Epidermal Cells of Skin
Dr Yugandar
• Epidermal cells:1.Melanocytes2.Keratinocytes ( 80 %
cells in epidermis )3.Langerhans cells4.Merkel cells
Keratinocytes• Passive BRICK in the defensive wall surrounding the body
• Ectoderm derived cells
• Contains number of structural proteins (filaggrin, keratin),
enzymes (proteases), lipids and antimicrobial peptides
(defensins)
• It contributes to maintain the important barrier function of
the skin
Keratinocytes• Keratinization is part of the physical barrier formation
(cornification),it produces more and more keratin
• Finally undergo programmed cell death
• The fully cornified keratinocytes are constantly shed off
and replaced by new cells
• Epidermal turn over time ranges from 52 to 75 days
• Appr. Transit time from basal layer to st. corneum 12 to
19 days & through st. corneum is 14 days
Keratinocytes
• 80 – 85 % epidermal cells
• Epidermal cells self renewal maitained via stem
cells in basal layer of interfollicular epithelium &
bulge region of hair follicles
• Keratinocytes produce 6 keratin filaments
Keratinocytes
• Keratinocytes proliferate within the basal cell layer
• As differentiation proceeds, it progress upwards
through the different epidermal layers (the spinous
layer, granular layer and cornified layer)
• It becomes anucleated and increasingly compacted in
size, before being eventually lost from the skin surface
by desquamation
• The smaller black dots in the cells of the granular layer
represent keratohyalin granules.
Keratinocyte Differentiation
• Keratinocytes Present in suprabasal layer lose
characteristics of underlying layer D/t Terminal
Differentiation ,they become flatten out assume shape
of corneocytes
• Four structures identified by Electron Microscopy
1.Keratohyalin granules 2.Cornified Envelopes
3.Lamellar bodies 4.Desmosome plaques
Characteristics of Self renewing Epidermis:
• Keratinocyte Stem Cells
• Keratinocyte Proliferation
• Keratinocyte Terminal Differentiation
KERATINOCYTE STEM CELLS
• Stem cells are slowly replicating cells
• It divides into another stem cell or a
cell committed to differentiation
• Protected in a specific tissue
niche,Protected by cell-ECM and
cell-cell interactions
• Located within the bulge region of
the hair follicle & at the base of rete
ridges of inter follicular epidermis
• Stem cells are located
within the bulge region of
the hair follicle and at the
base of rete ridges of
inter follicular epidermis
• Stem cells are multipotent, can
generate hair, sebaceous gland or
epidermal keratinocytes
• They allow for the maintenance of the
cell population in the epidermis with
little to no damage to the TISSUE
genome
• At times of tissue damage, it increase
their rate of proliferation to repopulate
the wounded area
Epidermopoiesis
• Epidermal thickness & number , size of epidermal
cells remain constant with rate of cell production
matching rate of cell loss
• Mitotic divisions occur in keratinocytes every 18 to
19 days , up to 5 to 6 times of mitotic divisions
Epidermopoiesis
Stimulatory• Human EGF• TGF alfa• KGF induced by Dermal
fibroblasts,PDGF,IL-1 beta,TNF
• IL-1 & IL- 6
Inhibitory• IFN alfa & gama
Low Calcium inhibits keratinocytes differentiation & stimulate Proliferation
KERATINOCYTE STEM CELLS
Control of stem cell function by Wnt family or Delta / Notch path ways
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 Langerhans cells• Delayed injury response• Delayed chemical clearance• Decreased immune response• Dcreased resistance to mechanical stress• Increased incidence of cancer
KERATINOCYTE PROLIFERATION
• Proliferation done by transient
amplifyingcells (TA cells)
• In normal epidermis, remain
attached to basement memb.
