Download - Abdel Hamid Derm Atlas

Functions of melanocytes
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The main function of melanocyte is synthesis of melanin pigments. However, it varies according
to their site:
• A. Epidermis:
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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.
Epidermal melanocyte unit & mechanism by which keratinocyte derived
factors act on human melanocyte proliferation & differentiation.
Hirobe, T. P. Pigment cell Res. 18: 2, 2OO5.
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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 ; GMCSF: granulocyte macrophage colony
stimulating factor ; MSH: melanin stimulating
hormone; Mc1R: Melanocyte 1 receptor ;
MITF: microphthalmic associated
transcription factor ; CRE: c- AMP response
element
5. Regulation of skin pigmentation via modification of tyrosinase function
Ando, H. et al J. Invest. Derm. 127:751, 2OO7
After 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)
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6. Increase function of melanocytes:
i. Dysfunction:
Freckles, melasma, oral contraceptives, melanosis of pregnancy, liver diseases, exposure to ultraviolet 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.
• B. Hair
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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. :
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They contain also melanocytes but their function are not yet elucidated.
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D. Mucous membrane: e.g Peutz jeghers syndrome
Skin “sees” U.V. light starts to producing pigment ( Oanacea, E. 2O11)
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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..
• E. Eye:
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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
Anterior uveal melanoma
Conjunctival melanocytic intraepithelial neoplasma
Slit lamp photographs. Damato, B. E. Saudi J. Ophthal. 26: 137, 2O12
Conjunctival melanocytes at limbus
Melanocytes are shown to exist as sporadic cells with dendrites
processes in corneal limbus
Higa, K. Experimental eye research 81: 218, 2OO5
Melanocytes are shown to exist as sporadic cells with dendrites
processes in corneal limbus
Higa, K. Experimental eye research 81: 218, 2OO5
Choroidal melanoma
Melanocyte hyperplasia in ciliary body showing spindle shaped
melanocytes with oval to elongated nuclei with stippled chromatin &
inconspicuous nuclei
O’Neal, K.D. al Survey of ophthalmology 48: 613, 2OO3
O’Neal, K.D. et al . Survey of ophthalmology 48: 613, 2OO3
Diffuse choroidal thickening by melanocyte hyperplasia
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 macrophage
O’ Neal, K.D. et al. Survey of Ophthalmology 48: 613 , 2OO3
Pigmented lesion on the eye
• Nevus of ota
• F. Ear:
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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.)
Melanocytes in inner ear cochlea
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• G. Brain:
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@ 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.
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Cranial meninges of sheep that are full of
melanocyte
Substantia nigra
Normal
Substantia nigra
Comparison o of Parkinson’s disease & the normal
Melanocyte: a window into the nervous system
Yaar, M. & Park, H. J. Investig. Derm. 132: 835, 2O12
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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.
• H. Heart:
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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.
Melanocyte pigmentation is observed in whole mount preparation of
murine heart J. of Royal Society Interface Online 1742 -5662, 2O13
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)
Dopa chrome toutmerase expressing cells in the heart.
Levin , M.D. J. Clin. Investigation 119: 342O, 2OO9
Cardiac melanocytes like cells persist in the heart in the absence of
dopa chrome toutomerase
Levin, M. D. J. Clin. Investigation 119: 342O, 2OO9
Liven et al (2OO9) described a population of melanocytes in the heart &
pulmonary veins of murine & human that appear to contribute to atrial
arrythmogenesis.
• H. Bone:
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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).
Postmigratory neural crest cells during embryonic development
The bone marrow stem cell may differentiate into another mesodermal
derived tissue such as muscle, cardiac muscle or liver.
Oral melanoma in the jawbone
of a cow with widespread metastasis
Brito, M. et al Ciec. Rurel 39: 2OO9
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I. Thyroid gland:
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Melanin stimulating hormone is a peptide
secreted by the intermediate lobe of the
pituitary that stimulate melanin release&
dispersal.
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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
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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
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K.Testis:
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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)
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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.
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@ 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
Q. & A.
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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.
Tyrosinemia type I
Deficiency 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
Tyrosinemia type II
Deficiency of TAT ( L- tyrosine aminotransferase ) result in elevation of tyrosine level
Treatment is by dietary restriction of phenylalanine &tyrosine in diet
Tyrosinemia type III
The mutated gene is 12 q 24 , 14 exon .Mutation in the enzyme(HPPD) hydroxyphenyl puruvate
dioxygenase
Treatment by a diet low in phenylalanine & tyrosine.
Tyrosine: aids in production of melanin