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Keratinization
keratinization is a genetically programmed, complex series of morphologic changes and metabolic events whose endpoint is a terminally differentiated, dead keratinocyte that contains keratin filaments, matrix protein, and a proteinreinforced plasma membrane with surfaceassociated lipids.
Epidermis
Epidermis is mainly composed of keratinocytes Thickness of epidermis- 0.05-0.1 mm formed by division of cells in basal layer which undergoes terminal differentiation to give rise to stratum spinosum , granular layer and stratum corneum
1.MITOSIS New epidermal cells are continuously formed by stratum basale to compensate for those that exfoliate at the surface.Some basal cells may remain quiescent which permits them to reenter the cell cycle and continue proliferation when required.
Turnover time-is the amount of time for whole cell population to replace itself.This depends on the time taken for individual cells to divide and the proportion of basal cells dividing . The mean turnover time of epidermis is estimated to be 39 days divided as follows: -13 days for proliferative compartment(proliferation of cells in basal layer) -12 days for differentiated compartment (transit time for a keratinocyte, from the time it detaches from the basal layer to the time it enters the stratum corneum) -14 days for cornified layers(transit time within the stratum corneum and subsequent desquamation)
Psoriasis is a consequence of an increase in the proliferating cell compartment in the basal and suprabasal levels of epidermis and not due to shortened cell cycle. The number of cycling cells is increased approximately sevenfold.
Characteristics of epidermis
Tissue renewal- continuous self renewal of keratinocytes Strength- intracellular and intercellular Cornification- formation of corneocyte and cornified cell envelope in stratum corneum
Differentiation
Notch signalling pathway and The transcription factors PPAR, AP2/, and C/EBP/
Stratum basale 1. stem cells 2. transit amplifying cells (TA cells) 3. postmitotic cells
Stem cells
Located in the bulge area of hair follicles, basal interfollicular epidermis and the base of sebaceous glands
Proliferation
division of stem cells daughter cells, the transit amplifying cells After undergoing several cell divisions(5-6), transit amplifying cells give rise to the postmitotic cells that undergo terminal differentiation which detach from the basal lamina to migrate to stratum spinosum
Recent evidence has suggested that asymmetric division of basal cells can directly give rise to a suprabasal differentiating daughter ce1l.
Epidermal Differentiation
1. 2. 3.
4. 5. 6.
Epidermal cells undergo characteristic changes during its ascent from undifferentiated basal cells to fully differentiated cornified cells When keratinocyte is released from stratum basale: Cells lose their mitotic potential Synthesis of keratohyaline granules, odland bodies changes in the expression of intracellular lipids, membrane glycoprotein, growth factor receptors and adhesion proteins gradual change in cell strength and water impermeability Loss of nuclei and cell organelles synthesis of a cornified envelope in the stratum corneum and programmed cell death
Keratinocyte morphology
Stratum basalecontains cuboidal cells, proliferating cells Stratum spinosum8-10 layers thick, no further cell division, cells are polyhedral in shape with a rounded nucleus, in upper spinous layer, cells have odland bodies/lamellar granules
Stratum granulosum- 2-5 cells thick,keratinocytes become elongated, accumulate amorphous keratohyaline granules Stratum corneum- 15-40 cells thick,
contains thickened envelope, loss of nucleus and organelles, imbedded in lipid matrix
p63 Stratum spinosum-Retain k5/14 keratins, new synthesis of k1/10 keratins (keratinisation specific keratins), involucrin, periplakin, envoplakin. Stratum granulosum- K1 and k10, loricrin, profilaggrin, transglutaminases
The sequences of differentiation will be dealt under 1. Fibrillar protein 2. Keratohyaline granules 3. Lamellar/ odland bodies 4. Intercellular junction formation 5. Cell membrane modification 6. Resorption of nuclei and organelles
Keratins are Intermediate filaments extend fron nuclear membrane to desmosomal plaques of cell membrane Forms the cytoskeletal component enable keratinocyte to sustain mechanical and non-mechanical stress Keratins of increasing molecular weight are synthesized as cells migrate from the basal layer to cornified layer 54 functional keratin genes(34 epithelial keratin and 17 hair keratin genes)