• Transition from stem cell to TA
cell is the first step in
keratinocyte differentiation
• TA cells migrate laterally along
the basement membrane
• TA cells only divide 2-3 times before they withdraw from the cell cycle
• TA cells carry-out cell proliferation for tissue without risk for long-term genetic damage to tissue
• Inc expression of c-myc associated with transition from stem cell to TA cell
• Retinoids, vitamin D, AP1 regulate proliferation and differentiation
KERATINOCYTE TERMINAL DIFFERENTIATION
• when a keratinocyte releases from the
basement membrane, it undergoes
changes in morphology & gene
expression
• Gradual change in cell strength &
water impermeability
• Terminally differentiated keratinocytes
synthesize a cornified cell envelope &
undergo programmed cell death
• Stem cells & their differentiated progeny are organized into
columns k/a epidermal proliferation units
• keratinocytes permanently withdraw from the cell
cycle,initiate expression of epidermal differentiation
markers & move suprabasally become corneocytes in the
stratum corneum
• Corneocytes are keratinocytes that have completed their
differentiation program & have lost their nucleus and
cytoplasmic organelles,will eventually be shed off through
desquamation as new one come in
KERATINOCYTE TERMINAL DIFFERENTIATION
• stratum basale – cuboidal
cells
• cells with in this layer
proliferate
• all cells attached to the
basement membrane
• one cell layer thick
• keratins K5 & K14 integrins,
p63
Stratum spinosum –
• cells increase in size
• increased cytoplasm:nucleus
ratio
• cell layer4-6 cells thick, no
further cell division
• Keratins K1 &
K10 ,involucrin,envoplakin,peripl
akin
Stratum granulosum
• cells become elongated
• usually 1-2 cell layers thick
• accumulate amorphous
keratohyaline granules
• Keratins K1 & K10 loricrin,
filaggrin,transglutaminase3
Stratum corneum-
• Keratinocytes contain
thickened cell envelopes
• contain no nucleus
• imbedded in lipid matrix
• no new proteins expressed
Factors promoting keratinocyte differentiation
• A calcium gradient,with the lowest concentration in the
st.basale & inc concentrations until the outer stratum
granulosum,where it reaches its maximum
• Calcium concentration in the stratum corneum is very low
b/c dry cells are not able to dissolve the ions
• Those elevations of extracellular Ca concentrations induces
an inc intracellular free Ca concentrations in keratinocyte.
• Part of that intracellular Ca inc comes from Ca released
from intracellular stores& from transmembrane Ca influx
• Vitamin D3 regulates keratinocyte proliferation &
differentiation by modulating Ca concentrations & regulating
the expression of genes involved in keratinocytes
differentiation
• Keratinocytes are the only cells in the body with the entire
vitamin D metabolic pathway from vitamin D production to
catabolism and Vitamin D receptor expression
Factors preventing epidermal stem cells to differentiate
into keratinocytes
• The transcription factor p63
• Vitamin A and its analogues
• Epidermal growth factor
• Tumor growth factor
• Cholera toxin
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 & differentiation specific manner
• IF proteins have a conserved central rod domain of helical
coiled-coil segments
• the amino-and carboxy-terminal sequences of IF proteins
are variable
KERATINOCYTE INTRACELLULAR STRENGTH
Keratins heterodimerize with specific pairing partners:
• Type I family• Type II family heterodimers then
oligomerize into longer fibrils
KERATINOCYTE INTRACELLULAR STRENGTH
• Keratins heterodimers
oligomerize into longer
fibrils
• fibrils continue to
assemble until IF is 10-
12 nm in diameter
Three types of interactions
hold keratinocytes together
in epidermal sheets:
