38. 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
  • 39. 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
  • 40. 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
  • 41. Epidermis proliferation sequences of failure
    • Dysregulation of proliferation can lead to hypo-proliferative
    • &
    • hyperproliferative diseases
  • 42.
    • KERATINOCYTE TERMINAL DIFFERENTIATION
  • 43.
    • - 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
  • 44.  
  • 45.  
  • 46.
    • 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.
  • 47. 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
  • 48.  
  • 49. 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 )
  • 50. 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
  • 51. Epidermis Tissue Strength
    • 1- Intracellular –Intermediate Filaments
    • 2-Intracellular -Adhesion Molecules
  • 52. 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
  • 53. 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
  • 54.  
  • 55.
    • - keratin filaments extend from the nuclear membrane to desmosomal plaques at the cell membrane
    • -keratins enable keratinocytes to sustain mechanical and non-mechanical stress
  • 56. 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
  • 57.  
  • 58. KERATINOCYTE INTERCELLULAR STRENGTH
    • Five types of interactions hold keratinocytes together in epidermal sheets:
    • Hemidesmosomes
    • Desmosomes
    • AdherensJunctions
    • Tight Junctions
    • Gap Junctions
  • 59.  
  • 60. Desmosomes
    • adhesion site that links the keratincyto skeletalcomponents of two cells
    • -Transmembrane components:
    • desmogleins
    • desmocollins
    • -Plaque components:
    • Desmoplakin
    • splakoglobin
    • plakophilin
    • keratoclamin-
    • Cytoskeletal component:
    • keratin
  • 61. Adherens Junctions :
    • -adhesion site that links the actin cytoskeletal components of two cells-
    • Transmembrane components:E-cadherin
    • Plaque components:catenin
    • -Cytoskeletal component: actins
  • 62. Tight Junctions
    • - form at the apical end of lateral membranes forming paracellular diffusion barriers
    • -transmembrane components: junctional adhesion molecules (JAM), claudins, occludins
  • 63. 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
  • 64.  
  • 65. 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
  • 66.  
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  • 75.
    • THANK YOU