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Functions of melanocytes

Functions of melanocytes. The main function of melanocyte is synthesis of melanin pigments. However, it varies according to their site: A. Epidermis: 1. Color of the skin 2. Protection from U.V. radiation 3. Repigmentation of vitiligo .

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Functions of melanocytes

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  1. Functions of melanocytes

  2. The main function of melanocyte is synthesis of melanin pigments. However, it varies according to their site: • A. Epidermis: • 1. Color of the skin • 2. Protection from U.V. radiation • 3. Repigmentation of vitiligo. • 4. Keratinocyte – melanocyte interaction during melanosome transfer ( Seiberg,M. Pig. Cell Res. 14: 236, 2OO1). Epidermal melanocyte unit is composed of one melanocyte & approximately 36 neighbouring keratinocytes. The suggested mechanism of melanosome transfer include; @ melanosome release & endocytosis, @ direct inoculation (injection), @ keratinocyte – melanocyte membrane fusion & @ phagocytosis.

  3. Epidermal melanocyte unit & mechanism by which keratinocyte derived factors act on human melanocyte proliferation & differentiation.Hirobe, T. P. Pigment cell Res. 18: 2, 2OO5. • The melanocyte keratinocyte unit responds quickly to a wide range of environmental stimuli after paracrine & / or autocrine stimulating hormone (MSH), endothelins, growth factors, cytokines…etc. • SCF: stem cell factor; HGF: hepatocyte growth factor ; b FGF: fibroblast growth factor ; LIF: leukemia inhibitory factor ; GM-CSF: granulocyte macrophage colony stimulating factor ; MSH: melanin stimulating hormone; Mc1R: Melanocyte 1 receptor ; MITF: microphthalmic associated transcription factor ; CRE: c- AMP response element

  4. 5. Regulation of skin pigmentation via modification of tyrosinase functionAndo, H. et al J. Invest. Derm. 127:751, 2OO7After maturation of tyrosinase enzyme in the Golgi apparatus, it will be transferred either to melanosome for melanin synthesis or for degradation machinery (ER: endoplasmic reticulum)

  5. 6. Increase function of melanocytes: • i. Dysfunction: • Freckles, melasma, oral contraceptives, melanosis of pregnancy, liver diseases, exposure to ultra-violet irradiation, neurofibromatosis, pellagra, porphyria, incontentia pigmenti, kwashirkor, minocyclin eruption, fixed drug eruption, xeroderma pigmentosa, amyloidosis, post inflammatory hyperpigmentation: lichen planus, eczema, lupus erythematosus, scleroderma. • ii. Proliferation: • Lentigens, melanocytic nevi, spitz nevus, halo nevus, nevus of Ota, nevus of Ito, blue nevus, combined nevus, Peutz jegher syndrome. • 7. Decreased function of melanocytes: • Post inflammatory hypopigmrentation: pityriasis alba, tinea versicolor, psoriasis, lichen planus, lupus erythematosus, syphilis , leplrosy. Incontentia pigmenti, tuberous sclerosus, phenylketonuria, Waardenberg syndrome. • 8. Abscent melanocytes: • Vitiligo, piebaldism, mono benzyl ether of hydroquinone,, leukoderma. • 9. Metabolic genetic disorder: • Hyperphenylanaemia syndromes, Tyrosinemia, alkaptonuria • 1O. Abnormal melanocytes: • Malignant melanoma.

  6. B. Hair • The reservoir for melanocytes is; • @ Stem cells in isthmus. • @ amelanotyic melanocytes in outer hair sheath. • Strangely enough, dead melanocytes are replaced by stem cells but not by proliferation as epidermal cells. Melanocytes have a low mitotic rate. • C.Sebaceous glands and sweat glands. : • They contain also melanocytes but their function are not yet elucidated. • D.Mucous membrane: e.g Peutz jeghers syndrome

  7. Skin “sees” U.V. light starts to producing pigment ( Oanacea, E. 2O11) • Human melanocyte skin cells fluoresce as their calcium signaling spikes after exposure To U.V. L. & retinal, a key step in producing Melanin. This lead Oancea (2O11) to discover Rhadopsen receptors in skin which detect U.V. light..