• Hemi desmosomes
• Desmosomes
• Adherens Junctions
HemidesmosomesAdhesion site that links the keratin
cytoskeletal components of a cell
to extracellular matrix (basement
membrane)
• Transmembrane components:
integrins α6β4,BPAG2
• Plaque components:BPAG1
(BP230),plectin
• Cytoskeletal component: keratin
DESMOSOMES
Adhesion site that links the keratin cyto skeletal components of two cells
• Transmembrane components: desmogleins,desmocollins• Plaque components: desmoplakins,plakoglobin,plakophilin,keratoclamin• Cytoskeletal component:keratin
Adherence JunctionsAdhesion site that links actin
cyto skeletal components of two cells
• Transmembrane components: E-cadherin• Plaque components: β-catenin,α-
catenin,vinculin,VASP,p120ctn
• Cyto skeletal component: actin
KERATINOCYTE CORNIFICATION
Process that begins in cells of the upper
spinous layers
• the induction of proteins that comprise the
cornified cell envelope (CCE) are
expressed as intracellular [Ca2+] rise in
differentiating keratinocytes
• chromosome 1q21 contains cluster of
genes called the Epidermal Differentiation
Complex
newly synthesized envoplakin, periplakin, and involucrin form heterotrimers that associate with the cell membrane-transglutaminase1 crosslinks these proteins via ε-(γ-lysine) isopeptide linkages-this scaffold forms along the entire inner surface of the cell membrane
• Lamellar bodies (containing free-fatty acids, cholesterols, and ceramides) bud off from the Golgi complex
• At the transition from the granular layer to the cornified layer, the lamellar bodies fuse with the cell membrane and extrude their contents into extracellular space
• Also at transition,filaggrin becomes post-translationally modified & directs the aggregation of keratin proteins
Keratohyalin granules
• Dense,Irregular amorphous deposits along keratin
filaments in St.Spinosum & St.Granulosum• Composed of Profilaggrin – Bundling of Keratin Intermediate filaments
to form MacrofibrilsFilaggrin – Water binding in SCLoricin & Cystatin A – Transglutaminase activity &
Components of Cornified EnvelopeKeratins – K1 & K10
• Mutations that occur post zygotically lead to Aplasia cutis
• X- linked ichthyosis – failure of cornified cells to slough
results in retention hyperkeratosis
• In PV – antibodies to Desmoglien 3 & 1
• In SSSS – antibodies to Dsmoglien 1
• In psoriasis – cell cycle reduced to 36 hrs
KERATINOCYTE CORNIFICATIONCONSEQUENCES OF FAILURE
Sunburn cells
• A sunburn cell is a keratinocyte with a pyknotic
nucleus and eosinophilic cytoplasm
• It appears after exposure to UVC or UVB radiation
or UVA in the presence of psoralens
• It shows premature and abnormal keratinization
• It has been described as an example of apoptosis
• Derived From?• Function?
• Synthesize & secrete?
• Neural Crest• Pigmentation/ protection• Melanin
Melanocytes
• They enter Epidermis B/W 7 to 8 weeks of Gestation
•Distributed in Basal layer,Extends towards dermis
below level of basal cells above lamina densa
-Curved arrow shows Langerhans cells
- straight arrow shows Melanocytes
Melanocytes
• High density on face & male genitalia, Lowest on
trunk
• Production of melanin,transfer to keratinocytes &
hair follicle shaft through Melanosomes
• One Melanocyte is in contact with 36 keratinocytes
these group of cells k/a Epidermal Melanin Unit
Melanocytes• Lightly pigmented skin are Melanosmes
small,mostly aggregated,Membrane bound clusters
• Dark skinned- Inc Melanization,Dec Melanosme
degradation,Larger melanosomes,singly
distributed,Individual organelles,contains larger &
more dendritic melanocytes
Melanocytes
• Hair melanocytes: 1 M = 5 K,Graying d/t Dec in no
of follicular melanocytes,1 M = 10 K in basal
• Chronic sun exposure - larger melanosomes
• No Racial defferences in no of Melanocytes