KERATINS
Keratins are rodlike proteins of two varieties, type I and type II and are paired to form dimers and are held together by hydrophobic interactions
Keratohyaline granules
Seen in keratinocytes of stratum granulosum Composed of profilaggrin, keratin filament and loricrin Histidine is required for the synthesis of profilaggrin Applied aspect Icthyosis vulgaris -affected skin is deficient in histidine -profilaggrin is not synthesised
Function of profilaggrin
keratohyaline granules release profilaggrin cleavage of profilaggrin Filaggrinbind with keratin causes keratin aggregation (keratin macrofibres) flattening of corneocyte
present in the cytoplasm of cells of upper spinous layer and granular layer. Lamellated membrane bound organelles contain ceramides, cholesterol, free fatty acids and acid hydrolases Found adjacent to the cell membrane with alternating thick and dense lines seperated by lighter lamellae In order to form odland bodies, three precursor lipids; namely, phospholipids along with cholesterol and glucosylceramides, are synthesized within the stratum spinosum and stratum granulosum cells
Intercellular junction
Link adjacent keratinocytes and responsible for mechanical, biochemical and signalling interactions between cells Components: 1. desmosomes 2. adheren junctions 3. gap junctions 4. tight junctions
chemically resistant, highly insoluble proteinaceous structure in the inner surface of plasma membrane Chromosome 1q21 contains cluster of genes known as epidermal differentiation complex
Rise in intacellular calcium levels Expression of plakins (envoplakin , periplakin) which form heterotetramers and associate with keratins and desmosomes As intracellular calcium levels continue to rise,activation of enzyme tranglutaminase 1 Cross-linking of the plakins and involucrin
Reinforcement
Loricrin: a cysteine-rich protein that forms the major protein component of the cornified envelope(70%) Loricrin and SPRs(small proline rich proteins) are cross linked by transglutaminase 3 which are again crosslinked to the existing scaffold with the help of transglutaminase 1
form a scaffold along the entire inner surface of plasma membrane reinforced by the addition of other precursor proteinrepetin, trichohyalin, cystostatin , elafin and LEP/XP-5 (skin-specific protein) Filaggrin bound keratin consisting almost entirely of keratin 1, keratin 2e and keratin 10, become crosslinked to the cornified cell envelope .
Lipid is synthesized and packaged in odland bodies in upper spinous layer and stratum granulosum odlland bodies cluster towards plasma membrane fuse with plasma membrane disperse lipids into intercellular space lipids are remodelled into neutral lipids by hydrolytic enzymes, lipases and glycosidases begin to organize into intercellular lamellae
After the differentiation, epidermal cells become transformed into horny cells. During this process, the nucleus and cell organelles disintegrate and are eliminated from the cells by lysosomal enzymatic lysis
Exfoliation
The horny cells at the surface of stratum corneum are continuoucly shed .As the cells reach the surface, the cementing substance become less effective and desquamation ensures. Cleavage between desmosomes in cornified layer results in shedding of corneocytes Cholesterol sulphate is an intercellular cement substance
Cholesterol sulphate is hydrolysed to cholesterol by enzyme-cholesterol sulphatase which leads to desquamation of corneocytes Applied aspect: X-linked recessive icthyosis: cholesterol sulphatase deficiencyaccumulation of cholesterol sulphate corneocyte retention
ATP2A2
HaileyHailey disease
ATP2C1
Keratin disorders Bullous congenital ichthyosiform erythroderma (BCIE) Diffuse non-epidermolytic palmoplantar keratoderma Epidermolytic palmoplantar keratoderma Focal non-epidermolytic palmoplantar keratoderma Ichthyosis bullosa of Siemens (IBS) Ichthyosis hystrix (CurthMacklin) Pachyonychia congenita type 1 Pachyonychia congenita type 2 Desmosome proteins Dilated cardiomyopathy with woolly hair and Keratoderma Ectodermal dysplasia with skin fragility KRT1, KRT10 KRT1 KRT9 KRT16 KRT2E KRT1 KRT6A, KRT16 KRT6B, KRT17A
TGM1 (Transglutaminase)
steroid sulphatase deficiency NSDHL, EBP 3 ABCA12 SPINK5 PAHX FALDH(fatty aldehydehye dehy)
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