  8. E. Eye: Melanocytes are present in the:@ uveal tract (iris, ciliary body, & choroid. @ Conjunctiva @ Retina with densely pigmented epithelium. There are 2 different types of pigmented cells in the uveal tract : the melanocytes & pigmented epithelial cells. The melanocytes localized in the iris are constantly exposed to U. V. radiation. The melanocytes in the iris have a photo screening effect. The anti-oxidant property of melanin is related to the type of melanin The greater the ratio of eumelanin to pheomelanin , the better the anti oxidant capacity of the melanin. The variation of the color of the eye is due to the amount of light reflects off from the surface of the iris. Melanocytes located in the ciliary body & choroid are protected by the lens & the pigmented Retinal epithelium. Eye color

  9. Anterior uveal melanoma

  10. Conjunctival melanocytic intraepithelial neoplasmaSlit lamp photographs. Damato, B. E. Saudi J. Ophthal. 26: 137, 2O12

  11. Conjunctival melanocytes at limbus

  12. Melanocytes are shown to exist as sporadic cells with dendrites processes in corneal limbusHiga, K. Experimental eye research 81: 218, 2OO5

  13. Melanocytes are shown to exist as sporadic cells with dendrites processes in corneal limbusHiga, K. Experimental eye research 81: 218, 2OO5

  14. Choroidal melanoma

  15. Melanocyte hyperplasia in ciliary body showing spindle shaped melanocytes with oval to elongated nuclei with stippled chromatin & inconspicuous nucleiO’Neal, K.D. al Survey of ophthalmology 48: 613, 2OO3

  16. Diffuse choroidal thickening by melanocyte hyperplasia O’Neal, K.D. et al . Survey of ophthalmology 48: 613, 2OO3

  17. The melanocyte hyperplasia abutted the choroid capillaries but erythrocyte were still visible within the vessels indicating their patency. Enlarged reactive retinal pigment epithelial cell with several overlying mammalian macrophageO’ Neal, K.D. et al. Survey of Ophthalmology 48: 613 , 2OO3

  18. Pigmented lesion on the eye • Nevus of ota

  19. F. Ear: • Melanin containing cells are present in cochlea of inner ear in stria vasculare. They play a role in Ca2+ homeostasis of endolymph. Melanocytes of inner ear play important role in both auditory & equilibrium function. Melanocytes in stria vasculaire may play a role in the development of the ability to hear. • Noises stimulate melanin synthesis in inner ear melanocyte ( El Said, M. et al. Egypt. Dermat. J. Online 2: 7, 2OO6.)

  20. Melanocytes in inner ear cochlea .

  21. G. Brain: • @ Melanin are polymorphous & multifunctional biopolymers that include eumelanin, pheomelanin , mixed melanin (combination of eumelanin & pheomelanin) & neuromelanin. Due to chemical structure of melanocyte in substantia nigra , we find that both eumelanin & pheomelanin are involved in binding to cations , anions , drugs & chemicals…etc. Neuromelanin which is produced in dopaminergic neurons of human substantia nigra can chelate active metals ( Cu, Mn, Cr) & toxic metals like Cad, Hg, Pb .Therefore, these melanocytes protects the brain against promotion of neurodegenerative conditions.( Zecca, L. et al. Neuroscience 73: 4O7,1996) • @ Melanin rich cells in substantia nigra are the ones most likely to be destroyed in people who have parkinsonism resulting in tremors & rigidity. • @ Melanin is the source of some ingredient from some neurotransmitters e.g. dopamine play a role in reward & movement. It is manufactured in nerve cell bodies located in the ventral tegumental area & perifrontal cortex. Its motor functions are linked to separate pathway with cell bodies in substantial nigra & ventral tegumental area with release of dopamine in the striatum. Dopamine is synthesized from phenyl alanine, tyrosine & DOPA. Dopamine dysfunction causes :@ Parkinson’s disease (age related degenerative condition) @ Schizophrenia : due to dopamine elevated activity . • @ The formation of melanin is controlled by the pituitary gland that secrete melanin stimulating hormone (MSH) in stimulation with ultraviolet light. • Melanocytes have been described (Fetissov, S.O. Pigment cell research 12: 312,1999) in the anterior lobe of pituitary around the median eminence of the hypothalamus& meninges of Zucker rats. In leptomeninges, numerous melanocytes were found. They added that the presence of melanocytes in the proximity of blood vessels suggests an endocrine factor.

