EPIDERMAL KINETICS

Dr. Rohit Kr.SinghP.G.Resident Skin centre(BH)

EPIDERMIS

Structure and ultrastructure Stratified squamous

Epithelium 95% cells are Keratinocytes

SC SL

SG

SS

SG

DERMIS

EPIDERMOPOIESIS

Epidermopoiesis

Epidermal dynamics Epidermal kinetics

EPIDERMAL DYNAMICS

Epidermal proliferative unit( EPU) Consists of Single Stem cell

Transit amplifying cells

Terminally differentiated cells (post mitotic cells)

EPIDERMAL KINETICS

Turn over time

Cell cycle Growth fraction

Mitotic index Is the fraction of basal cells that is in

mitotic phase at any time.

Labelling index Fraction of basal cells in DNA

synthesis

Turnover time of the germinative epithelium

Epidermal turnover time ( transit time= 14 days)

The time taken for a cell to pass from basal layer to the surface of the skin

next 14 days

Subsequent desquamation

Normal vs psoriatic cell cycle time

LabellingIndex( %)

S phase

hr

G2 Phase

hr

MPhase

hr

G1Phase

hr

TOTALTIME DURATION(hr )

NORMAL EPIDERMIS

5.2 8.5 6 - 8 1 146 163

PSORIATIC EPIDERMIS

22.7 8.5 4 0.3 25 37.5

TURN OVERTIME TIME NORMAL (DAYS)

PSORIATIC(DAYS)

VIABLE- EPIDERMIS GERMINATIVE

TRANSIT IN VIABLE EPITHELIUM

12 -19

26 - 42

1.5

4 – 6

STRATUM CORNEUM 14 2

TOTAL EPIDERMIS 52 - 75 8 - 10

Psoriasis

Cells in Go /G1 Stage

Enter the cell cycle

Regulation of epidermopoiesis

Stimulatory factors1. Human epidermal growth factor(EGF)2. Transforming growth factor(TGF alpha)3. Amphiregulin4. IL-1,IL-2,GM-CSF5. Basic FGF6. Keratinocyte growth factor(KGF)7. Vitamin A8. Androgens

Inhibitory factors

1. IFN alpha2. IFN gamma3. TNF alpha4. High calcium level5. Adrenaline 6. Glucocorticoids

EPIDERMAL DIFFERENTIATION

8 % of the basal cells -(K-1/K10) undergo differentiation.

Orchestrated expression of keratins and subunits of cornified envelope.

Terminal differentiation (keratinization):

Change in keratin expression . Formation of corneocyte.

TERMINAL DIFFERENTIATION

1.Formation of keratin

2.Keratin filaments aggregate into bundles with the help of filaggrin.

3.Cornified envelope.

4.Changes in expression of

Intracellular lipid Membrane glycoproteins Growth factor receptors Adhesion protein Blood group antigens Desmosomes.

KERATINOCYTES

Any one of the cells in the skin that synthesize keratin.

Contains actin ,tubulin , intermediate filaments.

Keratin is one of the 6 types of intermediate filaments.

KERATIN (CYTOKERATINS) 54 functional keratin genes. Two gene family :- type 1(basic) type 2(acidic) Retinoic acid , growth

factors ,hormones regulate keratin gene expression.

Type 1 keratins

K9,K10 Epidermis(suprabasal)

K12 Cornea

K13 Oral mucosa

K14,K15 Complex epithelia

K16,K17 Epithelial appendages

K18 Simple epithelia

K19 Broad distribution

K20 Gut epithelium

K23 pancreas

K24 unknown

K25-28,31-38,39,40 Hair shafts

Type 2 keratins

K1,K2 Epidermis (suprabasal)

K3 Cornea

K4 Oral mucosa

K5 Complex epithelia(basal layer)

K6a,K6b Epithelial appendages

K6c Skin

K7,K8 Simple epithelia

K71 – 74,75 Hair follicles

H76 Oral mucosa

K77 Sweat gland ducts

K78 tongue

DIFFERENTIATING EPIDERMAL KERATINOCYTES

Basal layer as proliferative cells express K-5 and K-14

The process of differentiation starts with the K – 10/K-1 expression (in TA cells)

K-2 is expressed at later stages of differentiation( granular layer)

Psoriasis Wound healing

Altered epidermal differentiation

Synthesis of suprabasal K-6 and K-16

BASIC K

ACIDIC K

TISSUE EXPRESSION DISEASE ASSOCITION

1 10 Suprabasal keratinocytes

Bullous congenital icthyosiformis erythroderma ; Diffuse non epidermolytic PPK

1 9 Suprabasal keratinocytes(palmo-plantar skin)

Epidermolytic PPK

2 10 Upper spinous , granular

Icthyosiform bullosa of siemens

3 12 cornea Meesmann’s corneal dystrophy

4 13 Mucosal epithelium White sponge nevus

5 14 Basal keratinocytes Epidermolytic bullosa complex

6a 16 Outer root sheath,hyperproliferative, palmo-plantar keratinocytes

Paronychia congenita type 1 ;Focal non-epiderdermolytic PPK

6b 17 Nail bed ,epidermal appendages

Paronychia congenita type II, Steatocystoma multiplex

8 18 Simple epithelium Cryptogenic cirrhosis

Keratohyaline granules

Keratinocytes of stratum granulosum.