• Difference in size,distribution & no of melanosomes
• All races have same density of Melanocytes
Melanocytes
Melanin : • Synthasized in melanosomes•Stimulated by MSH
Pheomelanin
• Red – Yellow in colour•Synthasized in Pheomelanosomes•Sperical structure
Eumelanin
• Brown to Black in colour•Synthasized in Eu Melanosomes•Oval shaped
Stages of Melanosomes 4 stages
St. 1 – round,membrane bound vesicles,No Melanin,Enzyme
activity in Concentric lamellae
St. 2 – Melanin deposited in cross linked longitudinal filaments
St. 3- Melanin deposition inc by enzyme & Non enzymatic
polymerization
St. 4 – fully developed,no enzyme activity
From 1 to 4 Inc Acid phospatase,Dec Tyrosinase
Melanocytes• Melanocortin 1 receptor controls type of melanin
produced
• Loss of function MC1R results in Inc PM & Dec EM
• Fair skin more prone to UV radiation absorption,Inc risk
of melanoma
• C – Kit activation plays key role in migration &
development of Melanocytes & Melanoblasts
Melanocytes
• Reduced - Piebaldism- Waardenburg syndrome
• Defective Pigment - Albinism- Chediak Higashi
syndrome
• Freckles result from localized inc in production of pigment by normal number of melanocytes•Naevi – benign proliferations of Melanocytes
The melanocyte is the dendritic pigment-producing cell of the epidermis and found in the basal layer.
•Different races have same # of melanocytes• amount of melanin produced differs•Melanin accumulates in keratinocytes
Langerhans cells
• Dendritic cells
• Dopa negative & ATPase Positive
• Distributed Basal & Spinous layers
• 2 to 8 % total Epidermal Population
• LC have folded nucleus,Clear cytoplasm,Well
developed Endoplasmic reticulum,Golgi complex
Langerhans cells
• Intracytoplasmic organelles k/a Birbeck
Granules/Tennis racket shaped/Rod shaped with
straited appearance
• Contains Actin & Vimentin
• Connected to Keratinocytes = E – Caderin Recp
• Exposure to UV radiation causes depletion of LC &
Dec ability to present antigen
• LC have become prospective vehicle for tumor
theraphy & tumor vaccines
• In Psoriasis,Contact Dermatitis, Sarcoidosis their
number is reduced
Langerhans cells
• LC histiocytosis seen in
Lettere siwe disease
Eosiniphilic granuloma ( skull bones)
Hand schuller christian disease : DI,Bone
lesions,Exophthalmos
Hashimoto Pritzker
• Derived From?• Function?• Contain?
• Neural Crest• Sensory• Dense-core graunles
Merkel Cells
More no of Merkel cells seen in high tactile
sensitivity areas such as high density of hair
follicles,digits,lips around oral cavity
Merkel Cells
• Oval in shape,15 micron,oriented parallel to BM
• Pale cytoplasm,lobulated nucleus with Cytoplasmic
spines towards Keratinocytes
• Merkel – Neurite complex along with sensory nerve
endings,serve as mechanoreceptors for touch
sensation
• Slow Adapting , type 1 Mechanoreceptors
Merkel Cells
• EM shows microvilli at cell surface with dense core
granules with intermediate filaments & lobulated
nucleus – Dot Like pattern
• Markers – Cytokeratin 20 ( CK 20)
• Contains battery of neuropeptides –
NSE,VIP,Chromogranin A,Calcitonin gene related
peptide
• Cells embedded in Basal layer & form desmosomal
connections with Basal Keratinocytes
• Merkel Hyperplasia - adnexal tumours Naevus
sebaceus,Trichoblastomas,Trichoepitheliomas &
nodular hidradenomas
Mast cell
• Most numerous in Subpapillary dermis,around blood
vessels,nerve & appendages
• Ovoid ,Mono or Binuclear,numerous round cytoplasmic
granules
• Play role in Innate & Adaptive immunity
• Mast cell reside in papillary dermis & undergo
migration through basal lamina in to epidermis
Mast cell
• Play role - Skin pathology in
AD,CD,Scleroderma,Immuno bullous disorders
Mast cell
Thank You
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