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  3. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 18. EPIDERMAL CHARACTERISTICS <ul><li>TISSUE RENEWAL </li></ul><ul><li>TISSUE STRENGTH </li></ul><ul><li>CORNIFICATION </li></ul><ul><li>STRUCTURE </li></ul><ul><li>FUNCTION </li></ul><ul><li>SEQUENCES OF FAILURE </li></ul>
  19. 20. FUNCTIONS OF THE EPIDERMIS <ul><li>Form a protective barrier from physical insults </li></ul><ul><li>Chemical </li></ul><ul><li>Biological </li></ul><ul><li>Temperature </li></ul><ul><li>Mechanical </li></ul><ul><li>-Protect body homeostasis </li></ul><ul><li>Temperature regulation </li></ul><ul><li>Prevent fluid loss </li></ul><ul><li>-Immune surveillance </li></ul><ul><li>-Sensory organ </li></ul>
  20. 21. CONSEQUENCES OF EPIDERMAL FAILURE: DEATH <ul><li>Toxic Epidermal Necrolysis –life-threatening consequences are dehydration and infection </li></ul><ul><li>Mutations in genes that severely compromise epidermal function are embryonic/neonatal lethal </li></ul>
  21. 22. CHARACTERISTICS OF THE EPIDERMIS <ul><li>TISSUE RENEWAL–Continuous self-renewal of keratinocytes </li></ul><ul><li>STRENGTH–Both intracellular and intercellular strength </li></ul><ul><li>CORNIFICATION–Process that creates a water impermeable barrier </li></ul>
  22. 23. Self-renewing tissue requires <ul><li>A highly regulated process that balances cellular proliferation and cell death </li></ul>
  23. 24. <ul><li>TISSUE RENEWAL </li></ul><ul><li>Stem cells </li></ul><ul><li>Proliferating cells </li></ul><ul><li>Terminal differentiation </li></ul>
  24. 25. Two functions required of proliferating cells in a self-renewing tissue: <ul><li>Maintain the integrity of the genome </li></ul><ul><li>Stem cells - located within the bulge region of the hair follicle and at the base of rete ridgesof interfollicular </li></ul><ul><li>epidermis </li></ul><ul><li>Maintain the correct cell number in epidermis </li></ul><ul><li>Transient amplifying cells - located immediately adjacent to clusters of stem cells </li></ul>
  25. 26. KERATINOCYTE STEM CELLS <ul><li>pluripotent cells </li></ul><ul><li>slowly replicating cells (label retaining cells) </li></ul><ul><li>replicate symmetrically (a stem cell can divide into two equal daughter stem cells) </li></ul>
  26. 27. How does a stem cell remain a stem cell? <ul><li>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” </li></ul><ul><li>Example of two proteins implicated in the maintenance of stemness </li></ul><ul><li>β-catenin </li></ul><ul><li>myc </li></ul>
  27. 28. <ul><li>β-catenin - Identified as part of the cytoplasmic plaque in adherens junctions “structural protein” link between cadherins and actin filaments </li></ul><ul><li>Keratinocyte stem cells have a high level of free, non-cadherin -associated β-catenin </li></ul>
  28. 30. KERATINOCYTE STEM CELLS <ul><li>β-catenin </li></ul><ul><li>Constitutively active β-catenin </li></ul><ul><li>leads to highly enriched stem cell populationβ </li></ul><ul><li>Dominant-negative β-catenin </li></ul><ul><li>stimulates exit from stem cell </li></ul><ul><li>compartment into transient </li></ul><ul><li>amplifying cellsβ- </li></ul>
  29. 31. KERATINOCYTE STEM CELL S <ul><li>myc (c-myc) </li></ul><ul><li>Proto-oncogene involved with induction of cell proliferationIn the epidermis. </li></ul><ul><li>myc stimulates exit from the stem cell compartment into transient amplifying cells </li></ul>
  30. 32. Stem cell failure in epidermis <ul><li>Loss of stem cells may lead to phenotype of aged epidermis? </li></ul><ul><li>-flattening of the epidermal/dermal junction </li></ul><ul><li>-keratinocyte cell size becomes variable </li></ul><ul><li>-nuclear atypia </li></ul><ul><li>-loss of melanocytes </li></ul><ul><li>-loss of Langerhanscells </li></ul><ul><li>-slowed injury response </li></ul><ul><li>-slowed chemical clearance </li></ul><ul><li>-decreased immune response </li></ul><ul><li>-decreased resistance to mechanical stress </li></ul><ul><li>-increased incidence of cancer </li></ul>