Disappear in cornified squames. They contain granules rich in

histidine . Keratin filament are aggregate into

bundles by the action of the histidine rich basic protein callled filaggrin.

Membrane – coating granules

Also called as lamellar granules or odland bodies.

Found in spinosum and Granulosum layers of skin.

Contains phospholipids, glycolipids and free sterols.

Forming an important barrier to permeability.

CORNIFIED ENVELOPE

Highly insoluble cell envelope. Present in stratum corneum. It’s development is triggered by intracellular

calcium. Involucrin is main envelope precursor. Others include1. Loricin 6. Envoplakin2. Cornifine 7. Periplakin3. Pancornulin 8. 61KDa protein4. Elafin 5. Keratolini

Transglutaminases cross-link plakins and involucrin.

Other desmosomal proteins are also cross-linked ,forming a scaffold along the entire inner surface of the plasma membrane.

High calcium level increases differentiation.

PROTEIN DISEASE ASSOCIATION

CYSTATIN A Harlequin ichthyosis

PROFILAGGRIN /FILAGGRIN

Ichthyosis vulgarisAtopic dermatitis

LORICIN Mutilating keratoderma with ichthyosis;

Progressive symmetric erythroderma

NORMAL HOMIEOSTASIS-EPIDERMIS

1.Mitotic rate of germinative cells

2.Generation time of epidermal cells

3.Desquamation rate of corneocytes

DISTURBANCE IN EPIDERMAL KINETICS

1. ACANTHOSIS Enhanced cell proliferation

Enlargement of the germinative cell

Increased mitotic rates

Broadening of epidermis

Conditions showing Acanthosis:-

1. Psoriasis2. Eczema3. Condyloma acuminatum

DISTURBANCE IN EPIDERMAL DIFFERENTIATION

2. PARAKERATOSIS

Incomplete differentiation in post mitotic phase

Faulty and accelerated cornification

Retension of of pyknotic nuclei of epidermal cells

Leads to gap between cells

Loss of barrier function of the epidermis

HISTOLOGICAL FINDINDS IN PSORIASIS

Conditions associated with Parakeratosis

1. Psoriasis2. Pellagra 3. Epidermolytic hyperkeratosis4. Scurvy

Note – it can be normally found in hard palate

3. DYSKERATOSIS

Morphologic presentaion of apoptosis of keratinocytes

Eosinophilic cytoplasm ,pyknotic nucleus Cells are packed with keratin filaments

Cell will tent to round up

Loose it’s attachment with surrounding cells

Conditions showing dyskeratosis

1. Darier disease2. Actinic keratosis3. Squamous cell carcinoma

CANCERS OF THE EPIDERMIS Squamous cell cancer

Irregular masses of epidermal cells.

Differentiation is in direction of keratinization

Horn pearls – concentric layers of squamous cells with increasing keratinization at centre.

Keratohyaline granules are sparse or absent.

Basal cell cancer Predominent basal cell type

Keratotic basal cell carcinoma Parakeratotic cells Horn cysts – fully keratinized cells,

represent attempt at hair shaft formation.

DRUGS ACTING ON EPIDERMAL CELL

Retinoic acids Acts on retinoic acid receptors RAR

and RXR CRABP II – in human epidermis Epidermal differentiation Increased in – 1. Psoriasis2. Lamellar ichtyosis3. Darier’s disease4. PRP

CRABP II

Retinoic acid

Epidermal differentiation

Vitamin D analogues(calcitriol,calcipotriol)

Acts on vit D receptors on keratinocytes

MOA- Regulate keratinocyte proliferation. Epidermal differentiation. Formation of cornified membrane.

Tazarotene

Acts on retinoic acid receptors Modulate abnormal epidermal

differentiation and proliferation. Upregulation of K-10 terminal

differentiation.

Coal tar

Inhibit DNA synthesis Atrophogenic effect

Salicylic acid

> 3% keratolytic MOA – Dissolves the intercellular cement

substance of the corneocytes.

REFERENCES

1) FITZPATRICK’S DERMATOLOGY IN GENERAL MEDICINE

2) ROOK’S TEXTBOOK OF DERMATOLOGY

3) IADVAL TEXTBOOK AND ATLAS OF DERMATOLOGY BY R.G AND AMEET VALIA

4) COLOUR ATLAS OF HISTOLOGY OF THE SKIN BY WALTER F.LEVER

THANK YOU