  22. Cranial meninges of sheep that are full of • melanocyte

  23. Substantia nigraNormal

  24. Substantia nigraComparison o of Parkinson’s disease & the normal

  25. Melanocyte: a window into the nervous systemYaar, M. & Park, H. J. Investig. Derm. 132: 835, 2O12 • Yaar & Park (2O12) reached to the conclusion that both the melanocytes & cells of nervous system share : @ common embryologic origin, @ signaling molecules , @ receptors & @ signaling pathways. • @ The signaling molecules include: endothelins, steel factor, hepatocyte growth factor, bone morphogenetic proteins, Wnt, fibroblast growth factor (FGF) & neurotrophins (NTs). • @ The signaling pathways include PKC & P53 / P73 dependant pathways. • Together, they allow precursors of melanocytes & neurons to reach their final distribution, differentiate in the target tissue, sprout dendrites to form connection with surrounding cells & help in the maintains & survival of melanocytes & neurons at steady state & after injury • It seems that melanocytes do their different functions through their relationship with C.N.S.

  26. H. Heart: • Melanocytes are localized in the valves (mitral, tricuspid, & aortic)& septal ( ventricular & atrial) in mice ( Levin, M. D. et al. J. Clin. Investigation 119: 342O, 2OO9). The number of melanocytes in the heart appears to reflect that in the skin. • The melanocytes seem to attract arrhythmias of the heart but the source & mechanism of these attacks remain unclear. The melanin synthesis enzyme dopachrome tautomerase (DCT) is involved in intracellular calcium & reactive species regulate in melanocytes . Levin et al . (2OO9) found that lacking of DCT (dopa chrome tautomerase) increased susceptibility of atrial arrhythmias. • Mjaatvedt et al. (Anat. Rec. Discov. Mol. cell Evol. Biol. 285: 798, 2OO5) reported the normal distribution of melanocytes in mouse heart. The pigmented cell population was apparent in atrial wall , inter-atrial septum,, interventricular septum below the surface of endocardium. The pigmente cells were also found in tricusped & mitral valve leaflets & chordae tindinae.

  27. Melanocyte pigmentation is observed in whole mount preparation of murine heart J. of Royal Society Interface Online 1742 -5662, 2O13

  28. Cardiac melanocyte like cells in mouse heart are located in the region of the atria & pulmonary veins & may serve as triggers for atrial arrythemia (Levin et al ,2OO9)

  29. Dopa chrome toutmerase expressing cells in the heart.Levin , M.D. J. Clin. Investigation 119: 342O, 2OO9

  30. Cardiac melanocytes like cells persist in the heart in the absence of dopa chrome toutomerase Levin, M. D. J. Clin. Investigation 119: 342O, 2OO9

  31. Liven et al (2OO9) described a population of melanocytes in the heart & pulmonary veins of murine & human that appear to contribute to atrial arrythmogenesis.

  32. H. Bone: • It has long been known that skin cells are capable of renewing themselves & they can generate multiple cell layers. Today, there is a more evidence that stem cells are present in far more tissues & organs e.g. bones that are capable of developing into more kinds of cells than previously imagined. – either a tissue from the same embryonic gene layer or from a different germ layer . This is called plasticity or transdifferentiation. • Both bones and cartilage are derivatives of neural crest • Kexim et al (2O11) ( kevim ,S et al . Acta Academic Medicenie Sincae 33: 4O2, 2O11)were able to construct tissue engineered skin by using melanocytes from the human foreskin & adult human bone marrow mesenchymal skin cells (BMSC) in vivo which contain bone morphogenetic P4. It is the progress to be able to build an organ (the SKIN). • Bone marrow morphogenetic protein (BMP-4) was shown (Yaar et al. J. Biol. Chem. 281, 253, 2OO7 to down regulates melanogenesis in part by decreasing the level of tyrosinase ( Park, H. et al. Int. J. cell biology. 75O : 2OO9).