  31. 34. KERATINOCYTE Proliferation <ul><li>most of proliferation done by transient amplifyingcells ( TA cells ) </li></ul><ul><li>-in normal epidermis, all TA cells remain attached to basement membrane </li></ul><ul><li>-transition from stem cell to TA cell is the first step in keratinocytes differentiation </li></ul>
  32. 35. Epidermal proliferation <ul><li>in normal epidermis, all TA cells remain attached to basement membrane </li></ul><ul><li>-transition from stem cell to TA cell is the first step in keratinocyte differentiation </li></ul><ul><li>-TA cells migrate laterally along the basement membrane </li></ul>
  33. 36. Epidermal proliferation <ul><li>- TA cells migrate laterally along the basement membrane </li></ul><ul><li>- TA cells have a restricted ability to proliferate -usually divide only 3-5 times </li></ul>
  34. 37. Epidermal proliferation <ul><li>Once TA cells stop proliferating, they lose their attachment to the basement membrane </li></ul><ul><li>Proceed towards terminal differentiation </li></ul>
  35. 38. Vitamin D in epidermis proliferation <ul><li>Vitamin D and the Vitamin D receptor </li></ul><ul><li>– active molecule is 1α,25(OH)2D3 </li></ul><ul><li>-binds to VDR inside of cell </li></ul><ul><li>-functions as a homodimer, or heterodimer with RXR, RAR, THR </li></ul><ul><li>-Dimers are transcriptional factors </li></ul>
  36. 39. Vitamin D in the epidermis : <ul><li>Activation of the VDR in quiescent or slowly cycling cells stimulates a proliferative response </li></ul><ul><li>-activation of the VDR in prfolierating cells stimulates a differentiation response </li></ul>
  37. 40. Epidermal proliferation <ul><li>NF-κB </li></ul><ul><li>transcription factor associated with response to cell stress </li></ul><ul><li>-maintained inactive in cytoplasm through association with IκB </li></ul><ul><li>cell stress activates IKK complex of IKKα, IKKβ, and IKKγleads to phosphorylation of IκB </li></ul><ul><li>-phosphorylation of IκB leads to degradation and release of NF-κB </li></ul><ul><li>-NF-κBis now free to enter nucleus and activate transcription </li></ul>
  38. 41. Epidermis proliferation sequences of failure <ul><li>Dysregulation of proliferation can lead to hypo-proliferative </li></ul><ul><li>& </li></ul><ul><li>hyperproliferative diseases </li></ul>
  40. 43. <ul><li>- when a keratinocyte releases from the basement membrane, it undergoes changes in morphology and gene expression </li></ul><ul><li>-gradual change in cell strength and water impermeability </li></ul><ul><li>-terminally differentiated keratinocytes synthesize a cornified cell envelope and undergo programmed cell death </li></ul>
  41. 46. <ul><li>Keratinocyte morphology and function </li></ul><ul><li>Stratum corneum–keratinocytes contain thickened cell envelopes, contain no nucleus, imbedded in lipid matrix </li></ul><ul><li>Stratum granulosum –cells become elongated, usually 1-2 cell layers thick,accumulate amorphous keratohyaline granules </li></ul><ul><li>Stratum spinosum –cells increase in size,increased cytoplasm:nucleus ratio, cell layer4-6 cells thick, no further cell division </li></ul><ul><li>Stratum basale –cuboidal cells , cells within this layer proliferate, all cells attached to thebasement membrane, one cell layer thick. </li></ul>
  42. 47. Differentiation-specific proteins expressed <ul><li>Stratum corneum : no new protein expression .. </li></ul><ul><li>Stratum granulosum : keratins K1 and K10 , loricrin, filaggrin, transglutaminase3 </li></ul><ul><li>Stratum spinosum : keratins K1 and K10,involucrin,envoplakin,periplakin, 14-3-3σ </li></ul><ul><li>Stratum basal : keratins K5 and K14integrins, p63 </li></ul>
  43. 49. Regulation of keratinocyte cell transitions <ul><li>Stem cells into TA : upregulation of catenin,integrins and vitamin D </li></ul><ul><li>TA cells into squamous cells : loss of integrins and vitamin D </li></ul><ul><li>Squamous cell into Granular cell : Epidermal differentiation complex ( EDC ) </li></ul>
  44. 50. Epidermal Differentiation Complex Chromosome 1q21 <ul><li>Involucrin : scaffolding protein, lipid attachment </li></ul><ul><li>Filaggrin : bundles keratin filaments </li></ul><ul><li>LEP/XP-5SPR family : cross-bridging proteins </li></ul><ul><li>Loricrin major reinforcement protein of CER </li></ul><ul><li>Repetins : cross-bridging protein </li></ul><ul><li>S100 A1-A13 : create membrane environment of CE initiation </li></ul><ul><li>Small proline rich SPR : cross-bridging proteins </li></ul><ul><li>Trichohyalin : flexible cross-bridging protein </li></ul>
  45. 51. Epidermis Tissue Strength <ul><li>1- Intracellular –Intermediate Filaments </li></ul><ul><li>2-Intracellular -Adhesion Molecules </li></ul>
  46. 52. KERATINOCYTE INTRACELLULAR STRENGTH <ul><li>Keratins are members of the intermediate filament (IF) gene family </li></ul><ul><li>there are over 50 members of the IF gene family that are expressed in a tissue-and differentiation-specific manner </li></ul>
  47. 53. KERATINOCYTE INTRACELLULAR STRENGTH <ul><li>- IF proteins have a conserved central rod domain of helical coiled-coil segments </li></ul><ul><li>-the amino-and carboxy-terminal sequences of IF proteins are variable </li></ul><ul><li>keratins heterodimerize with specific pairing partners: </li></ul><ul><li>one Type I family </li></ul><ul><li>one Type II family </li></ul><ul><li>-the heterodimers then oligomerize into longer fibrils </li></ul><ul><li>fibrils continue to assemble until IF is 10-12 nm in diameter </li></ul>
  48. 55. <ul><li>- keratin filaments extend from the nuclear membrane to desmosomal plaques at the cell membrane </li></ul><ul><li>-keratins enable keratinocytes to sustain mechanical and non-mechanical stress </li></ul>
  49. 56. Genodermatoses Keratin (mutation identified) <ul><li>Epidermolysis Bullosa Simplex : K5, K14 </li></ul><ul><li>Epidermolytic hyperkeratosis:K1 , K10 </li></ul><ul><li>Palmoplantar keratoderma , epidermolytic:K1, K9 </li></ul><ul><li>Palmoplantar keratoderma, diffuse non-epidermolytic : K1 </li></ul><ul><li>Palmoplantar keratoderma, focal non-epidermolytic : K16 </li></ul><ul><li>Ichthyosis hystrix type Curth-Macklin : K1 </li></ul>
  50. 58. KERATINOCYTE INTERCELLULAR STRENGTH <ul><li>Five types of interactions hold keratinocytes together in epidermal sheets: </li></ul><ul><li>Hemidesmosomes </li></ul><ul><li>Desmosomes </li></ul><ul><li>AdherensJunctions </li></ul><ul><li>Tight Junctions </li></ul><ul><li>Gap Junctions </li></ul>
  51. 60. Desmosomes <ul><li>adhesion site that links the keratincyto skeletalcomponents of two cells </li></ul><ul><li>-Transmembrane components: </li></ul><ul><li>desmogleins </li></ul><ul><li>desmocollins </li></ul><ul><li>-Plaque components: </li></ul><ul><li>Desmoplakin </li></ul><ul><li>splakoglobin </li></ul><ul><li>plakophilin </li></ul><ul><li>keratoclamin- </li></ul><ul><li>Cytoskeletal component: </li></ul><ul><li>keratin </li></ul>
  52. 61. Adherens Junctions : <ul><li>-adhesion site that links the actin cytoskeletal components of two cells- </li></ul><ul><li>Transmembrane components:E-cadherin </li></ul><ul><li>Plaque components:catenin </li></ul><ul><li>-Cytoskeletal component: actins </li></ul>
  53. 62. Tight Junctions <ul><li>- form at the apical end of lateral membranes forming paracellular diffusion barriers </li></ul><ul><li>-transmembrane components: junctional adhesion molecules (JAM), claudins, occludins </li></ul>
  54. 63. Tight Junctions <ul><li>intercellular channels between adjacent cells that allow the direct passage of low molecular weight metabolites between cells- </li></ul><ul><li>major protein -connexins, 15 different human genes, hexameric hemichannels dock with similar proteins on adjacent cell- </li></ul><ul><li>three major classes of connexin proteins: Gjα, GJβ, and GJγ </li></ul>
  55. 65. CORNIFICATION <ul><li>- process that begins in cells of the upper spinouslayers </li></ul><ul><li>-the induction of proteins that comprise the cornifiedcell envelope (CCE) are expressed as intracellular [Ca2+] rise in differentiating keratinocytes </li></ul><ul><li>-chromosome 1q21 contains cluster of genes called the Epidermal Differentiation Complex </li></ul>
  56. 75. <ul><li>THANK YOU </li></ul>