  33. Postmigratory neural crest cells during embryonic development

  34. The bone marrow stem cell may differentiate into another mesodermal derived tissue such as muscle, cardiac muscle or liver.

  35. Oral melanoma in the jawbone of a cow with widespread metastasis Brito, M. et al Ciec. Rurel 39: 2OO9

  36. I. Thyroid gland: • Melanin stimulating hormone is a peptide secreted by the intermediate lobe of the pituitary that stimulate melanin release& dispersal. • ***************************************(****** • Cleavage are indicted by the numbers 1-7 & consist of sequence Arg, Lys,. Lys,. Arg or Lys, Lys. ACTH & B lipotropin are products generated in the corticotrophic cells of the ant. Pituitary under the control of corticotrophic releasing hormone (CRH), alpha melanocyte stimulating hormone corticotropin - like intermediate peptide (CLIP), gamma lipoprotein & B endorphin are product generated by the intermediate pituitary under the control of dopamine. The presence & function of gamma MSH is unclear &hence the dotted lines

  37. J. Noradrenalin and Adrenaline : • Hyper pigmentation is found with primary adrenal insufficiency (Addison disease). • Cushing syndrome due to excess of adrenocorticotropin hormone can lead to hyper pigmentation

  38. K.Testis: • Thyroid hormone stimulates oxidatative metabolism in many tissues in the body but testis is not one of them. • However, recent findings ( Mendis- Handagam et al. (2OO4)Histology & histopathology 19 : 985) mentioned that recent findings clearly show that thiochrome have significant functions on the testis in general & Leydig cell in particular which begins from the onset of their differentiation through aging. In addition, it has been shown that thyrotropin releasing hormone TRH, TRH receptor& TRH mRNA in the testis in many mammalian species are seen exclusively in Leydig cells. It is possible instead hypothalamic –pituitary thyroid axis & hypothalmic pituitary testis axis, there are short looped through Leydig cells • The horse testis showed pigmentation in the interstitial tissue ( Murabay Shie et al J. Vet. Med. 5O61: 1183, 1999). The results of their histochemical studies suggests that they phagocytize Leydig cells& store their digested material as ceroid like pigment (Haider, S. G. Int. Rev. Cytol. 233, 181 : 2OO4)

  39. A. Melanoma synchronous metastasis in paratesticular region (tunica vaginalis) • B. Cutting the testis during histological study showed melanoma with no extravasations was evident of the testicular tumor of tunica albuginea. • *********************************** • @ Testosterone is the cause of pigmentation of scrotum & penis. • @ Cryptorchidism is associated with lack of hyper pigmentation & gynecomastia • @Syndrome of pigmentation , gynecomastia & testicular atrophy .( Report of 2 cases: J. Philipp. Med. Assoc. 32: 6O8, 1956

  40. Q. & A. • If a patient has generalized vitiligo: • In vitiligo, there is destruction of melanocytes. There is no use of some of tyrosine. could this means that he may develop metabolic disease : phenylketanuria or tyrosinemia ? • No. Tyrosinemia or phenylketonuria occur only if there is mutation of the responsible gene.

  41. Tyrosinemia type IDeficiency of FAH (fumeryl acetoacetase) is the cause of tyrosinemia. Its diagnosis & treatment ( by dietary restriction) are critical in the neonatal period for the survival of the child

  42. Tyrosinemia type IIDeficiency of TAT ( L- tyrosine aminotransferase ) result in elevation of tyrosine levelTreatment is by dietary restriction of phenylalanine &tyrosine in diet

  43. Tyrosinemia type IIIThe mutated gene is 12 q 24 , 14 exon .Mutation in the enzyme(HPPD) hydroxyphenyl puruvate dioxygenaseTreatment by a diet low in phenylalanine & tyrosine.

  44. Tyrosine: aids in production of melanin

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